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', 'molecu