6	32408516	A very elegant example of the functional phenotypic effect of gene retroposition is retrogene fgf4, which is responsible for chondrodysplasia in dogs.	('responsible', 'Reg', (109, 120))	('gene', 'Var', (62, 66))	('chondrodysplasia', 'Disease', (125, 141))	('chondrodysplasia', 'Disease', 'MESH:D010009', (125, 141))	('fgf4', 'Gene', (94, 98))	('dogs', 'Species', '9615', (145, 149))	('fgf4', 'Gene', '483680', (94, 98))
10	32408516	A study of the tumor-suppressor gene TP53 suggests that gene duplicates, which arose via retrotransposition, play a role in the reduction of cancer risk in elephants.	('gene duplicates', 'Var', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('reduction', 'NegReg', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
15	32408516	They are especially interesting for those studying cancer since a number of pseudogenes were already proven to be promising biomarkers.	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pseudogenes', 'Var', (76, 87))
35	32408516	An example could be the identification of pseudogenes related to lung carcinoma, breast carcinoma or other cancer types.	('lung carcinoma', 'Disease', (65, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('related', 'Reg', (54, 61))	('breast carcinoma', 'Disease', 'MESH:D001943', (81, 97))	('breast carcinoma', 'Disease', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pseudogenes', 'Var', (42, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('breast carcinoma', 'Phenotype', 'HP:0003002', (81, 97))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('lung carcinoma', 'Disease', 'MESH:D008175', (65, 79))	('cancer', 'Disease', (107, 113))
44	32408516	Specific domains with different identifiers were found for RHOG and RAC1, cd01875 and cd01871, respectively.	('RHOG', 'Gene', '391', (59, 63))	('cd01871', 'Var', (86, 93))	('RAC1', 'Gene', '5879', (68, 72))	('RAC1', 'Gene', (68, 72))	('cd01875', 'Var', (74, 81))	('RHOG', 'Gene', (59, 63))
53	32408516	Performed analysis also demonstrated that proteins encoded by retro_hsap_67, known as PTTG2, and by the parental gene PTTG1 contain a securin domain (pfam04856).	('PTTG1', 'Gene', (118, 123))	('PTTG1', 'Gene', '9232', (118, 123))	('PTTG2', 'Gene', '10744', (86, 91))	('retro_hsap_67', 'Var', (62, 75))	('contain', 'Reg', (124, 131))	('securin', 'Gene', '9232', (134, 141))	('PTTG2', 'Gene', (86, 91))	('securin', 'Gene', (134, 141))
60	32408516	Two of them, FUNDC2P (retro_hsap_2122) and TCEB2P2 (retro_hsap_940), were also identified in the course of this study as putatively encoding peptides.	('FUNDC2P', 'Gene', (13, 20))	('TCEB2P2', 'Gene', (43, 50))	('retro_hsap_940', 'Var', (52, 66))	('TCEB2P2', 'Gene', '253665', (43, 50))	('retro_hsap_2122', 'Var', (22, 37))	('FUNDC2P', 'Gene', '220793', (13, 20))
64	32408516	Recent studies on cancer resistance in elephants demonstrated that truncated proteins encoded by multiple retrocopies of the tumor suppressor gene TP53 may be behind the increased body size, the higher resistance to DNA damage, and a lower incidence of cancer in elephants.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('TP53', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lower', 'NegReg', (234, 239))	('higher', 'PosReg', (195, 201))	('resistance to DNA damage', 'MPA', (202, 226))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('increased', 'PosReg', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', (125, 130))	('cancer', 'Disease', (253, 259))	('TP53', 'Gene', '7157', (147, 151))	('truncated', 'Var', (67, 76))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
65	32408516	For example, retrocopy retro_hsap_4001, located in the gene CSMD3 locus, contributed to the first two exons of the shorter splice variant with a more upstream transcription start site (TSS) (Figure 5).	('CSMD3', 'Gene', (60, 65))	('CSMD3', 'Gene', '114788', (60, 65))	('retro_hsap_4001', 'Var', (23, 38))
85	32408516	This is significantly more than in the study by Muro et al., who found 87 transcripts expressed antisense of human pseudogenes and greatly expands the set of 58 transcripts previously identified by us.	('antisense', 'Var', (96, 105))	('human', 'Species', '9606', (109, 114))	('pseudogenes', 'Protein', (115, 126))
90	32408516	A very strong correlation, rho = 0.82, was also found for another retrocopy also embedded in the same FMO5 gene, retrocopy of the RPL7A gene (retro_hsap_218).	('RPL7A', 'Gene', (130, 135))	('FMO5', 'Gene', '2330', (102, 106))	('retrocopy', 'Var', (113, 122))	('RPL7A', 'Gene', '6130', (130, 135))	('FMO5', 'Gene', (102, 106))
92	32408516	An interesting example coming out of this study is retro_hsap_4762, a retrocopy of gene RAB28, which overlaps with transcripts of two genes and has a positive expression correlation with both of them.	('RAB28', 'Gene', (88, 93))	('expression', 'MPA', (159, 169))	('retro_hsap_4762', 'Var', (51, 66))	('RAB28', 'Gene', '9364', (88, 93))
100	32408516	Also, mutations in ERLIN2 cause the neurologic disorder spastic paraplegia type 18, lateral sclerosis, and mental retardation.	('mental retardation', 'Disease', (107, 125))	('ERLIN2', 'Gene', '11160', (19, 25))	('cause', 'Reg', (26, 31))	('mental retardation', 'Disease', 'MESH:D008607', (107, 125))	('paraplegia', 'Phenotype', 'HP:0010550', (64, 74))	('ERLIN2', 'Gene', (19, 25))	('lateral sclerosis', 'Disease', (84, 101))	('neurologic disorder', 'Phenotype', 'HP:0000707', (36, 55))	('neurologic disorder spastic paraplegia', 'Disease', (36, 74))	('spastic paraplegia', 'Phenotype', 'HP:0001258', (56, 74))	('neurologic disorder spastic paraplegia', 'Disease', 'MESH:C536857', (36, 74))	('lateral sclerosis', 'Disease', 'MESH:D016472', (84, 101))	('mutations', 'Var', (6, 15))	('mental retardation', 'Phenotype', 'HP:0001249', (107, 125))
118	32408516	While in chimpanzees and gorillas this retrocopy was relatively quickly under a negative selection and codes for a protein which possibly shares a function with the parental gene, in humans a number of mutations accumulated and the retrogene acts as a lncRNA.	('humans', 'Species', '9606', (183, 189))	('codes', 'Reg', (103, 108))	('gorillas', 'Species', '9593', (25, 33))	('chimpanzees', 'Species', '9598', (9, 20))	('accumulated', 'PosReg', (212, 223))	('mutations', 'Var', (202, 211))
120	32408516	Our analysis revealed that gene ATR contains a sequence of retro_hsap_2713 and may act as a trans-NAT for the retrocopy's parental gene.	('retro_hsap_2713', 'Var', (59, 74))	('ATR', 'Gene', '545', (32, 35))	('ATR', 'Gene', (32, 35))
124	32408516	Only in one case, involving a retrocopy of gene TUBG1, the chromosome broke over 6000 bp from the retrocopy.	('TUBG1', 'Gene', (48, 53))	('TUBG1', 'Gene', '7283', (48, 53))	('retrocopy', 'Var', (30, 39))
129	32408516	They also illustrate that retroposition of protein-coding genes had a profound impact on the human genome, proteome, and transcriptome.	('human', 'Species', '9606', (93, 98))	('impact', 'Reg', (79, 85))	('retroposition', 'Var', (26, 39))
132	31492770	After confirmation of a KRAS gene amplification, treatment with paclitaxel, carboplatin, and sorafenib was started, and response was promising.	('sorafenib', 'Chemical', 'MESH:C471405', (93, 102))	('KRAS gene', 'Gene', (24, 33))	('carboplatin', 'Chemical', 'MESH:D016190', (76, 87))	('men', 'Species', '9606', (54, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))	('amplification', 'Var', (34, 47))
137	31492770	Whole exome sequencing and low-depth whole genome sequencing confirmed the KRAS gene amplification, which may lead to the tumor cells' progression and proliferation.	('proliferation', 'CPA', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('amplification', 'Var', (85, 98))	('KRAS', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('lead to', 'Reg', (110, 117))	('tumor', 'Disease', (122, 127))
142	31492770	KRAS gene amplification occurs in nearly 20% of testicular cancer and 50% of chemotherapy-refractory testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (101, 118))	('testicular cancer', 'Disease', 'MESH:D013736', (101, 118))	('testicular cancer', 'Disease', (48, 65))	('occurs', 'Reg', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('testicular cancer', 'Disease', (101, 118))	('amplification', 'Var', (10, 23))	('testicular cancer', 'Phenotype', 'HP:0010788', (48, 65))	('testicular cancer', 'Disease', 'MESH:D013736', (48, 65))	('KRAS', 'Gene', (0, 4))
143	31492770	KRAS amplification may activate the MAPK signaling pathway, and inhibition of MAPK by sorafenib combined with paclitaxel and carboplatin could be a viable option based on a phase III clinical trial of melanoma.	('melanoma', 'Disease', (201, 209))	('activate', 'PosReg', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('KRAS amplification', 'Var', (0, 18))	('paclitaxel', 'Chemical', 'MESH:D017239', (110, 120))	('amplification', 'Var', (5, 18))	('sorafenib', 'Chemical', 'MESH:C471405', (86, 95))	('inhibition', 'NegReg', (64, 74))	('carboplatin', 'Chemical', 'MESH:D016190', (125, 136))	('MAPK signaling pathway', 'Pathway', (36, 58))	('MAPK', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
145	31492770	Clinical genomic profiling can confirm copy number variation of testicular cancer and provide insights on therapeutic options.	('testicular cancer', 'Phenotype', 'HP:0010788', (64, 81))	('testicular cancer', 'Disease', 'MESH:D013736', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('testicular cancer', 'Disease', (64, 81))	('copy number variation', 'Var', (39, 60))
148	31492770	The tumor markers for testicular cancer, such as alpha-fetal protein (AFP), beta-human chorionic gonadotropin (beta-HCG), and LDH, were 433.1 ng/mL (normal value [NV], 0-8.78 ng/mL), 6890 IU/L (NV, 0-5.00 IU/L), and 978 IU/L (NV,120-250 IU/L), respectively.	('tumor', 'Disease', (4, 9))	('testicular cancer', 'Phenotype', 'HP:0010788', (22, 39))	('testicular cancer', 'Disease', 'MESH:D013736', (22, 39))	('433.1', 'Var', (136, 141))	('AFP', 'Gene', '174', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('man', 'Species', '9606', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('testicular cancer', 'Disease', (22, 39))	('AFP', 'Gene', (70, 73))
152	31492770	Immunohistochemistry (IHC) revealed that the tumor was positive for SALL-4, LIN28, Nanog, D240, CD30, CAM5.2, CK8/18, and Oct3/4, focally positive for PLAP, AFP, and EBC, and negative for CD117, EMA,CEA, HCG, and CD56.	('tumor', 'Disease', (45, 50))	('CD56', 'Gene', (213, 217))	('SALL-4', 'Gene', '57167', (68, 74))	('SALL-4', 'Gene', (68, 74))	('CD30', 'Gene', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('CD56', 'Gene', '4684', (213, 217))	('CK8', 'Gene', '3856', (110, 113))	('Nanog', 'Gene', '79923', (83, 88))	('CD117', 'Gene', '3815', (188, 193))	('CD30', 'Gene', '943', (96, 100))	('D240', 'Var', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Nanog', 'Gene', (83, 88))	('Oct3/4', 'Gene', '5460', (122, 128))	('Oct3/4', 'Gene', (122, 128))	('CK8', 'Gene', (110, 113))	('CD117', 'Gene', (188, 193))	('AFP', 'Gene', (157, 160))	('AFP', 'Gene', '174', (157, 160))	('PLAP', 'Gene', (151, 155))	('LIN28', 'Gene', (76, 81))	('LIN28', 'Gene', '79727', (76, 81))	('PLAP', 'Gene', '9373', (151, 155))
160	31492770	After seven cycles of KN035, a PD-L1 antibody, he developed increasing chest pain and dyspnea and had radiographic disease progression, and his tumor markers continued to rise.	('dyspnea', 'Disease', 'MESH:D004417', (86, 93))	('tumor', 'Disease', (144, 149))	('KN035', 'Chemical', 'MESH:C031042', (22, 27))	('chest pain', 'Disease', 'MESH:D002637', (71, 81))	('PD-L1', 'Gene', '29126', (31, 36))	('chest pain', 'Disease', (71, 81))	('pain', 'Phenotype', 'HP:0012531', (77, 81))	('dyspnea', 'Phenotype', 'HP:0002094', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('KN035', 'Var', (22, 27))	('dyspnea', 'Disease', (86, 93))	('chest pain', 'Phenotype', 'HP:0100749', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('rise', 'PosReg', (171, 175))	('PD-L1', 'Gene', (31, 36))
169	31492770	This phenomenon was first described by Atkin and Baker in 1982; other studies revealed that the i12p was observed in more than 80% of all TGCTs [7], [8], [9].	('i12p', 'Var', (96, 100))	('TGCTs', 'Gene', (138, 143))	('men', 'Species', '9606', (10, 13))
171	31492770	Although the exact mechanism of generating the i12p in TGCTs is still unknown, many proto-oncogenes are involved, such as KRAS, CCND2, and GDF-3 [11].	('CCND2', 'Gene', (128, 133))	('CCND2', 'Gene', '894', (128, 133))	('i12p', 'Var', (47, 51))	('GDF-3', 'Gene', '9573', (139, 144))	('involved', 'Reg', (104, 112))	('man', 'Species', '9606', (79, 82))	('GDF-3', 'Gene', (139, 144))
172	31492770	The gain of i12p might cause overexpression of genes from 12p11.2-p12.1, especially for NSGCTs that have higher levels of expression than seminomas.	('gain', 'PosReg', (4, 8))	('NSGCTs', 'Disease', (88, 94))	('seminomas', 'Disease', 'MESH:D018239', (138, 147))	('seminomas', 'Disease', (138, 147))	('overexpression', 'MPA', (29, 43))	('i12p', 'Var', (12, 16))	('NSGCTs', 'Disease', 'MESH:C537844', (88, 94))
178	31492770	The KRAS amplification had higher frequency in TGCTs (19.70%), esophagogastric cancer (10.42%), and ovarian epithelial cancer (9.44%).	('epithelial cancer', 'Phenotype', 'HP:0031492', (108, 125))	('amplification', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian epithelial cancer', 'Disease', (100, 125))	('TGCTs', 'Disease', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('ovarian epithelial cancer', 'Disease', 'MESH:D010051', (100, 125))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('KRAS', 'Gene', (4, 8))	('ovarian epithelial cancer', 'Phenotype', 'HP:0025318', (100, 125))
181	31492770	Genomic alterations might mediate the development of chemotherapy resistance; hence, genomic profiling might find potentially druggable targets and identify therapeutic opportunities for this patient.	('mediate', 'Reg', (26, 33))	('patient', 'Species', '9606', (192, 199))	('alterations', 'Var', (8, 19))	('men', 'Species', '9606', (45, 48))
183	31492770	As KRAS amplification may activate the RAS-RAF-MEK-ERK signaling pathway, leading to tumor cell proliferation and progression, we anticipated that therapy with agents targeting the KRAS pathway may work.	('MEK', 'Gene', (47, 50))	('ERK', 'Gene', (51, 54))	('tumor', 'Disease', (85, 90))	('MEK', 'Gene', '5609', (47, 50))	('ERK', 'Gene', '2048', (51, 54))	('activate', 'PosReg', (26, 34))	('amplification', 'Var', (8, 21))	('leading to', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('RAF', 'Gene', '22882', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('progression', 'CPA', (114, 125))	('RAF', 'Gene', (43, 46))	('KRAS', 'Gene', (3, 7))
184	31492770	Studies have shown that KRAS amplification is associated with chemotherapy resistance and tumor progression in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('chemotherapy resistance', 'CPA', (62, 85))	('amplification', 'Var', (29, 42))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('associated', 'Reg', (46, 56))	('solid tumors', 'Disease', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('KRAS', 'Gene', (24, 28))
186	31492770	As for endometrial cancer, KRAS amplification is present in 3% and 18% of primary and metastatic tumors, respectively, and is significantly correlated with poor outcome [17].	('correlated with', 'Reg', (140, 155))	('endometrial cancer', 'Disease', (7, 25))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (7, 25))	('primary', 'Disease', (74, 81))	('amplification', 'Var', (32, 45))	('endometrial cancer', 'Disease', 'MESH:D016889', (7, 25))	('KRAS amplification', 'Var', (27, 45))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
190	31492770	A phase III clinical trial revealed that the combination of carboplatin, paclitaxel, and sorafenib (CPS) can improve overall survival (OS) in patients with melanoma with KRAS gene copy gains, and the CPS regimen had a better OS than just carboplatin and paclitaxel therapy (hazard ratio, 0.25; p = .035) [22], [23].	('overall survival', 'MPA', (117, 133))	('improve', 'PosReg', (109, 116))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('KRAS', 'Gene', (170, 174))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('paclitaxel', 'Chemical', 'MESH:D017239', (73, 83))	('men', 'Species', '9606', (208, 211))	('gene copy gains', 'Var', (175, 190))	('carboplatin', 'Chemical', 'MESH:D016190', (238, 249))	('patients', 'Species', '9606', (142, 150))	('sorafenib', 'Chemical', 'MESH:C471405', (89, 98))	('carboplatin', 'Chemical', 'MESH:D016190', (60, 71))	('paclitaxel', 'Chemical', 'MESH:D017239', (254, 264))
191	31492770	Another study showed that combined MEK and SHP2 inhibition can enhance the sensitivity of KRAS amplification models to MEK inhibition both in vivo and in vitro [24].	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('MEK', 'Gene', (35, 38))	('enhance', 'PosReg', (63, 70))	('MEK', 'Gene', '5609', (35, 38))	('inhibition', 'Var', (48, 58))	('SHP2', 'Gene', '5781', (43, 47))	('SHP2', 'Gene', (43, 47))	('sensitivity', 'MPA', (75, 86))
192	31492770	Some clinical trials investigating RAF inhibitors, as single agents or in combination with MEK inhibitors or alternative pathway inhibitors, in treating solid cancers with KRAS amplification are under way (www.clinicaltrials.gov).	('cancers', 'Disease', (159, 166))	('RAF', 'Gene', '22882', (35, 38))	('RAF', 'Gene', (35, 38))	('KRAS amplification', 'Var', (172, 190))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MEK', 'Gene', '5609', (91, 94))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('MEK', 'Gene', (91, 94))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
204	31492770	Because of the high frequency of KRAS amplification in chemotherapy-refractory NSGCTs, CPS regimen may provide a new therapy.	('KRAS', 'Gene', (33, 37))	('men', 'Species', '9606', (95, 98))	('NSGCTs', 'Disease', 'MESH:C537844', (79, 85))	('amplification', 'Var', (38, 51))	('NSGCTs', 'Disease', (79, 85))
205	31492770	Given that KRAS and NRAS mutations are reported in 45% of seminomas [25], those patients may benefit from CPS regimen as well, although this warrants further validation in clinical studies.	('seminomas', 'Disease', 'MESH:D018239', (58, 67))	('KRAS', 'Gene', (11, 15))	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (80, 88))	('seminomas', 'Disease', (58, 67))	('men', 'Species', '9606', (114, 117))	('NRAS', 'Gene', (20, 24))	('reported', 'Reg', (39, 47))	('NRAS', 'Gene', '4893', (20, 24))
232	29807233	Nonseminomas were further classified as: embryonal carcinoma (9070/3, 9072/3), yolk sac tumors (9071/3), teratoma (9080/3, 9082-9084/3, 9102/3), choriocarcinoma (9100/3, 9101/3), and mixed germ cell tumors (9081/3, 9085/3).	('9080/3', 'Var', (115, 121))	('tumors', 'Disease', (199, 205))	('choriocarcinoma', 'Disease', (145, 160))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('teratoma', 'Disease', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (145, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (41, 60))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (41, 60))	('embryonal carcinoma', 'Disease', (41, 60))	('9071/3', 'Var', (96, 102))	('germ cell tumors', 'Phenotype', 'HP:0100728', (189, 205))	('9070/3', 'Var', (62, 68))	('teratoma', 'Phenotype', 'HP:0009792', (105, 113))	('germ cell tumors', 'Disease', 'MESH:D009373', (189, 205))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('germ cell tumors', 'Disease', (189, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('teratoma', 'Disease', 'MESH:D013724', (105, 113))	('Nonseminomas', 'Disease', 'None', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', (88, 94))	('9100/3', 'Var', (162, 168))	('Nonseminomas', 'Disease', (0, 12))	('choriocarcinoma', 'Disease', 'MESH:D002822', (145, 160))
263	29807233	The etiology of sex cord stromal tumors is poorly understood, although associations with fumarate hydratase (FH) mutations, Klinefelter syndrome, hereditary leiomyomatosis, and renal cell carcinoma have been reported.	('renal cell carcinoma', 'Disease', (177, 197))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (177, 197))	('fumarate hydratase', 'Gene', '2271', (89, 107))	('hereditary leiomyomatosis', 'Disease', (146, 171))	('sex cord stromal tumors', 'Disease', 'MESH:D018312', (16, 39))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (177, 197))	('Klinefelter syndrome', 'Disease', 'MESH:D007713', (124, 144))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('fumarate hydratase', 'Gene', (89, 107))	('mutations', 'Var', (113, 122))	('sex cord stromal tumors', 'Disease', (16, 39))	('FH', 'Gene', '2271', (109, 111))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (146, 171))	('associations', 'Interaction', (71, 83))	('sex cord stromal tumors', 'Phenotype', 'HP:0031918', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('Klinefelter syndrome', 'Disease', (124, 144))
319	29717912	Delays in diagnosis can dramatically impact survival with 5-year median relative survivals dropping from 99% for cancer confined to the testis to 74% for metastatic disease [1].	('impact', 'Reg', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('metastatic disease', 'Disease', (154, 172))	('survival', 'MPA', (44, 52))	('cancer', 'Disease', (113, 119))	('Delays', 'Var', (0, 6))	('dropping', 'NegReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
353	29717912	Conversely, Friman and Finney point out that TSE would not cause excess anxiety but would reduce anxiety with regular practice.	('man', 'Species', '9606', (15, 18))	('excess anxiety', 'Disease', 'MESH:D001008', (65, 79))	('anxiety', 'Disease', 'MESH:D001008', (97, 104))	('anxiety', 'Disease', (72, 79))	('anxiety', 'Phenotype', 'HP:0000739', (72, 79))	('excess anxiety', 'Disease', (65, 79))	('anxiety', 'Disease', (97, 104))	('anxiety', 'Phenotype', 'HP:0000739', (97, 104))	('reduce', 'NegReg', (90, 96))	('anxiety', 'Disease', 'MESH:D001008', (72, 79))	('TSE', 'Var', (45, 48))	('excess anxiety', 'Phenotype', 'HP:0000739', (65, 79))
426	25418358	Because of its specific significance in testis, TEX101 has been utilized as a biomarker for male infertility, and this was confirmed to diagnose azoospermia by means of testicular biopsy by Drabovich's team.	('diagnose', 'Reg', (136, 144))	('TEX101', 'Var', (48, 54))	('male infertility', 'Disease', 'MESH:D007248', (92, 108))	('azoospermia', 'Disease', 'MESH:D053713', (145, 156))	('male infertility', 'Phenotype', 'HP:0003251', (92, 108))	('male infertility', 'Disease', (92, 108))	('infertility', 'Phenotype', 'HP:0000789', (97, 108))	('azoospermia', 'Disease', (145, 156))	('azoospermia', 'Phenotype', 'HP:0000027', (145, 156))
428	25418358	found that TEX101 could bind to uPA/uPAR complexes and interfere with the activities of uPA, matrix metalloproteinases and cathepsin B, which resulted in the reduction of extracellular matrix degradation and consequent suppression of cancer invasion.	('TEX101', 'Var', (11, 17))	('uPA', 'Gene', '5328', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('uPA', 'Gene', (88, 91))	('uPA', 'Gene', '5328', (88, 91))	('extracellular matrix degradation', 'MPA', (171, 203))	('interfere', 'NegReg', (55, 64))	('cathepsin B', 'Gene', (123, 134))	('cathepsin B', 'Gene', '1508', (123, 134))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('activities', 'MPA', (74, 84))	('uPAR', 'Gene', (36, 40))	('suppression', 'NegReg', (219, 230))	('bind', 'Interaction', (24, 28))	('uPA', 'Gene', (36, 39))	('uPA', 'Gene', '5328', (36, 39))	('uPAR', 'Gene', '5329', (36, 40))	('matrix metalloproteinases', 'Enzyme', (93, 118))	('reduction', 'NegReg', (158, 167))	('cancer', 'Disease', (234, 240))	('uPA', 'Gene', (32, 35))
442	25418358	Previous studies demonstrated that TEX101 could reduce the activities of uPA, MMPs and cathepsin B, leading to the suppression of cell growth and migration.	('uPA', 'Gene', '5328', (73, 76))	('TEX101', 'Var', (35, 41))	('activities', 'MPA', (59, 69))	('cathepsin B', 'Gene', (87, 98))	('suppression', 'NegReg', (115, 126))	('reduce', 'NegReg', (48, 54))	('uPA', 'Gene', (73, 76))	('cathepsin B', 'Gene', '1508', (87, 98))	('MMPs', 'Protein', (78, 82))
443	25418358	We speculated that the loss of TEX101 could disrupt the metabolic balance of the above-mentioned enzymes in the germinal epithelium, which could contribute to the growth and migration of mutant cancer cells.	('TEX101', 'Gene', (31, 37))	('cancer', 'Disease', (194, 200))	('men', 'Species', '9606', (87, 90))	('growth', 'CPA', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('disrupt', 'NegReg', (44, 51))	('loss', 'Var', (23, 27))	('contribute', 'Reg', (145, 155))	('metabolic balance of', 'MPA', (56, 76))	('migration', 'CPA', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
464	20800565	The combined unadjusted OR (95% CI) for testicular cancer risk in the lowest reported category of maternal BMI compared to a moderate maternal BMI category was 0.92 (0.75 - 1.12).	('maternal BMI', 'Var', (98, 110))	('testicular cancer', 'Phenotype', 'HP:0010788', (40, 57))	('testicular cancer', 'Disease', 'MESH:D013736', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('testicular cancer', 'Disease', (40, 57))
465	20800565	This meta-analysis, which included a small number of studies, showed an inverse association between high maternal BMI and testicular cancer risk of borderline statistical significance.	('testicular cancer', 'Disease', (122, 139))	('high maternal', 'Var', (100, 113))	('testicular cancer', 'Phenotype', 'HP:0010788', (122, 139))	('testicular cancer', 'Disease', 'MESH:D013736', (122, 139))	('inverse', 'NegReg', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
476	20800565	Research has also focused on maternal factors which could influence foetal development and it has been suggested that carcinoma in situ of the testis, a precursor of TGCT, has its origins in foetal life and that subnormal androgen exposure and/or increased oestrogen exposure are potentially important risk factors.	('subnormal', 'Var', (212, 221))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('subnormal androgen exposure', 'Phenotype', 'HP:0008226', (212, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (118, 135))	('influence', 'Reg', (58, 67))	('carcinoma', 'Disease', (118, 127))	('increased oestrogen', 'Phenotype', 'HP:0025134', (247, 266))	('men', 'Species', '9606', (82, 85))
492	20800565	The pooled estimate was based on data from over 2,400 cases and 3,500 controls obtained from six case-control studies and indicates that high compared with normal maternal BMI is associated with a decrease in testicular cancer risk (OR = 0.82; 95% CI 0.65:1.02), although the results were only borderline statistically significant (p=?).	('testicular cancer', 'Disease', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('high', 'Var', (137, 141))	('testicular cancer', 'Phenotype', 'HP:0010788', (209, 226))	('testicular cancer', 'Disease', 'MESH:D013736', (209, 226))	('decrease', 'NegReg', (197, 205))
493	20800565	Maternal BMI is positively associated with offspring birth weight and high birth weight has recently been shown to be positively, not inversely, associated with testicular cancer risk; Ramlau-Hansen (2009) reported an incidence rate ratio of 1.6 (95% CI 1.0-2.4) for men born with a high birth weight (>4,150 g) compared to those of normal birth weight.	('>4,150 g', 'Var', (302, 310))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('high birth weight', 'Phenotype', 'HP:0001520', (70, 87))	('testicular cancer', 'Phenotype', 'HP:0010788', (161, 178))	('testicular cancer', 'Disease', 'MESH:D013736', (161, 178))	('high birth weight', 'Phenotype', 'HP:0001520', (283, 300))	('men', 'Species', '9606', (267, 270))	('testicular cancer', 'Disease', (161, 178))
496	20800565	For example, it is known that multiparous women are more likely to be overweight than nulliparous women (Arroya et al, 1995) and that increased parity is associated with a decreased risk of TC in offspring compared with nulliparous women.	('TC', 'Phenotype', 'HP:0010788', (190, 192))	('women', 'Species', '9606', (98, 103))	('decreased', 'NegReg', (172, 181))	('women', 'Species', '9606', (232, 237))	('overweight', 'PosReg', (70, 80))	('women', 'Species', '9606', (42, 47))	('parity', 'Var', (144, 150))	('overweight', 'Phenotype', 'HP:0025502', (70, 80))	('multiparous', 'Var', (30, 41))
553	33926293	The model was assessed on the basis of the strength and significance of the model's direct (i.e., paths a, b1, b2, c1, and c2) and indirect (i.e., path a1b1 and a1b2) effects derived from a bootstrapping procedure that drew 5000 resamples with replacement.	('c2', 'Var', (123, 125))	('b1, b2, c1', 'Gene', '931;2925', (107, 117))	('path a1b1', 'Var', (147, 156))	('a1b2', 'Var', (161, 165))	('men', 'Species', '9606', (251, 254))
656	30634927	In addition, androgen receptor and androgen metabolic pathway genetic variation studies showed that Ser312-Asn polymorphism of the luteinizing hormone receptor was linked to an decreased relative risk of TGCT.	('androgen receptor', 'Gene', '367', (13, 30))	('decreased', 'NegReg', (177, 186))	('Ser312-Asn', 'Mutation', 'rs2293275', (100, 110))	('TGCT', 'Disease', (204, 208))	('androgen receptor', 'Gene', (13, 30))	('Ser312-Asn polymorphism', 'Var', (100, 123))
673	22536405	We identified seven differentially expressed miRNAs between gonocytes and spermatogonia (down-regulated: miR-293, 291a-5p, 290-5p and 294*, up-regulated: miR-136, 743a and 463*).	('down-regulated', 'NegReg', (89, 103))	('294*', 'Var', (134, 138))	('miR-293', 'Gene', (105, 112))	('miR-136', 'Gene', '387154', (154, 161))	('463*', 'Var', (172, 176))	('290-5p', 'Var', (123, 129))	('miR-293', 'Gene', '100049714', (105, 112))	('miR-136', 'Gene', (154, 161))	('up-regulated', 'PosReg', (140, 152))
678	22536405	There is concern that exposure to environmental toxicants in utero, especially endocrine disruptors, augments a genetic predisposition for testicular germ cell tumours such as defects in kit signalling (KITLG itself and SPRY an inhibitor of kit stimulated MAPK signalling), apoptosis (BAK), sex determination (DMRT1) and telomere regulation (TERT).	('kit', 'MPA', (187, 190))	('sex determination', 'CPA', (291, 308))	('DMRT1', 'Gene', '50796', (310, 315))	('KITLG', 'Gene', '17311', (203, 208))	('men', 'Species', '9606', (41, 44))	('KITLG', 'Gene', (203, 208))	('BAK', 'Gene', (285, 288))	('men', 'Species', '9606', (104, 107))	('MAPK', 'Gene', '26413;26417', (256, 260))	('defects', 'Var', (176, 183))	('BAK', 'Gene', '12018', (285, 288))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (139, 167))	('MAPK', 'Gene', (256, 260))	('exposure to environmental toxicants in utero', 'Phenotype', 'HP:0031437', (22, 66))	('testicular germ cell tumours', 'Disease', (139, 167))	('apoptosis', 'CPA', (274, 283))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('augments', 'NegReg', (101, 109))	('telomere regulation', 'CPA', (321, 340))	('DMRT1', 'Gene', (310, 315))
682	22536405	MicroRNA molecules are produced by an endonuclease Dicer, associate with a protein complex (RISC) in the cytoplasm, and target mRNA molecules by complementary base pairing, usually in the 3'UTR.	('men', 'Species', '9606', (151, 154))	('complementary base pairing', 'Var', (145, 171))	('RISC', 'Gene', '74617', (92, 96))	('associate', 'Interaction', (58, 67))	('RISC', 'Gene', (92, 96))
692	22536405	Aberrant expression of miRNA molecules and mutations in their recognition sites on mRNA are associated with infertility in men.	('Aberrant', 'Var', (0, 8))	('infertility', 'Disease', 'MESH:D007247', (108, 119))	('infertility', 'Phenotype', 'HP:0000789', (108, 119))	('mutations', 'Var', (43, 52))	('expression', 'MPA', (9, 19))	('infertility', 'Disease', (108, 119))	('miRNA molecules', 'Protein', (23, 38))	('men', 'Species', '9606', (123, 126))	('associated', 'Reg', (92, 102))
700	22536405	miR-449a has been found in high levels in the normal testis but is absent in testicular tumours.	('testicular tumours', 'Disease', (77, 95))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('miR-449a', 'Var', (0, 8))	('testicular tumours', 'Disease', 'MESH:D013736', (77, 95))
715	22536405	Antibodies were purchased from Abcam (Cambridge, MA, USA): anti-SOX2 (ab42635), anti-SOX11 (ab59776), anti-FZD4 (ab83042), anti-FZD7 (ab51049), anti-AKT1/2 (ab8933), anti-Cyclin D1 (ab16663), anti-UCHL1 (ab10404), anti-OCT3/4 (ab27985); Santa Cruz Biotechnology (Santa Cruz, CA, USA): anti-PTEN (sc7974), anti-SMAD4 (sc7154); Biocore (Sydney, NSW, Australia): anti-BMPR1a (ap2004b); Calbiochem (Merck KGaA, Darmstadt, Germany): anti-PLZF (op128); or Sigma: anti-ERK1/2 (M5670), anti-MEK1/2 (M5795) and anti-alpha-tubulin (T5168).	('SMAD4', 'Gene', (310, 315))	('FZD7', 'Gene', '14369', (128, 132))	('PTEN', 'Gene', (290, 294))	('ERK1/2', 'Gene', (462, 468))	('UCHL1', 'Gene', (197, 202))	('FZD7', 'Gene', (128, 132))	('BMPR1a', 'Gene', '12166', (365, 371))	('SOX2', 'Gene', '20674', (64, 68))	('MEK1/2', 'Gene', (483, 489))	('UCHL1', 'Gene', '22223', (197, 202))	('Cyclin D1', 'Gene', '12443', (171, 180))	('ERK1/2', 'Gene', '26417;26413', (462, 468))	('PLZF', 'Gene', (433, 437))	('AKT1/2', 'Gene', '11651;11652', (149, 155))	('T5168', 'Var', (522, 527))	('SOX2', 'Gene', (64, 68))	('FZD4', 'Gene', '14366', (107, 111))	('FZD4', 'Gene', (107, 111))	('PTEN', 'Gene', '19211', (290, 294))	('PLZF', 'Gene', '235320', (433, 437))	('OCT3/4', 'Gene', '18999', (219, 225))	('SMAD4', 'Gene', '17128', (310, 315))	('Cyclin D1', 'Gene', (171, 180))	('SOX11', 'Gene', '20666', (85, 90))	('BMPR1a', 'Gene', (365, 371))	('SOX11', 'Gene', (85, 90))	('AKT1/2', 'Gene', (149, 155))	('OCT3/4', 'Gene', (219, 225))	('MEK1/2', 'Gene', '26395;26396', (483, 489))
754	22536405	This program identified three significantly up-regulated (miR-136, 743a and 463* (q-value% = 3.811) and four significantly down-regulated miRNA species (MiR-293, 291a-5p, 290-5p and 294* q-value% = 0) between gonocytes and spermatogonia (Fig.	('MiR-293', 'Gene', '100049714', (153, 160))	('463*', 'Var', (76, 80))	('down-regulated', 'NegReg', (123, 137))	('294*', 'Var', (182, 186))	('MiR-293', 'Gene', (153, 160))	('miR-136', 'Gene', '387154', (58, 65))	('miRNA species', 'MPA', (138, 151))	('up-regulated', 'PosReg', (44, 56))	('miR-136', 'Gene', (58, 65))
755	22536405	The down-regulated miRNA molecules, miR-293, 291a-5p, 290-5p and 294* were each expressed at levels that were approximately five fold lower in spermatogonia compared to gonocytes (p<0.0001) (Fig.	('lower', 'NegReg', (134, 139))	('miR-293', 'Gene', (36, 43))	('294*', 'Var', (65, 69))	('291a-5p', 'Var', (45, 52))	('down-regulated', 'NegReg', (4, 18))	('miR-293', 'Gene', '100049714', (36, 43))
784	22536405	6), ERK1/2, was targeted by miR-136 (up-regulated molecule) while the negative regulator, GSK3, was targeted by miR-291a-5p (down-regulated molecule).	('GSK3', 'Gene', (90, 94))	('ERK1/2', 'Gene', (4, 10))	('miR-136', 'Gene', (28, 35))	('miR-291a-5p', 'Var', (112, 123))	('up-regulated', 'PosReg', (37, 49))	('GSK3', 'Gene', '56637', (90, 94))	('ERK1/2', 'Gene', '26417;26413', (4, 10))	('miR-136', 'Gene', '387154', (28, 35))
790	22536405	miR-293, 291a-5p, 290-5p and 294* belong to the miR-290-295 cluster and have previously been found to be highly enriched in the germ cell population of day 6 testis when compared to the somatic cell population.	('291a-5p', 'Var', (9, 16))	('miR-293', 'Gene', '100049714', (0, 7))	('miR-293', 'Gene', (0, 7))	('miR-290', 'Gene', '100049710', (48, 55))	('294*', 'Var', (29, 33))	('miR-290', 'Gene', (48, 55))
797	22536405	Additionally, knockout of the miR-290 cluster, besides inducing a partially penetrant embryonic lethality, leads to the defective migration of primordial germ cells to the genital ridges during development, resulting in reduced germ cell numbers in the nascent gonads.	('reduced', 'NegReg', (220, 227))	('miR-290', 'Gene', (30, 37))	('inducing', 'Reg', (55, 63))	('miR-290', 'Gene', '100049710', (30, 37))	('embryonic lethality', 'Disease', 'MESH:D020964', (86, 105))	('defective', 'NegReg', (120, 129))	('men', 'Species', '9606', (201, 204))	('rat', 'Species', '10116', (133, 136))	('germ cell numbers in the nascent gonads', 'CPA', (228, 267))	('embryonic lethality', 'Disease', (86, 105))	('knockout', 'Var', (14, 22))
806	22536405	Knockout of naked cuticle 1 (Nkd1), an antagonist of the canonical Wnt signalling pathway (controlling novel gene expression), caused sub fertility in male mice.	('naked cuticle 1', 'Gene', (12, 27))	('naked cuticle 1', 'Gene', '93960', (12, 27))	('sub fertility', 'Phenotype', 'HP:0000144', (134, 147))	('naked cuticle', 'Phenotype', 'HP:0030808', (12, 25))	('Nkd1', 'Gene', (29, 33))	('Nkd1', 'Gene', '93960', (29, 33))	('sub fertility', 'CPA', (134, 147))	('Knockout', 'Var', (0, 8))	('mice', 'Species', '10090', (156, 160))	('caused', 'Reg', (127, 133))
813	22536405	By analogy it is possible that dysregulation of the miRNAs may contribute to germ cell tumour development.	('tumour', 'Disease', (87, 93))	('men', 'Species', '9606', (101, 104))	('miRNAs', 'Protein', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('dysregulation', 'Var', (31, 44))	('contribute', 'Reg', (63, 73))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
817	22536405	Sox11 has also been found to be expressed in multipotent stromal stem cells, and Sox11 knockdown leads to reduced proliferation and promotes differentiation.	('Sox11', 'Gene', (0, 5))	('differentiation', 'CPA', (141, 156))	('rat', 'Species', '10116', (121, 124))	('proliferation', 'CPA', (114, 127))	('Sox11', 'Gene', '20666', (0, 5))	('Sox11', 'Gene', '20666', (81, 86))	('promotes', 'PosReg', (132, 140))	('knockdown', 'Var', (87, 96))	('reduced', 'NegReg', (106, 113))	('Sox11', 'Gene', (81, 86))
818	22536405	In contrast, knockdown of Sox11 in mantle cell lymphoma cell lines actually increases cell proliferation and promotes tumorigenesis when injected into nude mice.	('Sox11', 'Gene', (26, 31))	('tumorigenesis', 'CPA', (118, 131))	('cell lymphoma', 'Phenotype', 'HP:0012191', (42, 55))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (35, 55))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('increases', 'PosReg', (76, 85))	('mantle cell lymphoma', 'Disease', (35, 55))	('rat', 'Species', '10116', (98, 101))	('cell proliferation', 'CPA', (86, 104))	('Sox11', 'Gene', '20666', (26, 31))	('knockdown', 'Var', (13, 22))	('promotes', 'PosReg', (109, 117))	('nude mice', 'Species', '10090', (151, 160))
836	22536405	The PI3K/AKT is a key signalling pathway promoting cell proliferation, survival and migration which is subject to modulation by several negative regulators such as PTEN and PI3kip1.	('promoting', 'PosReg', (41, 50))	('AKT', 'Gene', '11651', (9, 12))	('survival', 'CPA', (71, 79))	('migration', 'CPA', (84, 93))	('AKT', 'Gene', (9, 12))	('cell proliferation', 'CPA', (51, 69))	('PTEN', 'Gene', '19211', (164, 168))	('PTEN', 'Gene', (164, 168))	('rat', 'Species', '10116', (63, 66))	('PI3kip1', 'Var', (173, 180))	('rat', 'Species', '10116', (87, 90))
837	22536405	Importantly, the ablation of PTEN is associated with the transformation of CIS cells, the precursor lesion for seminoma and nonseminoma into invasive cancer.	('PTEN', 'Gene', '19211', (29, 33))	('PTEN', 'Gene', (29, 33))	('seminoma and nonseminoma', 'Disease', 'MESH:D018239', (111, 135))	('ablation', 'Var', (17, 25))	('invasive cancer', 'Disease', (141, 156))	('invasive cancer', 'Disease', 'MESH:D009362', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
841	22536405	However, despite PTEN being expressed in all stages of male germ cells and very highly expressed in spermatogonia, the PTEN knockout mouse has normal spermatogenesis, are fertile and have no testicular tumours, indicating that PTEN may have a functional redundancy in mice.	('PTEN', 'Gene', (227, 231))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('mice', 'Species', '10090', (268, 272))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('spermatogenesis', 'CPA', (150, 165))	('PTEN', 'Gene', '19211', (119, 123))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '19211', (17, 21))	('PTEN', 'Gene', (17, 21))	('mouse', 'Species', '10090', (133, 138))	('testicular tumours', 'Disease', 'MESH:D013736', (191, 209))	('knockout', 'Var', (124, 132))	('testicular tumours', 'Disease', (191, 209))	('PTEN', 'Gene', '19211', (227, 231))
842	22536405	Knockdown of ETV5 and POU3F1 (oct6), both transcription factors activated by GDNF, caused apoptosis in spermatogonial stem cells in part due to the overexpression of PI3kip1, further indicating the importance of PI3K/AKT signalling and its regulation in normal spermatogenesis   In this study we identified seven miRNA molecules differentially expressed between postnatal gonocytes and spermatogonia.	('PI3kip1', 'Var', (166, 173))	('overexpression', 'PosReg', (148, 162))	('oct6', 'Gene', (30, 34))	('AKT', 'Gene', (217, 220))	('POU3F1', 'Gene', '18991', (22, 28))	('GDNF', 'Gene', '14573', (77, 81))	('oct6', 'Gene', '18991', (30, 34))	('GDNF', 'Gene', (77, 81))	('POU3F1', 'Gene', (22, 28))	('ETV5', 'Gene', '104156', (13, 17))	('ETV5', 'Gene', (13, 17))	('apoptosis', 'CPA', (90, 99))	('AKT', 'Gene', '11651', (217, 220))
843	22536405	The miRNA molecules down-regulated (miR-293, 291a-5p, 290-5p and 294*) are located in a miRNA cluster previously found to be involved in the maintenance of pluripotency within stem cells.	('miR-293', 'Gene', (36, 43))	('down-regulated', 'NegReg', (20, 34))	('294*', 'Var', (65, 69))	('pluripotency', 'Disease', (156, 168))	('pluripotency', 'Disease', 'None', (156, 168))	('miR-293', 'Gene', '100049714', (36, 43))
925	31196171	Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma Laryngeal squamous cell carcinoma (LSCC) is among the most common malignant tumors with poor prognosis.	('progression', 'CPA', (74, 85))	('malignant tumors', 'Disease', 'MESH:D018198', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 137))	('Aberrant methylation-mediated', 'Var', (0, 29))	('Laryngeal squamous cell carcinoma', 'Disease', (138, 171))	('malignant tumors', 'Disease', (204, 220))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', (90, 137))	('downregulation', 'NegReg', (30, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma Laryngeal squamous cell carcinoma', 'Phenotype', 'HP:0012118', (128, 171))	('SSTR5-AS1', 'Gene', (55, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('promotes', 'PosReg', (65, 73))	('methylation-mediated', 'Var', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('Laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 171))	('SSTR5-AS1', 'Gene', '146336;6755;5729', (55, 64))
954	31196171	There are two transcripts of SSTR5, and the main transcript (NM_001053) is located at chr16: 1078781-1081454 (GRCh38/hg38).	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hg38', 'Gene', (117, 121))	('hg38', 'Gene', '8549', (117, 121))	('NM_001053', 'Var', (61, 70))
973	31196171	3b, c, the expression levels of SSTR5 and SSTR5-AS1 were significantly increased in the 5-Aza-dC-, TSA-, 5-Aza-dC/TSA-treated laryngeal carcinoma cells, and the effect was more apparent in the 5-Aza-dC/TSA-treated cells, indicating that the expression of SSTR5 and SSTR5-AS1 might be co-regulated by DNA methylation and histone modification.	('SSTR5', 'Gene', (255, 260))	('SSTR5', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SSTR5', 'Gene', '6755', (255, 260))	('5-Aza-dC-', 'Var', (88, 97))	('TSA', 'Chemical', 'MESH:C012589', (99, 102))	('SSTR5', 'Gene', '6755', (32, 37))	('TSA', 'Chemical', 'MESH:C012589', (202, 205))	('laryngeal carcinoma', 'Disease', (126, 145))	('5-Aza-dC/TSA-treated', 'Var', (105, 125))	('TSA', 'Chemical', 'MESH:C012589', (114, 117))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (193, 201))	('TSA-', 'Var', (99, 103))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (105, 113))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (126, 145))	('SSTR5', 'Gene', (42, 47))	('SSTR5', 'Gene', (265, 270))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (88, 96))	('expression levels', 'MPA', (11, 28))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (126, 145))	('SSTR5', 'Gene', '6755', (42, 47))	('increased', 'PosReg', (71, 80))	('SSTR5', 'Gene', '6755', (265, 270))
975	31196171	3d, frequent CpG sites methylation was observed in the exon 1 region of SSTR5, while frequent methylated CpG sites were located in the promoter region of SSTR5-AS1 (Fig.	('methylation', 'Var', (23, 34))	('SSTR5', 'Gene', '6755', (154, 159))	('SSTR5', 'Gene', (154, 159))	('SSTR5', 'Gene', '6755', (72, 77))	('SSTR5', 'Gene', (72, 77))
982	31196171	The methylation status of promoter region of SSTR5 in LSCC tissues was not associated with any clinicopathologic characteristics, while the methylation status of exon 1 in LSCC tissues was associated with TNM stage and lymph node metastasis (P < 0.05) (Table 1).	('methylation', 'Var', (140, 151))	('TNM stage', 'CPA', (205, 214))	('associated', 'Reg', (189, 199))	('SSTR5', 'Gene', '6755', (45, 50))	('lymph node metastasis', 'CPA', (219, 240))	('SSTR5', 'Gene', (45, 50))
983	31196171	The mRNA expression level of SSTR5 in LSCC tissues with hypermethylation of exon 1 was significantly decreased than that with unmethylation of this region (P < 0.05); however, the expression level of SSTR5 was not associated with methylation status of promoter region (P > 0.05) (Fig.	('SSTR5', 'Gene', (200, 205))	('mRNA expression level', 'MPA', (4, 25))	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hypermethylation', 'Var', (56, 72))	('decreased', 'NegReg', (101, 110))	('SSTR5', 'Gene', '6755', (200, 205))
985	31196171	To determine the potential role of histone modifications on SSTR5 downregulation, the presence of active (H3K4me3, H3K9ac) and inactive (H3K9me2) histone modifications at SSTR5 promoter was further examined by chromatin immunoprecipitation assay in AMC-HN-8 cells (Fig.	('SSTR5', 'Gene', '6755', (171, 176))	('SSTR5', 'Gene', '6755', (60, 65))	('H3K4me3', 'Var', (106, 113))	('SSTR5', 'Gene', (171, 176))	('SSTR5', 'Gene', (60, 65))	('H3K9ac', 'Var', (115, 121))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (249, 257))
987	31196171	Increased enrichment of H3K4me3 and decreased enrichment of H3K9me2 were detected in 5-Aza-dC-treated AMC-HN-8 cells, and significant increased enrichment of H3K9ac was detected in TSA-treated AMC-HN-8 cells, indicating that in addition to DNA methylation, histone modification is also involved in the regulation of SSTR5 expression.	('SSTR5', 'Gene', (316, 321))	('TSA', 'Chemical', 'MESH:C012589', (181, 184))	('SSTR5', 'Gene', '6755', (316, 321))	('5-Aza-dC-treated', 'Var', (85, 101))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (85, 93))	('H3K4me3', 'Var', (24, 31))	('involved', 'Reg', (286, 294))	('enrichment', 'MPA', (10, 20))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (193, 201))	('enrichment', 'MPA', (46, 56))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (102, 110))	('decreased', 'NegReg', (36, 45))
1015	31196171	Promoter CpG sites hypermethylation of E-cadherin is a recognized mechanism of its inactivation in numerous cancers.	('numerous cancers', 'Disease', 'MESH:D009369', (99, 115))	('inactivation', 'NegReg', (83, 95))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('numerous cancers', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (19, 35))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
1019	31196171	The hMeDIP-qPCR assay was used to track the 5hmC change in the CpG-rich regions of E-cadherin promoters, and co-expression of SSTR5-AS1 and TET1 in AMC-HN-8 cells significantly increased 5hmC levels at the promoter regions of E-cadherin (Fig.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('TET1', 'Gene', '80312', (140, 144))	('SSTR5-AS1', 'Var', (126, 135))	('5hmC', 'Chemical', '-', (187, 191))	('increased', 'PosReg', (177, 186))	('5hmC levels', 'MPA', (187, 198))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (148, 156))	('E-cadherin', 'Gene', (226, 236))	('5hmC', 'Chemical', '-', (44, 48))	('E-cadherin', 'Gene', '999', (226, 236))	('TET1', 'Gene', (140, 144))
1031	31196171	AChE-AS represses AChE expression via epigenetic modification of the AChE promoter region and demonstrates an anti-apoptotic effect in hepatocellular carcinoma cells.	('AChE', 'Gene', '43', (0, 4))	('AChE', 'Gene', (18, 22))	('AChE', 'Gene', '43', (18, 22))	('AChE', 'Gene', '43', (69, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', (135, 159))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('epigenetic', 'Var', (38, 48))	('AChE', 'Gene', (0, 4))	('anti-apoptotic', 'CPA', (110, 124))	('AChE', 'Gene', (69, 73))
1033	31196171	Moreover, by genomic sequence analysis, obvious CpG islands were found in the promoter and exon 1 regions of SSTR5 and SSTR5-AS1, indicating the possible epigenetic regulation mechanisms on their expression regulation.	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', '6755', (119, 124))	('SSTR5', 'Gene', (109, 114))	('CpG', 'Var', (48, 51))	('SSTR5', 'Gene', (119, 124))
1037	31196171	In the present study, we verified the tumor suppressor role of SSTR5 and SSTR5-AS1 in LSCC progression; DNA hypermethylation and histone modification may co-regulate the expression of SSTR5 and SSTR5-AS1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SSTR5', 'Gene', '6755', (184, 189))	('SSTR5', 'Gene', '6755', (73, 78))	('SSTR5', 'Gene', (184, 189))	('SSTR5', 'Gene', (73, 78))	('SSTR5', 'Gene', '6755', (194, 199))	('SSTR5', 'Gene', (63, 68))	('SSTR5', 'Gene', (194, 199))	('SSTR5', 'Gene', '6755', (63, 68))	('co-regulate', 'Reg', (154, 165))	('DNA hypermethylation', 'Var', (104, 124))	('LSCC', 'Disease', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('histone modification', 'Var', (129, 149))	('expression', 'MPA', (170, 180))
1050	31196171	In the process of laryngeal squamous cell carcinogenesis, when CpG sites hypermethylation occurs in the promoter region of E-cadherin, SSTR5-AS1 may also act as a tumor suppressor gene to upregulate the expression of E-cadherin by recruiting TET1 to E-cadherin to hydrolyze 5'-mc to 5'-hmc, thus inhibiting the occurrence of EMT.	('hypermethylation', 'Var', (73, 89))	('laryngeal squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (18, 56))	('TET1', 'Gene', (242, 246))	('tumor', 'Disease', (163, 168))	('laryngeal squamous cell carcinogenesis', 'Disease', (18, 56))	("hydrolyze 5'-mc to 5'-hmc", 'MPA', (264, 289))	('SSTR5-AS1', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('E-cadherin', 'Gene', (250, 260))	('E-cadherin', 'Gene', '999', (250, 260))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('inhibiting', 'NegReg', (296, 306))	('upregulate', 'PosReg', (188, 198))	('E-cadherin', 'Gene', (217, 227))	('E-cadherin', 'Gene', '999', (217, 227))	("5'-mc", 'Chemical', 'MESH:D044503', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TET1', 'Gene', '80312', (242, 246))	('recruiting', 'PosReg', (231, 241))	('expression', 'MPA', (203, 213))	("5'-hmc", 'Chemical', 'MESH:C011865', (283, 289))
1051	31196171	SSTR5 may act as a tumor suppressor gene in LSCC, and aberrant DNA hypermethylation of the CpG sites clustered in the exon 1 and histone modification on its promoter region may be epigenetic mechanisms for its inactivation.	('LSCC', 'Disease', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CpG', 'Gene', (91, 94))	('SSTR5', 'Gene', '6755', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('SSTR5', 'Gene', (0, 5))	('histone modification', 'Var', (129, 149))	('aberrant', 'Var', (54, 62))
1052	31196171	SSTR5-AS1 may play anti-tumor role in LSCC and may be regulated by hypermethylation of the same CpG sites with SSTR5.	('SSTR5', 'Gene', '6755', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SSTR5', 'Gene', (111, 116))	('tumor', 'Disease', (24, 29))	('LSCC', 'Disease', (38, 42))	('SSTR5', 'Gene', '6755', (0, 5))	('hypermethylation', 'Var', (67, 83))	('SSTR5', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
1089	31196171	Antibodies against H3K4me3, H3K9ac, H3K9me2, MLL3, and TET1 (Upstate, Millipore, MA, USA) were used for immunoprecipitation.	('H3K9me2', 'Var', (36, 43))	('TET1', 'Gene', (55, 59))	('H3K4me3', 'Var', (19, 26))	('H3K9ac', 'Var', (28, 34))	('MLL3', 'Gene', (45, 49))	('TET1', 'Gene', '80312', (55, 59))	('MLL3', 'Gene', '58508', (45, 49))
1109	25501685	Furthermore, we will discuss how important indications of frailty variation may be deduced from data on familial disease association.	('familial disease', 'Disease', 'MESH:D030342', (104, 120))	('familial disease', 'Disease', (104, 120))	('variation', 'Var', (66, 75))
1116	25501685	They studied a population without high-risk individuals (individuals with BRCA1 and BRCA2 mutations excluded), and still suggest a 40-fold difference in the risk of breast cancer between the top 20% and bottom 20% of the study population.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('BRCA2', 'Gene', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA2', 'Gene', '675', (84, 89))	('BRCA1', 'Gene', (74, 79))
1132	25501685	showed that the children of those exposed to the Dutch famine in utero during World War II (WWII) were also at increased risk for ill health, which indicates that epigenetic effects in utero can even have transgenerational consequences.	('ill health', 'Disease', (130, 140))	('children', 'Species', '9606', (16, 24))	('epigenetic', 'Var', (163, 173))
1142	25501685	In an interesting Nature letter, Frank and Nowak suggest a model where random mutations at a very young age can produce a developmental disposition to cancer.The idea is that during the gestational phase, stem cells may mutate and then multiply randomly with long-lasting effects.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutate', 'Var', (220, 226))	('men', 'Species', '9606', (129, 132))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('multiply randomly', 'CPA', (236, 253))
1152	25501685	For example, in breast cancer some mutations in the genes BRCA1 and BRCA2 confer a very high risk in the specific family.	('breast cancer', 'Disease', (16, 29))	('BRCA2', 'Gene', '675', (68, 73))	('BRCA1', 'Gene', (58, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('BRCA2', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('BRCA1', 'Gene', '672', (58, 63))	('mutations', 'Var', (35, 44))
1177	25501685	Long before the Rb1 gene was identified, he separated a very frail group (those with an inherited germ line mutation) from a less frail group (those who had the non-hereditary form), and used this to formulate his famous two-hit hypothesis.	('Rb1', 'Gene', (16, 19))	('Rb1', 'Gene', '5925', (16, 19))	('mutation', 'Var', (108, 116))
1279	30967648	New results from the Cancer Genome Atlas Research Project have identified genetic mutations that are common among 12 different types of cancer, including carcinomas, adenocarcinomas and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (186, 195))	('Cancer', 'Disease', (21, 27))	('cancer', 'Disease', (136, 142))	('melanomas', 'Disease', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('carcinomas', 'Disease', (171, 181))	('common', 'Reg', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('carcinomas', 'Disease', (154, 164))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Disease', 'MESH:D009369', (171, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('mutations', 'Var', (82, 91))	('adenocarcinomas', 'Disease', 'MESH:D000230', (166, 181))	('carcinomas', 'Disease', 'MESH:D009369', (154, 164))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('adenocarcinomas', 'Disease', (166, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
1300	30967648	Usually this occurs by mutations in the CDKN2A gen.	('mutations', 'Var', (23, 32))	('occurs by', 'Reg', (13, 22))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))
1460	30797674	The increased risk of ovarian cancer could relate to shared hormonal and genetic (eg, BRCA1 and BRCA2 mutations) risk factors.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA2', 'Gene', '675', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('ovarian cancer', 'Disease', (22, 36))	('BRCA1', 'Gene', (86, 91))	('mutations', 'Var', (102, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('BRCA2', 'Gene', (96, 101))
1539	26742967	These alterations may be important in the pathogenesis of testicular cancers; however, further prospective studies are needed to identify the relationship between testicular cancer and trace elements.	('alterations', 'Var', (6, 17))	('testicular cancer', 'Disease', 'MESH:D013736', (163, 180))	('testicular cancers', 'Phenotype', 'HP:0010788', (58, 76))	('testicular cancer', 'Phenotype', 'HP:0010788', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('testicular cancers', 'Disease', (58, 76))	('men', 'Species', '9606', (194, 197))	('testicular cancer', 'Disease', (163, 180))	('testicular cancer', 'Phenotype', 'HP:0010788', (58, 75))	('testicular cancer', 'Disease', 'MESH:D013736', (58, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('testicular cancers', 'Disease', 'MESH:D013736', (58, 76))
1552	26742967	Alterations in the ion content of trace elements including iron, copper and zinc can affect activity of antioxidants.	('iron', 'Chemical', 'MESH:D007501', (59, 63))	('copper', 'Chemical', 'MESH:D003300', (65, 71))	('Alterations', 'Var', (0, 11))	('activity of antioxidants', 'MPA', (92, 116))	('ion content', 'MPA', (19, 30))	('men', 'Species', '9606', (43, 46))	('affect', 'Reg', (85, 91))
1594	26742967	In cadmium carcinogenicity, proto-oncogene activation, tumor suppressor gene inactivation, disrupted cell adhesion and inhibition of DNA repair are the implied cellular and molecular mechanisms.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cadmium', 'Chemical', 'MESH:D002104', (3, 10))	('tumor', 'Disease', (55, 60))	('inhibition', 'NegReg', (119, 129))	('inactivation', 'Var', (77, 89))	('DNA', 'Gene', (133, 136))
1649	20019899	The U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinant (STEED) Study, a large case-control investigation of TGCTs (754 cases, 928 controls) conducted among U.S. servicemen, similarly found elevated pre-diagnostic concentrations of cis-nonachlor, trans-nonachlor, and the insecticide metabolite p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) among cases versus controls.	('trans-nonachlor', 'Var', (270, 285))	("p,p'-dichlorodiphenyldichloroethylene", 'Chemical', 'MESH:D003633', (318, 355))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (270, 285))	('men', 'Species', '9606', (192, 195))	('cis-nonachlor', 'MPA', (255, 268))	('men', 'Species', '9606', (46, 49))	('men', 'Species', '9606', (16, 19))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (357, 365))	('Tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (255, 268))	('elevated', 'PosReg', (213, 221))	('Testicular Tumor', 'Phenotype', 'HP:0010788', (22, 38))
1685	20019899	Two chlordane metabolites were also associated with increased risk of TGCT at a borderline level of statistical significance: oxychlordane and trans-nonachlor (pWilcoxon = 0.05 and 0.07, respectively).	('chlordane', 'Chemical', 'MESH:D002706', (4, 13))	('trans-nonachlor', 'Var', (143, 158))	('oxychlordane', 'Chemical', 'MESH:C008743', (126, 138))	('TGCT', 'Disease', (70, 74))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (143, 158))	('pWilcoxon', 'Chemical', '-', (160, 169))	('chlordane', 'Chemical', 'MESH:D002706', (129, 138))	('oxychlordane', 'Var', (126, 138))
1690	20019899	The summed concentration of all PCB congeners was not associated with TGCT (pWilcoxon = 0.17), although associations were observed for PCBs 99, 138, 167, and 183 (pWilcoxon = 0.04, 0.06, 0.02 and 0.07, respectively.	('associations', 'Interaction', (104, 116))	('PCBs', 'Var', (135, 139))	('PCB', 'Chemical', 'MESH:D011078', (135, 138))	('PCBs', 'Chemical', 'MESH:D011078', (135, 139))	('PCB', 'Chemical', 'MESH:D011078', (32, 35))	('TGCT', 'Disease', (70, 74))	('pWilcoxon', 'Chemical', '-', (76, 85))	('pWilcoxon', 'Chemical', '-', (163, 172))
1693	20019899	Findings from analyses investigating associations with seminoma are summarized in Table 3 [results for all compounds are available in Supplemental Material, Table 2 (doi:10.1289/ehp.0800359.S1)].	('men', 'Species', '9606', (140, 143))	('seminoma', 'Disease', 'MESH:D018239', (55, 63))	('p.0', 'SUBSTITUTION', 'None', (180, 183))	('p.0', 'Var', (180, 183))	('seminoma', 'Disease', (55, 63))
1694	20019899	We observed evidence of association with p,p'-DDE and oxychlordane (pWilcoxon = 0.06 and 0.006, respectively), but not with trans-nonachlor or total chlordanes.	('trans-nonachlor', 'Chemical', 'MESH:C001870', (124, 139))	('oxychlordane', 'Chemical', 'MESH:C008743', (54, 66))	('pWilcoxon', 'Chemical', '-', (68, 77))	('association', 'Interaction', (24, 35))	('oxychlordane', 'Var', (54, 66))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (41, 49))	('chlordanes', 'Chemical', 'MESH:D002706', (149, 159))
1700	20019899	In this nested case-control investigation of OC compounds and TGCT risk, we observed elevated prediagnostic serum concentrations oxychlordane, trans-nonachlor, and p,p- ' DDE among TGCT cases compared with controls.	('TGCT', 'Disease', (181, 185))	('oxychlordane', 'Chemical', 'MESH:C008743', (129, 141))	('OC', 'Chemical', 'MESH:D006843', (45, 47))	('serum concentrations oxychlordane', 'MPA', (108, 141))	('trans-nonachlor', 'Var', (143, 158))	("p,p- ' DDE", 'Chemical', 'MESH:D003633', (164, 174))	('elevated', 'PosReg', (85, 93))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (143, 158))
1704	20019899	We observed a particularly strong and statistically significant association with oxychlordane for seminoma cases.	('seminoma', 'Disease', (98, 106))	('seminoma', 'Disease', 'MESH:D018239', (98, 106))	('oxychlordane', 'Chemical', 'MESH:C008743', (81, 93))	('oxychlordane', 'Var', (81, 93))	('significant association', 'Reg', (52, 75))
1705	20019899	In the STEED study, statistically significant associations with TGCT were observed for cis-nonachlor and trans-nonachlor, whereas oxychlordane was associated with seminoma risk.	('trans-nonachlor', 'Var', (105, 120))	('associated', 'Reg', (147, 157))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (105, 120))	('oxychlordane', 'Chemical', 'MESH:C008743', (130, 142))	('seminoma', 'Disease', 'MESH:D018239', (163, 171))	('cis-nonachlor', 'Var', (87, 100))	('significant associations', 'Reg', (34, 58))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (87, 100))	('seminoma', 'Disease', (163, 171))
1706	20019899	In addition, the case mothers in that study had significantly higher levels of cis-nonachlor, trans-nonachlor, and the sum of chlordanes compared with control mothers, suggesting that the antenatal period may be a particularly important time window of exposure for influencing TGCT development.	('trans-nonachlor', 'Chemical', 'MESH:C001870', (94, 109))	('men', 'Species', '9606', (289, 292))	('TGCT development', 'CPA', (277, 293))	('cis-nonachlor', 'MPA', (79, 92))	('chlordanes', 'Chemical', 'MESH:D002706', (126, 136))	('higher', 'PosReg', (62, 68))	('trans-nonachlor', 'Var', (94, 109))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (79, 92))
1712	20019899	However, chlordane may also exert antiestrogenic effects by inhibiting aromatase activity through estrogen-related receptor alpha1 antagonism.	('inhibiting', 'NegReg', (60, 70))	('estrogen-related receptor alpha1', 'Protein', (98, 130))	('aromatase', 'Protein', (71, 80))	('chlordane', 'Var', (9, 18))	('antagonism', 'NegReg', (131, 141))	('antiestrogenic effects', 'MPA', (34, 56))	('activity', 'MPA', (81, 89))	('chlordane', 'Chemical', 'MESH:D002706', (9, 18))
1722	20019899	The associations with semi-noma risk observed for the moderate chlorination, mixed-type induction, and Wolff 1A, 2 and 2B groupings appear to reflect the associations with the aforementioned congeners.	('associations', 'Interaction', (4, 16))	('moderate chlorination', 'Var', (54, 75))	('associations', 'Interaction', (154, 166))	('semi-noma', 'Disease', 'MESH:D009625', (22, 31))	('semi-noma', 'Disease', (22, 31))	('men', 'Species', '9606', (181, 184))
1726	20019899	In maternal comparisons, however, mothers of seminoma and nonseminoma cases had significantly higher levels of total PCBs and several individual congeners, including PCBs 99, 138, 153, 183, and 195 (PCB 167 was not measured).	('PCB', 'Chemical', 'MESH:D011078', (117, 120))	('PCBs', 'Var', (166, 170))	('seminoma and nonseminoma', 'Disease', 'MESH:D018239', (45, 69))	('PCB', 'Chemical', 'MESH:D011078', (166, 169))	('PCBs', 'MPA', (117, 121))	('153', 'Var', (180, 183))	('PCBs', 'Chemical', 'MESH:D011078', (117, 121))	('PCBs', 'Chemical', 'MESH:D011078', (166, 170))	('higher', 'PosReg', (94, 100))	('PCB', 'Chemical', 'MESH:D011078', (199, 202))
1733	20019899	In addition, given the large number of measured compounds and generally borderline significance level of our observed findings, we cannot rule out the possibility that some of the observed associations may have arisen due to chance, although it is worth noting that associations with oxychlordane, trans-nonachlor, and p,p'-DDE have been previously reported.	('oxychlordane', 'Chemical', 'MESH:C008743', (284, 296))	('trans-nonachlor', 'Var', (298, 313))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (298, 313))	('associations', 'Interaction', (266, 278))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (319, 327))
1821	19035442	Aggregation of cancer in families of men with testicular germ cell tumors could be due to inheritance of traits, such as genetic variation or inherited epigenetic modification, and/or common environmental risk factors.	('inherited epigenetic modification', 'Var', (142, 175))	('genetic variation', 'Var', (121, 138))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('men', 'Species', '9606', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('germ cell tumor', 'Phenotype', 'HP:0100728', (57, 72))	('men', 'Species', '9606', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', (67, 73))	('germ cell tumors', 'Phenotype', 'HP:0100728', (57, 73))
1906	31145545	To examine the possible mechanisms how drug resistance to cordycepin occurred, MA-10 cells were treated with cordycepin (100 and 1000 mumol/L), taxol (100 and 1000 nmol/L), cisplatin (100 and 200 mumol/L), or plain media (control) for 24 hours, respectively.	('100', 'Var', (121, 124))	('MA-10', 'Chemical', '-', (79, 84))	('cordycepin', 'Chemical', 'MESH:C058120', (109, 119))	('cordycepin', 'Chemical', 'MESH:C058120', (58, 68))	('100', 'Var', (151, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('taxol', 'Chemical', 'MESH:D017239', (144, 149))	('drug resistance', 'Phenotype', 'HP:0020174', (39, 54))
1912	31145545	Results showed that the phosphorylation of Akt and mTOR in attached MA-10 cells were induced more by cordycepin as compared to the suspended MA-10 cells (Figure 7A,B).	('mTOR', 'Gene', (51, 55))	('MA-10', 'Chemical', '-', (68, 73))	('mTOR', 'Gene', '56717', (51, 55))	('Akt', 'Gene', '11651', (43, 46))	('induced', 'Reg', (85, 92))	('MA-10', 'Chemical', '-', (141, 146))	('Akt', 'Gene', (43, 46))	('phosphorylation', 'MPA', (24, 39))	('cordycepin', 'Chemical', 'MESH:C058120', (101, 111))	('cordycepin', 'Var', (101, 111))
1991	27500561	Men with Medicaid insurance and those without insurance were also more likely to present with a larger tumor compared to those who had insurance (Table 2).	('Medicaid', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Men', 'Species', '9606', (0, 3))
1996	27500561	As shown in Figure 1, insurance was associated with improved GCT-specific survival in unadjusted analyses, compared with Medicaid or no insurance.	('GCT', 'Gene', (61, 64))	('GCT', 'Gene', '25797', (61, 64))	('insurance', 'Var', (22, 31))	('improved', 'PosReg', (52, 60))
2009	27500561	Similarly, men with Medicaid had a 69% and 51% increased risk of all-cause and GCT-specific mortality, respectively, compared with men with insurance.	('GCT', 'Gene', '25797', (79, 82))	('men', 'Species', '9606', (131, 134))	('Medicaid', 'Var', (20, 28))	('GCT', 'Gene', (79, 82))	('men', 'Species', '9606', (11, 14))
2024	27500561	First, Medicaid-insured men may have lower socioeconomic status and poorer access to healthcare than uninsured men.	('men', 'Species', '9606', (111, 114))	('Medicaid-insured', 'Var', (7, 23))	('men', 'Species', '9606', (24, 27))	('lower', 'NegReg', (37, 42))
2034	27500561	However, as highlighted in this and other analyses, Medicaid insurance in its current form was associated with poorer cancer outcomes compared to traditional insurance.	('cancer', 'Disease', (118, 124))	('Medicaid insurance', 'Var', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('poorer', 'NegReg', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
2074	27248499	Furthermore, additional evidence was found while analyzing chromatin state tracks based on 127 samples in the Roadmap Epigenomics Project: region around PIWIL2 exon 7 harbors epigenetic marks of a promoter in 10 primary and 4 imputed datasets (S2 and S3 Figs, respectively).	('epigenetic marks', 'Var', (175, 191))	('PIWIL2', 'Gene', '55124', (153, 159))	('PIWIL2', 'Gene', (153, 159))
2076	27248499	However, closer examination of the Roadmap Epigenomics project data revealed that between 6 and 28 primary datasets (S2 Fig) and between 44 and 55 imputed datasets (S3 Fig) displayed combinations of epigenetic marks around PIWIL2 exons 1, 5 and 7 that are characteristic for enhancers.	('PIWIL2', 'Gene', (223, 229))	('epigenetic marks', 'Var', (199, 215))	('PIWIL2', 'Gene', '55124', (223, 229))
2078	27248499	Additionally, binding sites for proteins typically associated with enhancers, such as CTCF and P300, are also located adjacent to the alternative promoters in exons 5 and 7 (S4 Fig).	('P300', 'Var', (95, 99))	('CTCF', 'Gene', (86, 90))	('CTCF', 'Gene', '10664', (86, 90))	('proteins', 'Protein', (32, 40))
2082	27248499	Interestingly, though PIWIL2 canonical promoter in exon 1 harbors histone modifications characteristic both for promoters (H3K4me3) and for enhancers (H3K4me1) in all cell lines tested, it is likely to be inactive due to the presence of the silencing H3K27me3 mark (Fig 1).	('silencing', 'NegReg', (241, 250))	('histone modifications', 'MPA', (66, 87))	('H3K4me3', 'Var', (123, 130))	('PIWIL2', 'Gene', '55124', (22, 28))	('H3K27me3', 'Var', (251, 259))	('PIWIL2', 'Gene', (22, 28))
2090	27248499	However, the data clearly demonstrate that all tumor samples and some adjacent normal testis tissues feature prominent and statistically significant peaks for some exon junctions, particularly 4-5 and 8-9 (Fig 2 and S6 Fig).	('exon junctions', 'MPA', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('4-5', 'Var', (193, 196))
2132	27885307	Many studies have shown that high socioeconomic status is associated with a higher risk of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('testicular cancer', 'Phenotype', 'HP:0010788', (91, 108))	('testicular cancer', 'Disease', 'MESH:D013736', (91, 108))	('high socioeconomic status', 'Var', (29, 54))	('testicular cancer', 'Disease', (91, 108))
2146	27885307	Other substances that have been proposed to be associated with an increased risk of testicular cancer are the polychlorinated biphenyls, polyvinyl chloride, and cigarette smoking.	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (110, 135))	('testicular cancer', 'Phenotype', 'HP:0010788', (84, 101))	('polyvinyl', 'Var', (137, 146))	('testicular cancer', 'Disease', 'MESH:D013736', (84, 101))	('polyvinyl chloride', 'Chemical', 'MESH:D011143', (137, 155))	('testicular cancer', 'Disease', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
2154	27885307	We used SEER site recodes to restrict our analysis to men with testicular cancer, which included International Classification of Diseases of Oncology, Third Edition/World Health Organization (ICDO-3/WHO) 2008 site codes of C620-C629, excluding histology codes of 9050-9055, 9140, 9590-9992 (lymphomas, Kaposi sarcoma, and mesothelioma).	('lymphomas', 'Phenotype', 'HP:0002665', (291, 300))	('Oncology', 'Phenotype', 'HP:0002664', (141, 149))	('testicular cancer', 'Disease', (63, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (322, 334))	('sarcoma', 'Phenotype', 'HP:0100242', (309, 316))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (302, 316))	('lymphomas', 'Disease', (291, 300))	('C620-C629', 'Var', (223, 232))	('lymphomas', 'Disease', 'MESH:D008223', (291, 300))	('Kaposi sarcoma', 'Disease', (302, 316))	('testicular cancer', 'Disease', 'MESH:D013736', (63, 80))	('9590-9992', 'Var', (280, 289))	('men', 'Species', '9606', (54, 57))	('9140', 'Var', (274, 278))	('testicular cancer', 'Phenotype', 'HP:0010788', (63, 80))	('mesothelioma', 'Disease', (322, 334))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (302, 316))
2176	27885307	The reasons for this are largely unknown, although recent research has demonstrated an association between a single nucleotide polymorphism affecting a p53 binding site on the KITLG gene and the development of testicular cancer.	('testicular cancer', 'Disease', 'MESH:D013736', (210, 227))	('single nucleotide polymorphism', 'Var', (109, 139))	('men', 'Species', '9606', (202, 205))	('testicular cancer', 'Phenotype', 'HP:0010788', (210, 227))	('p53', 'Gene', (152, 155))	('testicular cancer', 'Disease', (210, 227))	('p53', 'Gene', '7157', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('binding', 'Interaction', (156, 163))	('KITLG', 'Gene', '4254', (176, 181))	('KITLG', 'Gene', (176, 181))
2180	27885307	Furthermore, another study reported that African American race and low SES appeared to predispose men to more advanced disease stages, and that men of African American race and men with low SES had higher overall mortality and cancer-specific mortality than Caucasian patients.	('African American race', 'Var', (151, 172))	('men', 'Species', '9606', (144, 147))	('men', 'Species', '9606', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('predispose', 'Reg', (87, 97))	('men', 'Species', '9606', (177, 180))	('overall mortality', 'CPA', (205, 222))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('advanced disease stages', 'CPA', (110, 133))	('patients', 'Species', '9606', (268, 276))	('higher', 'PosReg', (198, 204))
2190	22937135	Prevalence of c-KIT Mutations in Gonadoblastoma and Dysgerminomas of Patients with Disorders of Sex Development (DSD) and Ovarian Dysgerminomas Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816).	('c-KIT', 'Gene', (14, 19))	('c-KIT', 'Gene', '3815', (14, 19))	('missense point mutations (codon 816', 'Var', (253, 288))	('Gonadoblastoma', 'Phenotype', 'HP:0000150', (33, 47))	('c-KIT', 'Gene', (155, 160))	('c-KIT', 'Gene', '3815', (155, 160))	('Gonadoblastoma and Dysgerminomas', 'Disease', 'MESH:D004407', (33, 65))	('Ovarian Dysgerminomas', 'Disease', (122, 143))	('testicular seminomas', 'Disease', (212, 232))	('DSD', 'Disease', (113, 116))	('testicular seminomas', 'Phenotype', 'HP:0100617', (212, 232))	('Activating', 'PosReg', (144, 154))	('testicular seminoma', 'Phenotype', 'HP:0100617', (212, 231))	('Patients', 'Species', '9606', (69, 77))	('testicular seminomas', 'Disease', 'MESH:D018239', (212, 232))	('DSD', 'Disease', 'MESH:D058533', (113, 116))	('Mutations', 'Var', (20, 29))	('mutations', 'Var', (161, 170))	('Ovarian Dysgerminomas', 'Disease', 'MESH:D004407', (122, 143))
2195	22937135	c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas).	('detected', 'Reg', (31, 39))	('c-KIT', 'Gene', (0, 5))	('c-KIT', 'Gene', '3815', (0, 5))	('dysgerminoma', 'Phenotype', 'HP:0100621', (104, 116))	('ovarian dysgerminomas', 'Disease', (96, 117))	('codon 816 mutations', 'Var', (6, 25))	('ovarian dysgerminomas', 'Disease', 'MESH:D004407', (96, 117))
2196	22937135	A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma.	('bilateral disease', 'Disease', 'MESH:D006312', (82, 99))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (50, 58))	('patient', 'Species', '9606', (68, 75))	('bilateral disease', 'Disease', (82, 99))	('dysgerminoma', 'Disease', (122, 134))	('DSD', 'Disease', 'MESH:D058533', (64, 67))	('dysgerminoma', 'Disease', 'MESH:D004407', (122, 134))	('DSD', 'Disease', (64, 67))	('rs 5578615', 'Var', (18, 28))	('dysgerminoma', 'Phenotype', 'HP:0100621', (122, 134))	('patient', 'Species', '9606', (50, 57))
2198	22937135	In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD.	('c-KIT', 'Gene', (20, 25))	('ovarian dysgerminomas', 'Disease', (57, 78))	('DSD', 'Disease', (87, 90))	('c-KIT', 'Gene', '3815', (20, 25))	('ovarian dysgerminomas', 'Disease', 'MESH:D004407', (57, 78))	('dysgerminoma', 'Phenotype', 'HP:0100621', (65, 77))	('mutations', 'Var', (26, 35))	('activating', 'PosReg', (9, 19))	('DSD', 'Disease', 'MESH:D058533', (87, 90))
2199	22937135	In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma.	('dysgerminoma', 'Disease', 'MESH:D004407', (121, 133))	('D820E', 'Mutation', 'rs1057519711', (41, 46))	('DSD', 'Disease', (19, 22))	('D820E', 'Var', (41, 46))	('patient', 'Species', '9606', (89, 96))	('gonadoblastoma', 'Disease', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('dysgerminoma', 'Phenotype', 'HP:0100621', (121, 133))	('gonadoblastoma', 'Disease', 'MESH:D018238', (102, 116))	('DSD', 'Disease', 'MESH:D058533', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('found', 'Reg', (60, 65))	('N505I', 'Mutation', 'p.N505I', (31, 36))	('tumor', 'Disease', (78, 83))	('gonadoblastoma', 'Phenotype', 'HP:0000150', (102, 116))	('dysgerminoma', 'Disease', (121, 133))	('N505I', 'Var', (31, 36))
2202	22937135	This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY.	('dysgerminoma', 'Disease', 'MESH:D004407', (93, 105))	('c-KIT', 'Gene', (137, 142))	('TSPY', 'Gene', (174, 178))	('dysgerminoma', 'Phenotype', 'HP:0100621', (93, 105))	('c-KIT', 'Gene', '3815', (137, 142))	('TSPY', 'Gene', '7258', (174, 178))	('dysgerminoma', 'Disease', (93, 105))	('mutational status', 'Var', (116, 133))
2205	22937135	Expression of c-KIT and gain-of-function mutations in c-KIT has been found in mastocytosis, leukemia and gastro-intestinal stromal tumors (GIST).	('leukemia', 'Disease', (92, 100))	('mutations', 'Var', (41, 50))	('leukemia', 'Disease', 'MESH:D007938', (92, 100))	('mastocytosis', 'Disease', 'MESH:D008415', (78, 90))	('c-KIT', 'Gene', '3815', (54, 59))	('gastro-intestinal stromal tumors', 'Disease', (105, 137))	('mastocytosis', 'Disease', (78, 90))	('c-KIT', 'Gene', (14, 19))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('gastro-intestinal stromal tumors', 'Disease', 'MESH:D046152', (105, 137))	('c-KIT', 'Gene', '3815', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('gain-of-function', 'PosReg', (24, 40))	('mastocytosis', 'Phenotype', 'HP:0100495', (78, 90))	('gastro-intestinal stromal tumors', 'Phenotype', 'HP:0100723', (105, 137))	('c-KIT', 'Gene', (54, 59))
2206	22937135	In GIST activating mutations in c-KIT exons 8, 9, 11, 13 and 17 are found in 75-80% of cases, mutations in PDGFRA exons 12, 14 and 18 in 5-8%, and they are mutually exclusive (for review).	('c-KIT', 'Gene', '3815', (32, 37))	('PDGFRA', 'Gene', (107, 113))	('PDGFRA', 'Gene', '5156', (107, 113))	('mutations', 'Var', (19, 28))	('c-KIT', 'Gene', (32, 37))	('activating', 'PosReg', (8, 18))
2207	22937135	Activating c-KIT mutations have also been found in human germ cell tumors/cancers (GCC), and 10-40% of testicular seminomas harbor activating mutations in exons 11 and 17.	('testicular seminoma', 'Phenotype', 'HP:0100617', (103, 122))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (142, 151))	('testicular seminomas', 'Phenotype', 'HP:0100617', (103, 123))	('c-KIT', 'Gene', (11, 16))	('tumors/cancers', 'Disease', (67, 81))	('tumors/cancers', 'Disease', 'MESH:D009369', (67, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('human', 'Species', '9606', (51, 56))	('testicular seminomas', 'Disease', 'MESH:D018239', (103, 123))	('c-KIT', 'Gene', '3815', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (17, 26))	('testicular seminomas', 'Disease', (103, 123))	('germ cell tumors', 'Phenotype', 'HP:0100728', (57, 73))
2208	22937135	About two thirds are missense point mutations at codon 816, which are also found in almost all mast cell tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mast cell tumors', 'Phenotype', 'HP:0100495', (95, 111))	('missense point mutations at codon', 'Var', (21, 54))	('found', 'Reg', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
2209	22937135	Noteworthy is that activating c-KIT mutations have been found in a subset of tumors showing the same histology as testicular seminoma, namely; mediastinal seminomas, intracranial germinomas and ovarian dysgerminomas.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('dysgerminoma', 'Phenotype', 'HP:0100621', (202, 214))	('activating', 'PosReg', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('c-KIT', 'Gene', '3815', (30, 35))	('seminomas', 'Disease', (155, 164))	('seminomas', 'Disease', 'MESH:D018239', (155, 164))	('testicular seminoma', 'Phenotype', 'HP:0100617', (114, 133))	('testicular seminoma', 'Disease', 'MESH:D018239', (114, 133))	('testicular seminoma', 'Disease', (114, 133))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('intracranial germinomas and ovarian dysgerminomas', 'Disease', 'MESH:D018237', (166, 215))	('c-KIT', 'Gene', (30, 35))
2210	22937135	Next to mutations in c-KIT, amplification of chromosome 4q12, harboring the c-KIT gene, has been described in testicular GCC, likely related to the progression to seminoma.	('c-KIT', 'Gene', (21, 26))	('described', 'Reg', (97, 106))	('seminoma', 'Disease', 'MESH:D018239', (163, 171))	('related', 'Reg', (133, 140))	('c-KIT', 'Gene', (76, 81))	('c-KIT', 'Gene', '3815', (21, 26))	('testicular GCC', 'Disease', (110, 124))	('c-KIT', 'Gene', '3815', (76, 81))	('seminoma', 'Disease', (163, 171))	('amplification', 'Var', (28, 41))
2221	22937135	If mutations in c-KIT or PDGFRA play a significant role in the development of GB and the development of dysgerminoma in DSD patients is not clear so far because of the lack of multiple studies.	('PDGFRA', 'Gene', (25, 31))	('dysgerminoma', 'Phenotype', 'HP:0100621', (104, 116))	('PDGFRA', 'Gene', '5156', (25, 31))	('dysgerminoma', 'Disease', (104, 116))	('DSD', 'Disease', 'MESH:D058533', (120, 123))	('c-KIT', 'Gene', (16, 21))	('dysgerminoma', 'Disease', 'MESH:D004407', (104, 116))	('mutations', 'Var', (3, 12))	('patients', 'Species', '9606', (124, 132))	('c-KIT', 'Gene', '3815', (16, 21))	('DSD', 'Disease', (120, 123))
2222	22937135	Here we report the analysis of activating mutations in codon 816 of c-KIT in 31 patients with a GB and/or dysgerminoma by LightCycler analysis, together with conventional sequence analysis of c-KIT exons 8, 9, 11, 13 and 17, and PDGFRA exons 12, 14 and 18, mutations in which are frequently found in GIST.	('c-KIT', 'Gene', (68, 73))	('patients', 'Species', '9606', (80, 88))	('c-KIT', 'Gene', '3815', (68, 73))	('dysgerminoma', 'Disease', (106, 118))	('c-KIT', 'Gene', '3815', (192, 197))	('dysgerminoma', 'Disease', 'MESH:D004407', (106, 118))	('activating', 'PosReg', (31, 41))	('PDGFRA', 'Gene', '5156', (229, 235))	('PDGFRA', 'Gene', (229, 235))	('mutations in', 'Var', (42, 54))	('dysgerminoma', 'Phenotype', 'HP:0100621', (106, 118))	('c-KIT', 'Gene', (192, 197))
2223	22937135	These results are linked with karyotype, histology of the gonads, expression of TSPY in the tumors and putative role of the mutations found in the etiology of the disease.	('mutations', 'Var', (124, 133))	('TSPY', 'Gene', '7258', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TSPY', 'Gene', (80, 84))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
2243	22937135	All cases found to be positive in the c-KIT c.816 screen were confirmed by sequence analysis.	('c-KIT', 'Gene', '3815', (38, 43))	('c.816', 'Var', (44, 49))	('c-KIT', 'Gene', (38, 43))
2251	22937135	LightCycler analysis detected variants in exon 17 of c-KIT in five out of the total group of 31 patients (19%).	('c-KIT', 'Gene', '3815', (53, 58))	('variants in', 'Var', (30, 41))	('c-KIT', 'Gene', (53, 58))	('patients', 'Species', '9606', (96, 104))	('detected', 'Reg', (21, 29))
2252	22937135	Four were found in the group of ovarian dysgerminomas (27%: four out of fifteen cases), consisting of two D816V, one D816H and one D816Y mutation (cases 17, 19, 22 and 25, Table 1).	('D816V', 'Var', (106, 111))	('D816Y', 'Var', (131, 136))	('ovarian dysgerminomas', 'Disease', 'MESH:D004407', (32, 53))	('D816V', 'Mutation', 'rs121913507', (106, 111))	('D816H', 'Mutation', 'rs121913506', (117, 122))	('dysgerminoma', 'Phenotype', 'HP:0100621', (40, 52))	('ovarian dysgerminomas', 'Disease', (32, 53))	('D816Y', 'Mutation', 'rs121913506', (131, 136))	('D816H and', 'Var', (117, 126))
2256	22937135	This confirmed the presence of the four c.816 mutations found by the LightCycler analysis (cases 17, 19, 22 and 25, Table 1), but also revealed an additional D816V mutation (case 31, Table 1).	('D816V', 'Var', (158, 163))	('D816V', 'Mutation', 'rs121913507', (158, 163))	('c.816', 'Var', (40, 45))
2257	22937135	Furthermore, in three ovarian dysgerminoma cases a N822K mutation was found (cases 21, 24 and 27 Table 1).	('ovarian dysgerminoma', 'Disease', (22, 42))	('ovarian dysgerminoma', 'Disease', 'MESH:D004407', (22, 42))	('N822K', 'Var', (51, 56))	('dysgerminoma', 'Phenotype', 'HP:0100621', (30, 42))	('N822K', 'Mutation', 'rs121913514', (51, 56))
2260	22937135	In case 16 a D820E mutation in exon 17, next to a N505I mutation in exon 9 was found, being the only DSD case showing mutations in c-KIT (6%, 1 out of 16).	('DSD', 'Disease', 'MESH:D058533', (101, 104))	('N505I', 'Mutation', 'p.N505I', (50, 55))	('DSD', 'Disease', (101, 104))	('c-KIT', 'Gene', (131, 136))	('D820E', 'Var', (13, 18))	('D820E', 'Mutation', 'rs1057519711', (13, 18))	('c-KIT', 'Gene', '3815', (131, 136))
2268	22937135	The highest percentages are seen in gastro-intestinal tumors, seminomas, adenoid-cystic carcinomas and malignant melanomas, and amplification and enhanced expression is associated with seminoma progression.	('adenoid-cystic carcinomas', 'Disease', (73, 98))	('malignant melanomas', 'Disease', 'MESH:D008545', (103, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('malignant melanomas', 'Disease', (103, 122))	('seminoma', 'Disease', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('seminomas', 'Disease', 'MESH:D018239', (62, 71))	('seminomas', 'Disease', (62, 71))	('seminoma', 'Disease', 'MESH:D018239', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('malignant melanomas', 'Phenotype', 'HP:0002861', (103, 122))	('gastro-intestinal tumors', 'Disease', 'MESH:D007414', (36, 60))	('seminoma', 'Disease', (185, 193))	('gastro-intestinal tumors', 'Disease', (36, 60))	('amplification', 'Var', (128, 141))	('seminoma', 'Disease', 'MESH:D018239', (185, 193))	('adenoid-cystic carcinomas', 'Disease', 'MESH:D003528', (73, 98))	('expression', 'MPA', (155, 165))	('associated', 'Reg', (169, 179))	('enhanced', 'PosReg', (146, 154))
2272	22937135	Mutations in c-KIT codon 816 were found in 5 (33%) and mutations in codon 822 in 3 (20%) out of the 15 pure ovarian dysgerminoma cases (case 17, 19, 22, 25, 31 and 21, 24, 27 respectively, Table 1), accounting for 53% of cases analyzed.	('c-KIT', 'Gene', (13, 18))	('ovarian dysgerminoma', 'Disease', 'MESH:D004407', (108, 128))	('c-KIT', 'Gene', '3815', (13, 18))	('Mutations', 'Var', (0, 9))	('ovarian dysgerminoma', 'Disease', (108, 128))	('found', 'Reg', (34, 39))	('mutations in', 'Var', (55, 67))	('dysgerminoma', 'Phenotype', 'HP:0100621', (116, 128))
2275	22937135	It is known that in GIST in addition to mutations in c-KIT, also mutations in PDGFRA exon 12, 14 and 18 play a role and that these are mutually exclusive.	('c-KIT', 'Gene', '3815', (53, 58))	('PDGFRA', 'Gene', (78, 84))	('c-KIT', 'Gene', (53, 58))	('PDGFRA', 'Gene', '5156', (78, 84))	('mutations', 'Var', (65, 74))
2276	22937135	Sequencing PDGFRA did not reveal mutations in any of the dysgerminoma DNA samples analyzed, only a variation in exon 12 was found in almost all cases (homozygous synonymous SNP, rs.	('variation', 'Var', (99, 108))	('PDGFRA', 'Gene', (11, 17))	('dysgerminoma', 'Disease', (57, 69))	('PDGFRA', 'Gene', '5156', (11, 17))	('dysgerminoma', 'Disease', 'MESH:D004407', (57, 69))	('dysgerminoma', 'Phenotype', 'HP:0100621', (57, 69))
2277	22937135	This indicates that mutations in PDGFRA do not play a major role in the development of (ovarian) dysgerminomas or GB.	('(ovarian) dysgerminomas', 'Disease', 'MESH:D004407', (87, 110))	('PDGFRA', 'Gene', (33, 39))	('dysgerminoma', 'Phenotype', 'HP:0100621', (97, 109))	('PDGFRA', 'Gene', '5156', (33, 39))	('mutations', 'Var', (20, 29))
2278	22937135	analyzed 22 cases of dysgerminoma and found a c-KIT codon 816 mutation in 27% of cases, and KIT expression in 87%.	('dysgerminoma', 'Phenotype', 'HP:0100621', (21, 33))	('dysgerminoma', 'Disease', (21, 33))	('c-KIT', 'Gene', (46, 51))	('codon 816 mutation', 'Var', (52, 70))	('dysgerminoma', 'Disease', 'MESH:D004407', (21, 33))	('c-KIT', 'Gene', '3815', (46, 51))	('KIT', 'MPA', (92, 95))
2279	22937135	found c-KIT codon 816 mutations in five out of seventeen dysgerminoma cases (29%) with 80% expressing c-KIT.	('c-KIT', 'Gene', (6, 11))	('c-KIT', 'Gene', '3815', (102, 107))	('dysgerminoma', 'Disease', (57, 69))	('dysgerminoma', 'Disease', 'MESH:D004407', (57, 69))	('c-KIT', 'Gene', '3815', (6, 11))	('codon 816 mutations', 'Var', (12, 31))	('dysgerminoma', 'Phenotype', 'HP:0100621', (57, 69))	('c-KIT', 'Gene', (102, 107))
2280	22937135	Furthermore, also in gastro-intestinal tumors KIT mutation rate is lower than the expression rate of KIT.	('lower', 'NegReg', (67, 72))	('gastro-intestinal tumors', 'Disease', (21, 45))	('mutation', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('gastro-intestinal tumors', 'Disease', 'MESH:D007414', (21, 45))
2281	22937135	The results presented here suggest that in about half of ovarian dysgerminomas activating mutations in c-KIT play a role, with about a third consisting of codon 816 mutations, as has been reported by others, while the remaining 20% consisted of N822K mutations.	('ovarian dysgerminomas', 'Disease', (57, 78))	('mutations', 'Var', (90, 99))	('c-KIT', 'Gene', (103, 108))	('dysgerminoma', 'Phenotype', 'HP:0100621', (65, 77))	('ovarian dysgerminomas', 'Disease', 'MESH:D004407', (57, 78))	('N822K', 'Mutation', 'rs121913514', (245, 250))	('codon 816 mutations', 'Var', (155, 174))	('c-KIT', 'Gene', '3815', (103, 108))	('N822K', 'Var', (245, 250))
2283	22937135	Next to these mutations a known synonymous SNP (rs55789615) was detected in exon 17 of case 28, which has been described before in a patient having a N822K mutation in the GCC of the contralateral testis.	('N822K', 'Var', (150, 155))	('GCC', 'Gene', (172, 175))	('patient', 'Species', '9606', (133, 140))	('rs55789615', 'Mutation', 'rs55789615', (48, 58))	('N822K', 'Mutation', 'rs121913514', (150, 155))	('rs55789615', 'Var', (48, 58))
2306	22937135	Analyzing the presence of c-KIT activating - and PDGFRA mutations, either by LightCycler melting curve analysis or conventional sequencing, in the group of sixteen DSD cases showing GB, with or without an invasive tumor, showed that in the majority of cases no mutations could be detected (15 out of 16 cases, 94%).	('mutations', 'Var', (56, 65))	('PDGFRA', 'Gene', (49, 55))	('c-KIT', 'Gene', '3815', (26, 31))	('activating -', 'PosReg', (32, 44))	('PDGFRA', 'Gene', '5156', (49, 55))	('DSD', 'Disease', 'MESH:D058533', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('invasive tumor', 'Disease', 'MESH:D009369', (205, 219))	('invasive tumor', 'Disease', (205, 219))	('c-KIT', 'Gene', (26, 31))	('DSD', 'Disease', (164, 167))
2308	22937135	In three patients a shift in melting curve not corresponding to one of the c-KIT c.816 mutations investigated was found, and subsequent sequencing of the LightCycler products revealed a wild type exon 17 sequence in case 1 and 2, and a known synonymous SNP (rs 55789615) in case 4 (I798I), although this latter finding was not confirmed by conventional sequencing of the original DNA sample.	('patients', 'Species', '9606', (9, 17))	('I798I', 'Mutation', 'rs55789615', (282, 287))	('c-KIT', 'Gene', '3815', (75, 80))	('c.816', 'Gene', (81, 86))	('melting', 'MPA', (29, 36))	('c-KIT', 'Gene', (75, 80))	('rs 55789615', 'Var', (258, 269))
2310	22937135	The I798I variant was also detected in a patient with ovarian dysgerminoma (case 28, see above).	('I798I', 'Var', (4, 9))	('ovarian dysgerminoma', 'Disease', (54, 74))	('dysgerminoma', 'Phenotype', 'HP:0100621', (62, 74))	('patient', 'Species', '9606', (41, 48))	('ovarian dysgerminoma', 'Disease', 'MESH:D004407', (54, 74))	('I798I', 'Mutation', 'rs55789615', (4, 9))	('detected', 'Reg', (27, 35))
2311	22937135	In one patient (case 16) showing GB and mainly dysgerminoma, missense mutations in c-KIT were found in exon 9 and 17, resulting in N505I and D820E respectively, which were not present in normal adjacent adnexal material.	('D820E', 'Mutation', 'rs1057519711', (141, 146))	('missense mutations', 'Var', (61, 79))	('c-KIT', 'Gene', (83, 88))	('patient', 'Species', '9606', (7, 14))	('dysgerminoma', 'Phenotype', 'HP:0100621', (47, 59))	('dysgerminoma', 'Disease', (47, 59))	('dysgerminoma', 'Disease', 'MESH:D004407', (47, 59))	('c-KIT', 'Gene', '3815', (83, 88))	('N505I', 'Mutation', 'p.N505I', (131, 136))	('N505I', 'Var', (131, 136))	('D820E', 'Var', (141, 146))
2313	22937135	A mutation in c-KIT codon 816 in a DSD patient presenting with GB and dysgerminoma has also been reported previously, indicating that in rare cases these mutations can be found in DSD patients.	('DSD', 'Disease', 'MESH:D058533', (180, 183))	('DSD', 'Disease', (35, 38))	('patient', 'Species', '9606', (39, 46))	('c-KIT', 'Gene', (14, 19))	('patients', 'Species', '9606', (184, 192))	('codon 816', 'Var', (20, 29))	('mutation in', 'Var', (2, 13))	('patient', 'Species', '9606', (184, 191))	('c-KIT', 'Gene', '3815', (14, 19))	('dysgerminoma', 'Phenotype', 'HP:0100621', (70, 82))	('DSD', 'Disease', (180, 183))	('dysgerminoma', 'Disease', (70, 82))	('DSD', 'Disease', 'MESH:D058533', (35, 38))	('dysgerminoma', 'Disease', 'MESH:D004407', (70, 82))
2315	22937135	To our knowledge this is the first time a N505I mutation in exon 9 of c-KIT has been found.	('N505I', 'Mutation', 'p.N505I', (42, 47))	('c-KIT', 'Gene', '3815', (70, 75))	('N505I', 'Var', (42, 47))	('c-KIT', 'Gene', (70, 75))
2316	22937135	c-KIT mutations in exon 9 have been described in GIST, and it is thought that these mutations mimic the conformational change that the extracellular KIT receptor undergoes when SCF is bound.	('c-KIT', 'Gene', (0, 5))	('SCF', 'Gene', (177, 180))	('c-KIT', 'Gene', '3815', (0, 5))	('SCF', 'Gene', '4254', (177, 180))	('mutations', 'Var', (6, 15))
2317	22937135	The activating c-KIT D820E mutation has been described together with mutations in exon 9, related to sunitinib resistance in GIST.	('activating', 'PosReg', (4, 14))	('sunitinib', 'Chemical', 'MESH:D000077210', (101, 110))	('c-KIT', 'Gene', (15, 20))	('D820E', 'Var', (21, 26))	('D820E', 'Mutation', 'rs1057519711', (21, 26))	('c-KIT', 'Gene', '3815', (15, 20))	('sunitinib resistance', 'MPA', (101, 121))
2319	22937135	Besides the specific c-KIT c.816 mutations investigated here, other mutations in exon 17 have been reported in GCC; c-KIT gain-of-function D820G and Y823D have been found, next to S821F, C809S, Y823N and D816E together with D820H amongst others, which are not present in the cases analyzed here, and thus do not seem to be involved in ovarian dysgerminomas or DSD.	('Y823N', 'Mutation', 'p.Y823N', (194, 199))	('dysgerminoma', 'Phenotype', 'HP:0100621', (343, 355))	('D820G', 'Var', (139, 144))	('Y823D', 'Mutation', 'rs1057519761', (149, 154))	('c-KIT', 'Gene', (116, 121))	('D816E', 'Var', (204, 209))	('S821F', 'Var', (180, 185))	('c-KIT', 'Gene', (21, 26))	('c-KIT', 'Gene', '3815', (116, 121))	('ovarian dysgerminomas', 'Disease', (335, 356))	('C809S', 'Mutation', 'p.C809S', (187, 192))	('D816E', 'Mutation', 'rs1057519711', (204, 209))	('c-KIT', 'Gene', '3815', (21, 26))	('Y823N', 'Var', (194, 199))	('gain-of-function', 'PosReg', (122, 138))	('ovarian dysgerminomas', 'Disease', 'MESH:D004407', (335, 356))	('D820H', 'Mutation', 'rs1057519710', (224, 229))	('S821F', 'Mutation', 'p.S821F', (180, 185))	('DSD', 'Disease', (360, 363))	('GCC', 'Disease', (111, 114))	('Y823D', 'Var', (149, 154))	('D820G', 'Mutation', 'rs121913682', (139, 144))	('C809S', 'Var', (187, 192))	('D820H', 'Var', (224, 229))	('DSD', 'Disease', 'MESH:D058533', (360, 363))
2320	22937135	Interestingly, recently genome-wide association studies of have identified SNPs within KITLG (SCF) as having the strongest association with an increased risk of developing a testicular GCC, pointing to the importance of the SCF-cKIT pathway in this disease.	('KITLG', 'Gene', (87, 92))	('SCF', 'Gene', (94, 97))	('SCF', 'Gene', '4254', (224, 227))	('SCF', 'Gene', '4254', (94, 97))	('testicular GCC', 'Disease', (174, 188))	('SNPs', 'Var', (75, 79))	('KITLG', 'Gene', '4254', (87, 92))	('SCF', 'Gene', (224, 227))
2321	22937135	Taken together, c-KIT mutations occur in approximately half of pure ovarian dysgerminoma cases, all residing in exon 17, indicating a role in the etiology of the disease.	('dysgerminoma', 'Phenotype', 'HP:0100621', (76, 88))	('ovarian dysgerminoma', 'Disease', (68, 88))	('mutations', 'Var', (22, 31))	('ovarian dysgerminoma', 'Disease', 'MESH:D004407', (68, 88))	('c-KIT', 'Gene', (16, 21))	('c-KIT', 'Gene', '3815', (16, 21))
2323	22937135	In DSD, presence of Y-chromosomal material leads to the gonadal dysgenesis, in which the germ cells survive because of prolonged expression of both OCT3/4 and TSPY, setting the stage for GB and subsequent dysgerminoma development; although in a minority of cases mutations in c-KIT might play a role.	('dysgerminoma', 'Disease', 'MESH:D004407', (205, 217))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (56, 74))	('presence', 'Var', (8, 16))	('gonadal dysgenesis', 'Disease', (56, 74))	('TSPY', 'Gene', '7258', (159, 163))	('c-KIT', 'Gene', (276, 281))	('OCT3/4', 'Gene', '5460', (148, 154))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (56, 74))	('dysgerminoma', 'Phenotype', 'HP:0100621', (205, 217))	('TSPY', 'Gene', (159, 163))	('DSD', 'Disease', 'MESH:D058533', (3, 6))	('OCT3/4', 'Gene', (148, 154))	('c-KIT', 'Gene', '3815', (276, 281))	('dysgerminoma', 'Disease', (205, 217))	('leads to', 'Reg', (43, 51))	('DSD', 'Disease', (3, 6))
2327	19263492	The association of aberrant expression of signaling molecules and cascades with abnormal spermatogenesis and testicular cancer are also discussed.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('testicular cancer', 'Phenotype', 'HP:0010788', (109, 126))	('testicular cancer', 'Disease', 'MESH:D013736', (109, 126))	('abnormal spermatogenesis', 'CPA', (80, 104))	('abnormal spermatogenesis', 'Phenotype', 'HP:0008669', (80, 104))	('testicular cancer', 'Disease', (109, 126))	('aberrant', 'Var', (19, 27))
2331	19263492	Aberrant expression of the signaling molecules and the intracellular signaling pathways may lead to male infertility and testicular cancer.	('Aberrant', 'Var', (0, 8))	('lead to', 'Reg', (92, 99))	('testicular cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (9, 19))	('male infertility', 'Phenotype', 'HP:0003251', (100, 116))	('male infertility', 'Disease', (100, 116))	('male infertility', 'Disease', 'MESH:D007248', (100, 116))	('infertility', 'Phenotype', 'HP:0000789', (105, 116))	('testicular cancer', 'Phenotype', 'HP:0010788', (121, 138))	('testicular cancer', 'Disease', 'MESH:D013736', (121, 138))
2350	19263492	We did a double staining, using antibodies to GFRA1 and POU5F1 (also know as Oct-4), showing that mouse SSCs co-express GFRA1 and POU5F1 (Figure 3).	('Oct-4', 'Gene', '18999', (77, 82))	('POU5F1', 'Gene', '18999', (56, 62))	('POU5F1', 'Gene', (130, 136))	('Oct-4', 'Gene', (77, 82))	('GFRA1', 'Var', (120, 125))	('mouse', 'Species', '10090', (98, 103))	('POU5F1', 'Gene', '18999', (130, 136))	('POU5F1', 'Gene', (56, 62))
2354	19263492	A recent study in the human identified the following four spermatogonial markers [CD49f (alpha6-integrin), CD90 (Thy-1), CD133, GFRA1], that may also be SSC markers.	('CD133', 'Gene', (121, 126))	('CD133', 'Gene', '8842', (121, 126))	('Thy-1', 'Gene', (113, 118))	('Thy-1', 'Gene', '7070', (113, 118))	('[CD49f', 'Var', (81, 87))	('human', 'Species', '9606', (22, 27))	('CD90', 'Var', (107, 111))
2366	19263492	In vivo, overexpression of GDNF leads to an accumulation of undifferentiated spermatogonia including SSCs, and conversely, ablation of GDNF by gene targeting results in the depletion of spermatogonia, suggesting that GDNF is essential for the self-renewal and maintenance of SSCs.	('GDNF', 'Gene', (217, 221))	('overexpression', 'PosReg', (9, 23))	('GDNF', 'Gene', '14573', (135, 139))	('ablation', 'Var', (123, 131))	('GDNF', 'Gene', (135, 139))	('depletion', 'MPA', (173, 182))	('GDNF', 'Gene', '14573', (27, 31))	('GDNF', 'Gene', '14573', (217, 221))	('GDNF', 'Gene', (27, 31))	('accumulation', 'PosReg', (44, 56))
2370	19263492	Recently, we have demonstrated that the silencing of GFRA1 by RNA interference results in a switch from proliferation of mouse SSCs to differentiation into A1-A4 spermatogonia, an initial stage of spermatogenesis.	('rat', 'Species', '10116', (111, 114))	('proliferation', 'CPA', (104, 117))	('mouse', 'Species', '10090', (121, 126))	('differentiation', 'CPA', (135, 150))	('silencing', 'Var', (40, 49))	('rat', 'Species', '10116', (25, 28))	('GFRA1', 'Gene', (53, 58))	('RNA interference', 'MPA', (62, 78))
2374	19263492	Mutations in PLZF results in an intrinsic defect in SSC self-renewal.	('PLZF', 'Gene', '235320', (13, 17))	('defect', 'NegReg', (42, 48))	('SSC self-renewal', 'CPA', (52, 68))	('Mutations', 'Var', (0, 9))	('PLZF', 'Gene', (13, 17))
2378	19263492	However, loss of ERM expression doesn't change the expression of GDNF, indicating that ERM doesn't signal through the GDNF pathway.	('GDNF', 'Gene', '14573', (118, 122))	('GDNF', 'Gene', (118, 122))	('ERM', 'Gene', (17, 20))	('loss', 'Var', (9, 13))	('GDNF', 'Gene', '14573', (65, 69))	('GDNF', 'Gene', (65, 69))
2392	19263492	Transplantation of undifferentiated germ cells (KIT-negative spermatogonia) into seminiferous tubules of steel factor (Sl)/Sld mutant testes results in proliferation and colony formation that are unable to further differentiate.	('steel factor', 'Gene', (105, 117))	('mutant', 'Var', (127, 133))	('colony formation', 'CPA', (170, 186))	('proliferation', 'CPA', (152, 165))	('steel factor', 'Gene', '17311', (105, 117))	('rat', 'Species', '10116', (159, 162))
2404	19263492	In the Upd-deficiency mutants, SSCs are depleted rapidly, whereas overexpression of Upd results in an accumulation of stem cell-like cells and block their differentiation.	('accumulation', 'PosReg', (102, 114))	('block', 'NegReg', (143, 148))	('differentiation', 'CPA', (155, 170))	('stem cell-like cells', 'CPA', (118, 138))	('Upd', 'Gene', (84, 87))	('Upd', 'Gene', '32813', (84, 87))	('Upd', 'Gene', (7, 10))	('mutants', 'Var', (22, 29))	('Upd', 'Gene', '32813', (7, 10))
2405	19263492	Moreover, the blockage in JAK/STAT signaling by the mutation of JAK (the Hopscotch) or Stat92E leads to SSC loss, and conversely, the activation of JAK/STAT signaling by Upd results in self-renewal of SSCs.	('JAK', 'Gene', '32080', (64, 67))	('SSC loss', 'Disease', 'MESH:D015431', (104, 112))	('Upd', 'Gene', (170, 173))	('JAK', 'Gene', (26, 29))	('STAT', 'Gene', '42428', (30, 34))	('STAT', 'Gene', (152, 156))	('JAK', 'Gene', '32080', (26, 29))	('JAK', 'Gene', (64, 67))	('self-renewal', 'CPA', (185, 197))	('SSC loss', 'Disease', (104, 112))	('JAK', 'Gene', '32080', (148, 151))	('Upd', 'Gene', '32813', (170, 173))	('mutation', 'Var', (52, 60))	('STAT', 'Gene', (30, 34))	('STAT', 'Gene', '42428', (152, 156))	('Stat92E', 'Gene', (87, 94))	('blockage', 'NegReg', (14, 22))	('JAK', 'Gene', (148, 151))
2406	19263492	Removal of JAK-STAT signaling causes germ line stem cells to differentiate into clusters of interconnected spermatogonial cysts.	('STAT', 'Gene', (15, 19))	('JAK', 'Gene', '32080', (11, 14))	('Removal', 'Var', (0, 7))	('germ line stem cells', 'CPA', (37, 57))	('JAK', 'Gene', (11, 14))	('STAT', 'Gene', '42428', (15, 19))
2415	19263492	Inhibition of PI3K by its specific inhibitor LY294002 blocks proliferation of SSCs in culture, and conversely, conditioned activation of Akt in SSCs by transfecting myr-Akt-Mer plasmid and in the presence of 4-hydroxy-tamoxifen stimulates their self-renewal and rescues apoptosis of SSCs due to the absence of GDNF.	('stimulates', 'PosReg', (228, 238))	('blocks', 'NegReg', (54, 60))	('self-renewal', 'CPA', (245, 257))	('LY294002', 'Var', (45, 53))	('GDNF', 'Gene', '14573', (310, 314))	('Akt', 'Gene', (169, 172))	('apoptosis', 'CPA', (270, 279))	('GDNF', 'Gene', (310, 314))	('4-hydroxy-tamoxifen', 'Chemical', '-', (208, 227))	('transfecting', 'Var', (152, 164))	('Akt', 'Gene', '11651', (137, 140))	('rescues', 'PosReg', (262, 269))	('rat', 'Species', '10116', (68, 71))	('activation', 'PosReg', (123, 133))	('Akt', 'Gene', (137, 140))	('LY294002', 'Chemical', 'MESH:C085911', (45, 53))	('proliferation', 'CPA', (61, 74))	('Akt', 'Gene', '11651', (169, 172))
2420	19263492	Furthermore, in vivo research confirms that the failure of binding of PI3K to KIT receptor diminishes activation of Akt, which leads to a decrease of proliferation and an increase of apoptosis of SSCs and eventually results in an arrest of spermatogenesis.	('activation', 'MPA', (102, 112))	('spermatogenesis', 'CPA', (240, 255))	('binding', 'Interaction', (59, 66))	('arrest of spermatogenesis', 'Phenotype', 'HP:0031038', (230, 255))	('PI3K', 'Var', (70, 74))	('Akt', 'Gene', '11651', (116, 119))	('rat', 'Species', '10116', (157, 160))	('decrease', 'NegReg', (138, 146))	('results in', 'Reg', (216, 226))	('Akt', 'Gene', (116, 119))	('increase', 'PosReg', (171, 179))	('apoptosis', 'CPA', (183, 192))	('diminishes', 'NegReg', (91, 101))	('proliferation', 'CPA', (150, 163))
2423	19263492	Blocking the MAPK/ERK pathway by the MEK-specific inhibitor PD098059 results in a slight decrease in the proliferation of male germline stem cells from neonatal mice.	('MAPK', 'Gene', (13, 17))	('mice', 'Species', '10090', (161, 165))	('ERK', 'Gene', (18, 21))	('MAPK', 'Gene', '26413;26417', (13, 17))	('PD098059', 'Var', (60, 68))	('ERK', 'Gene', '26413', (18, 21))	('decrease', 'NegReg', (89, 97))	('proliferation', 'CPA', (105, 118))	('MEK', 'Gene', '17242', (37, 40))	('rat', 'Species', '10116', (112, 115))	('PD098059', 'Chemical', 'MESH:C093973', (60, 68))	('MEK', 'Gene', (37, 40))
2436	19263492	Abnormal expression of signaling molecules and the disruption of signaling cascades have been demonstrated to result in disrupted spermatogenesis.	('rat', 'Species', '10116', (101, 104))	('disruption', 'Reg', (51, 61))	('disrupted spermatogenesis', 'Phenotype', 'HP:0008669', (120, 145))	('signaling', 'Protein', (23, 32))	('expression', 'MPA', (9, 19))	('Abnormal', 'Var', (0, 8))	('spermatogenesis', 'CPA', (130, 145))
2437	19263492	Genetic studies show that abnormality of GDNF expression blocks spermatogenic development and results in successive germ cell depletion.	('spermatogenic development', 'CPA', (64, 89))	('results in', 'Reg', (94, 104))	('GDNF', 'Gene', '14573', (41, 45))	('GDNF', 'Gene', (41, 45))	('blocks', 'NegReg', (57, 63))	('abnormality', 'Var', (26, 37))
2439	19263492	FGFR1 signaling cascade has also been implicated in normal spermiogenesis and male fertility, and disrupted FGFR1 signaling results in a remarkable reduction in daily production of sperm with functionally compromised capacitation.	('reduction', 'NegReg', (148, 157))	('FGFR1', 'Gene', '14182', (108, 113))	('daily production', 'MPA', (161, 177))	('disrupted', 'Var', (98, 107))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '14182', (0, 5))	('FGFR1', 'Gene', (108, 113))
2440	19263492	Studies with the PI3K pathway indicate that KIT-induced activation of the PI3K pathway is essential for male fertility since mutant males with disruption of PI3K binding to KIT are sterile due to a blockage of both the proliferation of spermatogonia and early stages of spermatogenesis.	('mutant', 'Var', (125, 131))	('KIT', 'Gene', (173, 176))	('blockage', 'NegReg', (198, 206))	('PI3K', 'Gene', (157, 161))	('disruption', 'Var', (143, 153))	('binding', 'Interaction', (162, 169))	('rat', 'Species', '10116', (226, 229))
2443	19263492	Aberrant expression or disruption of the signaling molecules and intracellular signaling pathways may result in an enhanced risk of testicular cancer and other tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Aberrant expression', 'Var', (0, 19))	('signaling molecules', 'Pathway', (41, 60))	('testicular cancer', 'Disease', 'MESH:D013736', (132, 149))	('testicular cancer', 'Disease', (132, 149))	('disruption', 'Reg', (23, 33))	('tumors', 'Disease', (160, 166))	('testicular cancer', 'Phenotype', 'HP:0010788', (132, 149))	('intracellular signaling pathways', 'Pathway', (65, 97))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
2688	20535289	There is evidence that many patients with ITGCN in a solitary testis are infertile even prior to treatment, though paternity has been documented and improvement in spermatogenesis has been demonstrated following the removal of unilateral TGCTs.	('ITGCN', 'Var', (42, 47))	('infertile', 'Disease', 'MESH:D007247', (73, 82))	('improvement', 'PosReg', (149, 160))	('men', 'Species', '9606', (138, 141))	('men', 'Species', '9606', (156, 159))	('infertile', 'Disease', (73, 82))	('patients', 'Species', '9606', (28, 36))	('men', 'Species', '9606', (102, 105))	('spermatogenesis', 'CPA', (164, 179))
2690	20535289	This has prompted studies on dose reduction, which had similar effects on endocrine function which was not dose- dependent, and worse treatment outcomes at lower doses.	('men', 'Species', '9606', (139, 142))	('dose reduction', 'Var', (29, 43))	('endocrine function', 'MPA', (74, 92))
2852	30237722	A known risk factor for cardiovascular disease, metabolic syndrome is defined as >=3 of the following characteristics: central or abdominal obesity, TGs >= 150 mg/dL, high-density lipoprotein <= 40 mg/dL, elevated BP > 130/85 mmHg, and fasting glucose >= 100 mg/dL.	('metabolic syndrome', 'Disease', (48, 66))	('glucose', 'Chemical', 'MESH:D005947', (244, 251))	('cardiovascular disease', 'Disease', (24, 46))	('abdominal obesity', 'Disease', (130, 147))	('elevated', 'PosReg', (205, 213))	('obesity', 'Phenotype', 'HP:0001513', (140, 147))	('TGs >= 150 mg/dL', 'Var', (149, 165))	('TGs', 'Chemical', 'MESH:D014280', (149, 152))	('elevated BP', 'Phenotype', 'HP:0032263', (205, 216))	('abdominal obesity', 'Phenotype', 'HP:0012743', (130, 147))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (24, 46))	('high-density lipoprotein', 'MPA', (167, 191))	('metabolic syndrome', 'Disease', 'MESH:D008659', (48, 66))	('BP > 130/85 mmHg', 'MPA', (214, 230))	('cardiovascular disease', 'Disease', 'MESH:D002318', (24, 46))	('abdominal obesity', 'Disease', 'MESH:D056128', (130, 147))
2893	27584029	The role of epigenetics in TGCT development and prognosis is also being further characterized.	('men', 'Species', '9606', (39, 42))	('TGCT', 'Disease', (27, 31))	('epigenetics', 'Var', (12, 23))
2906	27584029	Several gene loci were identified using genome-wide association studies (GWAS) that appear related to TGCT predisposition, including KITLG, SPRY4, BAK1, DMRT1, TERT, and ATF7IP, proposed gene TGCT1 on Xq27, and gr/gr deletion in the AZFc region on Y-chromosome.	('gr/gr', 'Gene', (211, 216))	('TERT', 'Gene', '7015', (160, 164))	('KITLG', 'Gene', '4254', (133, 138))	('BAK1', 'Gene', '578', (147, 151))	('DMRT1', 'Gene', (153, 158))	('DMRT1', 'Gene', '1761', (153, 158))	('KITLG', 'Gene', (133, 138))	('SPRY4', 'Gene', '81848', (140, 145))	('ATF7IP', 'Gene', (170, 176))	('deletion', 'Var', (217, 225))	('BAK1', 'Gene', (147, 151))	('TGCT', 'Gene', (102, 106))	('TGCT1', 'Gene', '50830', (192, 197))	('TERT', 'Gene', (160, 164))	('TGCT1', 'Gene', (192, 197))	('ATF7IP', 'Gene', '55729', (170, 176))	('SPRY4', 'Gene', (140, 145))
2916	27584029	Florescence in situ hybridization (FISH) confirmed extra copies of 12p in virtually all TGCT specimens, becoming a hallmark pathognomonic for TCGT.	('men', 'Species', '9606', (98, 101))	('extra copies of 12p', 'Var', (51, 70))	('TGCT', 'Gene', (88, 92))
2919	27584029	Cytogenetic analysis on 124 microdissected specimens identified nonrandom rearrangements with an association to certain histologies (1p32-36 and 7q11.2 rearrangements associated with teratoma; 1p22 rearrangements associated with yolk-sac tumor) and other clinical characteristics.	('associated', 'Reg', (213, 223))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('men', 'Species', '9606', (48, 51))	('teratoma', 'Phenotype', 'HP:0009792', (183, 191))	('men', 'Species', '9606', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('teratoma', 'Disease', (183, 191))	('teratoma', 'Disease', 'MESH:D013724', (183, 191))	('men', 'Species', '9606', (207, 210))	('association', 'Interaction', (97, 108))	('tumor', 'Disease', (238, 243))	('rearrangements', 'Var', (198, 212))	('rearrangements', 'Var', (152, 166))	('associated', 'Reg', (167, 177))	('men', 'Species', '9606', (161, 164))
2920	27584029	Genomic studies investigating the clinical significance of i12p and other chromosomal abnormalities have generally been plagued by inconsistent results.	('chromosomal abnormalities', 'Disease', (74, 99))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (74, 99))	('i12p', 'Var', (59, 63))
2921	27584029	A query of the Catalogue of Somatic Mutations in Cancer (COSMIC) database identified KIT mutations in 19% (52/261) of seminomas and just 2% (2/98) of NSGCT, confirming that while rare in nonseminomas, a significant proportion of seminomas harbor KIT mutations.	('seminomas', 'Disease', 'MESH:D018239', (190, 199))	('nonseminomas', 'Disease', (187, 199))	('seminomas', 'Disease', 'MESH:D018239', (229, 238))	('seminomas', 'Disease', (190, 199))	('seminomas', 'Disease', (118, 127))	('KIT', 'Gene', (85, 88))	('seminomas', 'Disease', (229, 238))	('mutations', 'Var', (89, 98))	('nonseminomas', 'Disease', 'None', (187, 199))	('seminomas', 'Disease', 'MESH:D018239', (118, 127))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))
2922	27584029	KIT mutations in TCGT pose attractive treatment possibilities in light of highly effective response rates of gastrointestinal stromal tumor (GIST) that harbor KIT mutations to imatinib (Gleevec).	('mutations', 'Var', (163, 172))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (109, 139))	('imatinib', 'Chemical', 'MESH:D000068877', (176, 184))	('GIST', 'Phenotype', 'HP:0100723', (141, 145))	('gastrointestinal stromal tumor', 'Disease', (109, 139))	('men', 'Species', '9606', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (109, 139))	('TCGT', 'Gene', (17, 21))
2924	27584029	Recent next generation sequencing (NGS) efforts identified that most patients with TGCT harbor exon 17 mutations, which are generally imatinib-resistant, emphasizing the need for precise genotyping and potentially explaining the disappointing results of the phase II study.	('exon', 'Var', (95, 99))	('mutations', 'Var', (103, 112))	('TGCT', 'Gene', (83, 87))	('patients', 'Species', '9606', (69, 77))	('imatinib', 'Chemical', 'MESH:D000068877', (134, 142))
2926	27584029	A query of the COSMIC database indicates KRAS and NRAS mutations in just 5-7% of seminomas and 0% of nonseminomas.	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (50, 54))	('seminomas', 'Disease', 'MESH:D018239', (104, 113))	('seminomas', 'Disease', (104, 113))	('NRAS', 'Gene', '4893', (50, 54))	('nonseminomas', 'Disease', (101, 113))	('nonseminomas', 'Disease', 'None', (101, 113))	('KRAS', 'Gene', (41, 45))	('seminomas', 'Disease', 'MESH:D018239', (81, 90))	('seminomas', 'Disease', (81, 90))
2927	27584029	RAS mutations and FGFR3 mutations were identified at a higher frequency in chemoresistant versus sensitive tumors and given the potential clinical relevance of RAS pathway mutations and potential therapeutic approaches, further research is needed to clarify the roles of such mutations in TGCTs.	('FGFR3', 'Gene', '2261', (18, 23))	('RAS', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('chemoresistant', 'Disease', (75, 89))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('FGFR3', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (4, 13))	('mutations', 'Var', (24, 33))
2929	27584029	COSMIC query indicates that BRAF mutations are rare in TGCT (1% of seminoma, 2% of nonseminomas).	('BRAF', 'Gene', '673', (28, 32))	('seminoma', 'Disease', (67, 75))	('seminoma', 'Disease', 'MESH:D018239', (86, 94))	('nonseminomas', 'Disease', (83, 95))	('mutations', 'Var', (33, 42))	('nonseminomas', 'Disease', 'None', (83, 95))	('seminoma', 'Disease', 'MESH:D018239', (67, 75))	('BRAF', 'Gene', (28, 32))	('seminoma', 'Disease', (86, 94))
2931	27584029	These findings were not reproduced in a subsequent study in patients with cisplatin-resistant TGCT, where BRAF mutations were not identified though hotspot variants in PIK3CA, AKT1, and FGFR3 were noted.	('patients', 'Species', '9606', (60, 68))	('PIK3CA', 'Gene', (168, 174))	('BRAF', 'Gene', '673', (106, 110))	('PIK3CA', 'Gene', '5290', (168, 174))	('variants', 'Var', (156, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('BRAF', 'Gene', (106, 110))	('AKT1', 'Gene', '207', (176, 180))	('AKT1', 'Gene', (176, 180))	('FGFR3', 'Gene', '2261', (186, 191))	('TGCT', 'Disease', (94, 98))	('FGFR3', 'Gene', (186, 191))
2932	27584029	The disparate reported incidence of BRAF mutations highlights the need for further research with contemporary sequencing platforms.	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (36, 40))
2935	27584029	While TP53 mutations are common in somatic tumors, they are rare in TGCTs, with the COSMIC database finding TP53 mutations in 7% of seminomas (10/148) and 0% of nonseminomas (0/9).	('seminomas', 'Disease', 'MESH:D018239', (164, 173))	('seminomas', 'Disease', (164, 173))	('TP53', 'Gene', '7157', (6, 10))	('somatic tumors', 'Disease', 'MESH:C563610', (35, 49))	('TP53', 'Gene', (6, 10))	('nonseminomas', 'Disease', 'None', (161, 173))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('somatic tumors', 'Disease', (35, 49))	('seminomas', 'Disease', 'MESH:D018239', (132, 141))	('seminomas', 'Disease', (132, 141))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('nonseminomas', 'Disease', (161, 173))
2938	27584029	The incidence of TP53 pathway mutations, including MDM2 amplifications, was recently reported to be approximately 25% among patients with cisplatin-resistant disease.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (17, 21))	('patients', 'Species', '9606', (124, 132))	('TP53', 'Gene', (17, 21))
2940	27584029	To date, whole exome sequencing of 42 TGCT cases demonstrated that in addition to 12p amplification and KIT mutations, recurrent mutations were noted in the tumor suppressor gene CDC27 (11.9%) and copy number analysis demonstrated amplification of the spermatocyte development gene FSIP2 (15.3%) in a 0.4 Mb region at Xq28 (15.3%).	('tumor', 'Disease', (157, 162))	('CDC27', 'Gene', (179, 184))	('men', 'Species', '9606', (272, 275))	('FSIP2', 'Gene', (282, 287))	('mutations', 'Var', (108, 117))	('mutations', 'Var', (129, 138))	('amplification', 'Var', (231, 244))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CDC27', 'Gene', '996', (179, 184))	('FSIP2', 'Gene', '401024', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
2941	27584029	These authors also reported missense mutations in the DNA repair gene XRCC2 in two treatment-resistant tumors, implying that impaired DNA repair may lead to cisplatin resistance.	('cisplatin resistance', 'MPA', (157, 177))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('missense mutations', 'Var', (28, 46))	('XRCC2', 'Gene', '7516', (70, 75))	('men', 'Species', '9606', (88, 91))	('XRCC2', 'Gene', (70, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('lead to', 'Reg', (149, 156))
2942	27584029	Another study which performed whole exome sequencing on 8 patients with seminoma found a total of 98 novel and distinct gene mutations, in addition to well-known KIT and KRAS mutations.	('mutations', 'Var', (125, 134))	('KRAS', 'Gene', (170, 174))	('seminoma', 'Disease', 'MESH:D018239', (72, 80))	('KRAS', 'Gene', '3845', (170, 174))	('patients', 'Species', '9606', (58, 66))	('seminoma', 'Disease', (72, 80))
2946	27584029	Certain polymorphisms, including GSTP1, are associated with the development of neurotoxicity though genetic predisposition factors for the development of long-term sequelae of chemotherapy have not been identified for most treatment-related toxicities.	('toxicities', 'Disease', (241, 251))	('neurotoxicity', 'Disease', (79, 92))	('GSTP1', 'Gene', '2950', (33, 38))	('men', 'Species', '9606', (71, 74))	('men', 'Species', '9606', (146, 149))	('toxicities', 'Disease', 'MESH:D064420', (241, 251))	('men', 'Species', '9606', (228, 231))	('neurotoxicity', 'Disease', 'MESH:D020258', (79, 92))	('polymorphisms', 'Var', (8, 21))	('GSTP1', 'Gene', (33, 38))	('associated with', 'Reg', (44, 59))
2956	27584029	Epigenetic modifications in DNA or associated proteins beyond the DNA sequence itself are recognized to play a role in the development of many malignancies, including TGCT development and associated with chemotherapy resistance.	('men', 'Species', '9606', (179, 182))	('role', 'Reg', (111, 115))	('associated', 'Reg', (188, 198))	('malignancies', 'Disease', 'MESH:D009369', (143, 155))	('proteins', 'Protein', (46, 54))	('DNA', 'Gene', (28, 31))	('malignancies', 'Disease', (143, 155))	('play', 'Reg', (104, 108))	('Epigenetic modifications', 'Var', (0, 24))	('TGCT development', 'Disease', (167, 183))	('men', 'Species', '9606', (130, 133))
2959	27584029	found that RASSF1A and HIC1 promoter hypermethylation was associated with cisplatin-resistance, while MGMT and RARB promoter hypermethylation was associated with cisplatin sensitivity.	('RARB', 'Gene', (111, 115))	('HIC1', 'Gene', '3090', (23, 27))	('associated', 'Reg', (58, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('RASSF1A', 'Gene', (11, 18))	('promoter hypermethylation', 'Var', (28, 53))	('cisplatin-resistance', 'MPA', (74, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('RASSF1A', 'Gene', '11186', (11, 18))	('RARB', 'Gene', '5915', (111, 115))	('MGMT', 'Gene', (102, 106))	('MGMT', 'Gene', '4255', (102, 106))	('HIC1', 'Gene', (23, 27))	('associated', 'Reg', (146, 156))
2964	27584029	Furthermore, a cell line from this tumor specimen demonstrated cisplatin sensitivity after demethylation with 5-azacytidine.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('demonstrated', 'Reg', (50, 62))	('demethylation', 'Var', (91, 104))	('tumor', 'Disease', (35, 40))	('men', 'Species', '9606', (46, 49))	('cisplatin sensitivity', 'MPA', (63, 84))	('5-azacytidine', 'Chemical', 'MESH:D001374', (110, 123))
2965	27584029	miRNA 449a and 449b, which are believed to suppress cell proliferation through various p53 dependent and independent mechanisms, are decreased in TGCT specimens compared to normal testes.	('miRNA 449a', 'Var', (0, 10))	('449b', 'Var', (15, 19))	('cell proliferation', 'CPA', (52, 70))	('men', 'Species', '9606', (156, 159))	('suppress', 'NegReg', (43, 51))	('TGCT', 'Disease', (146, 150))	('decreased', 'NegReg', (133, 142))
2966	27584029	Promoter hypermethylation of miRNA 199a has been implicated in the upregulation of PODXL, an anti-adhesion protein expressed in TGCT and implicated in development of invasiveness and metastasis.	('PODXL', 'Gene', '5420', (83, 88))	('PODXL', 'Gene', (83, 88))	('upregulation', 'PosReg', (67, 79))	('invasiveness', 'Disease', 'MESH:D009362', (166, 178))	('miRNA 199a', 'Gene', (29, 39))	('invasiveness', 'Disease', (166, 178))	('men', 'Species', '9606', (158, 161))	('Promoter hypermethylation', 'Var', (0, 25))
2980	27584029	Furthermore, they confirmed the previous findings of gain of chromosome 12p, KIT mutations and also found novel mutations implicated in cisplatin-resistance.	('gain', 'PosReg', (53, 57))	('KIT', 'Gene', (77, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('mutations', 'Var', (81, 90))
2985	27584029	High rates of alterations within the TP53-MDM2 axis are seen in patients with platinum-resistant disease as are potentially actionable targets, including TP53-MDM2, PI3 Kinase, and MAPK signaling pathway alterations.	('alterations', 'Var', (14, 25))	('MDM2', 'Gene', (159, 163))	('TP53', 'Gene', (154, 158))	('patients', 'Species', '9606', (64, 72))	('platinum-resistant disease', 'Disease', (78, 104))	('platinum', 'Chemical', 'MESH:D010984', (78, 86))	('MDM2', 'Gene', '4193', (42, 46))	('MDM2', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('MAPK signaling pathway', 'Pathway', (181, 203))	('TP53', 'Gene', '7157', (154, 158))	('MDM2', 'Gene', '4193', (159, 163))
3000	28821959	Tumour cells exhibit higher levels of oxidative stress in comparison with normal cells, with a greater production of reactive oxygen species (ROS) secondary to their increased metabolic activity, abnormal mitochondrial function and oncogenic pressures.	('levels', 'MPA', (28, 34))	('oxidative stress', 'MPA', (38, 54))	('metabolic activity', 'CPA', (176, 194))	('increased', 'PosReg', (166, 175))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))	('oxidative stress', 'Phenotype', 'HP:0025464', (38, 54))	('abnormal mitochondrial function', 'Phenotype', 'HP:0003287', (196, 227))	('mitochondrial function', 'CPA', (205, 227))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (117, 140))	('production of reactive oxygen species', 'MPA', (103, 140))	('abnormal', 'Var', (196, 204))
3007	28821959	The kidneys are particularly susceptible to cisplatin toxicity, as they are almost exclusively responsible for its excretion.	('toxicity', 'Disease', (54, 62))	('cisplatin', 'Var', (44, 53))	('responsible', 'Reg', (95, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('toxicity', 'Disease', 'MESH:D064420', (54, 62))	('excretion', 'MPA', (115, 124))
3062	28821959	Increased levels of retinol-binding protein in the urine of paediatric patients receiving cisplatin suggest decreased physiological reabsorption indicative of tubular injury but do not provide information on prognosis.	('levels', 'MPA', (10, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('patients', 'Species', '9606', (71, 79))	('protein in the urine', 'Phenotype', 'HP:0000093', (36, 56))	('decreased', 'NegReg', (108, 117))	('tubular injury', 'Disease', 'MESH:D005198', (159, 173))	('physiological reabsorption', 'MPA', (118, 144))	('tubular injury', 'Disease', (159, 173))	('cisplatin', 'Var', (90, 99))
3079	28821959	This is despite evidence from both animal and clinical models that hypomagnesaemia may not only contribute to Cis-N but also that preventing hypomagnesaemia may even confer a degree of protection against cisplatin's nephrotoxic effects.	('nephrotoxic', 'Disease', (216, 227))	('hypomagnesaemia', 'Disease', (141, 156))	('Cis-N', 'Var', (110, 115))	('hypomagnesaemia', 'Disease', (67, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('nephrotoxic', 'Disease', 'MESH:D007674', (216, 227))	('contribute', 'Reg', (96, 106))	('hypomagnesaemia', 'Disease', 'None', (141, 156))	('Cis-N', 'Chemical', '-', (110, 115))	('hypomagnesaemia', 'Disease', 'None', (67, 82))
3081	28821959	Further, pretreatment magnesium supplementation in adult lung cancer patients has been demonstrated to reduce Cis-N, though specific mechanisms for this renoprotective effect are poorly understood.	('Cis-N', 'MPA', (110, 115))	('adult lung cancer', 'Disease', 'MESH:D008175', (51, 68))	('supplementation', 'Var', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('magnesium', 'Chemical', 'MESH:D008274', (22, 31))	('reduce', 'NegReg', (103, 109))	('patients', 'Species', '9606', (69, 77))	('Cis-N', 'Chemical', '-', (110, 115))	('adult lung cancer', 'Disease', (51, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
3084	28821959	While the long-term sequelae of Cis-N include longitudinal growth restriction, the role of hypomagnesaemia, either acute or chronic, within this purview is not understood.	('hypomagnesaemia', 'Disease', 'None', (91, 106))	('growth restriction', 'Phenotype', 'HP:0001510', (59, 77))	('Cis-N', 'Chemical', '-', (32, 37))	('hypomagnesaemia', 'Disease', (91, 106))	('Cis-N', 'Var', (32, 37))
3182	21366607	Taken together, this may indicate that the 15% from the latest birth cohort having less than 15 million/mL may get difficulties in fathering children by natural means and that the remaining 28% (difference up to 43%) that have less than 40 million/mL may experience a longer waiting time to pregnancy than men having higher sperm concentrations.	('men', 'Species', '9606', (306, 309))	('children', 'Species', '9606', (141, 149))	('less than 15 million/mL', 'Var', (83, 106))	('fathering children', 'CPA', (131, 149))
3219	20833340	In agreement with this assumption, recent candidate gene association analyses have identified the chromosome Y gr/gr deletion and mutations in the PDE11A gene as genetic modifiers of FTGCT risk.	('FTGCT', 'Disease', (183, 188))	('men', 'Species', '9606', (8, 11))	('PDE11A', 'Gene', '50940', (147, 153))	('PDE11A', 'Gene', (147, 153))	('mutations', 'Var', (130, 139))	('deletion', 'Var', (117, 125))
3232	20833340	Several observations indicate that heritable factors influence TGCT risk: (1) Approximately 1.4% of men with newly-diagnosed TGCT report a positive family history for this cancer; (2) Sons of men with TGCT have a 4-6 fold increase in TGCT risk, and brothers of men with TGCT have an 8-10 fold increased risk.	('men', 'Species', '9606', (261, 264))	('men', 'Species', '9606', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('TGCT', 'Disease', (234, 238))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('increase', 'PosReg', (222, 230))	('men', 'Species', '9606', (192, 195))	('cancer', 'Disease', (172, 178))	('TGCT', 'Var', (201, 205))
3264	20833340	The calculated perallele odds ratio for variants in the region of KITLG is the highest reported for any malignancy to date.	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('malignancy', 'Disease', (104, 114))	('variants', 'Var', (40, 48))	('KITLG', 'Gene', '4254', (66, 71))	('KITLG', 'Gene', (66, 71))
3272	20833340	Germline mutations in KIT and KITLG have been shown previously to be etiologically associated with several human diseases.	('Germline mutations', 'Var', (0, 18))	('human', 'Species', '9606', (107, 112))	('KIT', 'Gene', (22, 25))	('KITLG', 'Gene', '4254', (30, 35))	('KITLG', 'Gene', (30, 35))	('associated', 'Reg', (83, 93))	('etiologically', 'Reg', (69, 82))
3273	20833340	Germline KITLG mutations cause familial progressive hyperpigmentation, while KIT germline mutations are associated with familial gastrointestinal stromal tumors and familial diffuse cutaneous mastocytosis.	('cutaneous mastocytosis', 'Phenotype', 'HP:0200151', (182, 204))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (129, 160))	('KITLG', 'Gene', (9, 14))	('KITLG', 'Gene', '4254', (9, 14))	('mutations', 'Var', (15, 24))	('familial gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (120, 160))	('associated', 'Reg', (104, 114))	('familial diffuse cutaneous mastocytosis', 'Disease', (165, 204))	('mastocytosis', 'Phenotype', 'HP:0100495', (192, 204))	('cause', 'Reg', (25, 30))	('familial diffuse cutaneous mastocytosis', 'Disease', 'MESH:D034701', (165, 204))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('familial gastrointestinal stromal tumors', 'Disease', (120, 160))	('hyperpigmentation', 'Disease', 'MESH:D017495', (52, 69))	('progressive hyperpigmentation', 'Phenotype', 'HP:0007505', (40, 69))	('hyperpigmentation', 'Disease', (52, 69))
3275	20833340	In a murine model, on the other hand, loss of the transmembrane Kitl isoform increases susceptibility to TGCT (see below).	('TGCT', 'MPA', (105, 109))	('loss', 'Var', (38, 42))	('susceptibility', 'MPA', (87, 101))	('murine', 'Species', '10090', (5, 11))
3277	20833340	Finally, results of a loss of heterozygosity study, published in 1992, are consistent with a germline deletion of KITLG in a patient with TGCT; this patient's tumor (a seminoma) harbored a homozygous deletion in this gene.	('KITLG', 'Gene', '4254', (114, 119))	('KITLG', 'Gene', (114, 119))	('seminoma', 'Disease', 'MESH:D018239', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('deletion', 'Var', (102, 110))	('tumor', 'Disease', (159, 164))	('patient', 'Species', '9606', (149, 156))	('seminoma', 'Disease', (168, 176))	('patient', 'Species', '9606', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
3278	20833340	Revealing the mechanisms through which the recently-identified polymorphisms in KITLG, SPRY4 and BAK1 contribute to TGCT development has now emerged as a major scientific priority.	('KITLG', 'Gene', '4254', (80, 85))	('KITLG', 'Gene', (80, 85))	('men', 'Species', '9606', (128, 131))	('SPRY4', 'Gene', (87, 92))	('polymorphisms', 'Var', (63, 76))	('contribute', 'Reg', (102, 112))	('BAK1', 'Gene', '578', (97, 101))	('SPRY4', 'Gene', '81848', (87, 92))	('BAK1', 'Gene', (97, 101))
3283	20833340	Based on a previous finding that germline mutations in Dnd1 caused testicular tumors in strain 129 inbred mice, ITCLC investigators analyzed DND1, the human ortholog of this gene, in 434 familial and 671 sporadic human TGCT subjects.	('Dnd1', 'Gene', '213236', (55, 59))	('germline mutations', 'Var', (33, 51))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('human', 'Species', '9606', (213, 218))	('testicular tumors', 'Disease', 'MESH:D013736', (67, 84))	('mice', 'Species', '10090', (106, 110))	('human', 'Species', '9606', (151, 156))	('testicular tumors', 'Phenotype', 'HP:0010788', (67, 84))	('testicular tumor', 'Phenotype', 'HP:0010788', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DND1', 'Gene', (141, 145))	('DND1', 'Gene', '213236', (141, 145))	('caused', 'Reg', (60, 66))	('Dnd1', 'Gene', (55, 59))	('testicular tumors', 'Disease', (67, 84))
3285	20833340	Recognizing that male infertility is an established risk factor for sporadic testicular cancer, and that the E gr/gr deletion is the most commonly-identified genetic cause of male infertility, the Y chromosome gr/gr deletion has been studied as an TGCT risk factor.	('sporadic testicular cancer', 'Disease', 'MESH:D013736', (68, 94))	('sporadic testicular cancer', 'Disease', (68, 94))	('male infertility', 'Phenotype', 'HP:0003251', (17, 33))	('testicular cancer', 'Phenotype', 'HP:0010788', (77, 94))	('male infertility', 'Disease', 'MESH:D007248', (17, 33))	('male infertility', 'Phenotype', 'HP:0003251', (175, 191))	('male infertility', 'Disease', (175, 191))	('male infertility', 'Disease', 'MESH:D007248', (175, 191))	('male infertility', 'Disease', (17, 33))	('infertility', 'Phenotype', 'HP:0000789', (180, 191))	('infertility', 'Phenotype', 'HP:0000789', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cause', 'Reg', (166, 171))	('E gr/gr', 'Gene', (109, 116))	('deletion', 'Var', (117, 125))
3286	20833340	This ~1.6 Mb deletion deletes parts of the AZoospermia Factor c (AZFc) region of the Y chromosome, but the breakpoints vary among patients.	('AZoospermia', 'Phenotype', 'HP:0000027', (43, 54))	('AZoospermia Factor c', 'Disease', 'MESH:D053713', (43, 63))	('deletion', 'Var', (13, 21))	('patients', 'Species', '9606', (130, 138))	('AZoospermia Factor c', 'Disease', (43, 63))	('deletes', 'NegReg', (22, 29))
3290	20833340	Pde11a null mice are infertile, and germline variations in this gene have been implicated in adrenal gland neoplasia.	('infertile', 'Disease', 'MESH:D007247', (21, 30))	('Pde11a', 'Gene', '241489', (0, 6))	('adrenal gland neoplasia', 'Phenotype', 'HP:0100631', (93, 116))	('mice', 'Species', '10090', (12, 16))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('adrenal gland neoplasia', 'Disease', 'MESH:D000307', (93, 116))	('infertile', 'Disease', (21, 30))	('Pde11a', 'Gene', (0, 6))	('implicated', 'Reg', (79, 89))	('adrenal gland neoplasia', 'Disease', (93, 116))	('germline variations', 'Var', (36, 55))
3292	20833340	The prevalence of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (p = 0.0002) than controls; they were detected in 19% of the families studied.	('TGCT', 'Disease', (99, 103))	('higher', 'Reg', (72, 78))	('PDE11A', 'Gene', (22, 28))	('variants', 'Var', (34, 42))	('patients', 'Species', '9606', (85, 93))	('PDE11A', 'Gene', '50940', (22, 28))
3293	20833340	Functional studies showed that all these mutations decreased phosphodiesterase activity, and that PDE11A protein expression was reduced or undetectable in TGCT tumor tissue from subjects carrying these variants.	('mutations', 'Var', (41, 50))	('expression', 'MPA', (113, 123))	('undetectable', 'NegReg', (139, 151))	('PDE11A', 'Gene', '50940', (98, 104))	('variants', 'Var', (202, 210))	('reduced', 'NegReg', (128, 135))	('PDE11A', 'Gene', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('decreased', 'NegReg', (51, 60))	('phosphodiesterase', 'Gene', (61, 78))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('protein', 'Protein', (105, 112))	('tumor', 'Disease', (160, 165))	('phosphodiesterase', 'Gene', '50940;241489', (61, 78))
3294	20833340	We concluded that PDE11A-inactivating sequence variants appear to modify the risk of familial TGCT.	('familial TGCT', 'Disease', (85, 98))	('variants', 'Var', (47, 55))	('PDE11A', 'Gene', (18, 24))	('PDE11A', 'Gene', '50940', (18, 24))	('modify', 'Reg', (66, 72))
3295	20833340	Interestingly, some of the somatic changes detected in TGCT affect the KIT-KITLG signaling pathway, indicating that germline variations in this pathway may pave the way for somatic alterations.	('TGCT', 'Gene', (55, 59))	('KITLG', 'Gene', '4254', (75, 80))	('KITLG', 'Gene', (75, 80))	('affect', 'Reg', (60, 66))	('changes', 'Var', (35, 42))
3297	20833340	We hypothesize that germline variants deregulate KIT-KITLG signaling, creating a microenvironment in the developing testis in which the acquisition of somatic mutations confers a selective growth advantage to primordial germ cells.	('KITLG', 'Gene', '4254', (53, 58))	('men', 'Species', '9606', (93, 96))	('mutations', 'Var', (159, 168))	('deregulate', 'Reg', (38, 48))	('KITLG', 'Gene', (53, 58))	('variants', 'Var', (29, 37))	('growth advantage', 'CPA', (189, 205))
3298	20833340	Among the large number of known cytogenetic abnormalities, alterations affecting chromosome 12p are the only recurrent structural changes in TGCT; most tumors are characterized by one or several copies of isochromosme 12p (i(12p)).	('alterations', 'Var', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('isochromosme', 'Var', (205, 217))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
3299	20833340	Of note, spermatocytic seminoma, which occurs typically in older men and which has not been reported in FTGCT, has been recently shown to originate from mutations in FGFR3 and HRAS.	('men', 'Species', '9606', (65, 68))	('mutations', 'Var', (153, 162))	('HRAS', 'Gene', '3265', (176, 180))	('FGFR3', 'Gene', '2261', (166, 171))	('spermatocytic seminoma', 'Disease', (9, 31))	('HRAS', 'Gene', (176, 180))	('spermatocytic seminoma', 'Phenotype', 'HP:0100617', (9, 31))	('FGFR3', 'Gene', (166, 171))	('originate from', 'Reg', (138, 152))	('spermatocytic seminoma', 'Disease', 'MESH:C563236', (9, 31))
3300	20833340	Interestingly, moderately activating mutations in the same genes also occur in the male germline and can lead to rare developmental syndromes (e.g., Apert and Costello syndromes) in the offspring.	('activating', 'PosReg', (26, 36))	('lead to', 'Reg', (105, 112))	('men', 'Species', '9606', (125, 128))	('mutations', 'Var', (37, 46))	('Apert', 'Disease', (149, 154))
3304	20833340	However, several known genetic variants act as modifiers of TGCT susceptibility on the 129/Sv background.	('129/Sv', 'Species', '10090', (87, 93))	('TGCT', 'Disease', (60, 64))	('variants', 'Var', (31, 39))	('modifiers', 'Reg', (47, 56))
3305	20833340	Variants that increase the risk of TGCT in 129/Sv mice include Dnd1Ter (point mutation in Dnd1), KitSl, KitlSlJ, and KitlSlgb (different deletions of Kitl), while the Ay variant (a contiguous deletion affecting the three genes Raly, Eif2s2 and Agouti) decreases TGCT incidence.	('Variants', 'Var', (0, 8))	('Dnd1', 'Gene', (90, 94))	('Dnd1', 'Gene', '213236', (90, 94))	('Dnd1', 'Gene', (63, 67))	('TGCT', 'Disease', (262, 266))	('129/Sv', 'Species', '10090', (43, 49))	('TGCT', 'Disease', (35, 39))	('mice', 'Species', '10090', (50, 54))	('decreases', 'NegReg', (252, 261))	('Dnd1', 'Gene', '213236', (63, 67))
3306	20833340	Finally, it has been shown that genetic variants may act epistatically to modulate TGCT susceptibility in the 129/Sv strain.	('TGCT', 'Disease', (83, 87))	('variants', 'Var', (40, 48))	('modulate', 'Reg', (74, 82))	('129/Sv', 'Species', '10090', (110, 116))
3311	20833340	Participants were more likely to be interested in genetic testing if they were younger and had higher levels of family support, a physician's recommendation supporting testing, cancer distress, and a need for information to inform the health care of their children.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('higher', 'PosReg', (95, 101))	('Participants', 'Species', '9606', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('children', 'Species', '9606', (256, 264))	('genetic testing', 'Var', (50, 65))	('men', 'Species', '9606', (147, 150))	('family support', 'CPA', (112, 126))
3320	20833340	Candidate gene studies have implicated the chromosome Y gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT.	('FTGCT', 'Disease', (121, 126))	('PDE11A', 'Gene', (75, 81))	('PDE11A', 'Gene', '50940', (75, 81))	('deletion', 'Var', (62, 70))	('mutations', 'Var', (87, 96))
3329	20833340	Identifying additional genetic factors contributing to TGCT; Identifying the functional variants in KITLG, SPRY4, and BAK1; Confirming the role of PDE11A and the chromosome Y gr/gr deletion in TGCT; Clarifying the complex interplay between germline and somatic genetics in TGCT; Assessing the role of epigenetic changes and other mechanisms such as copy number variations in the pathogenesis of TGCT; and Translating genetic findings into better patient care.	('BAK1', 'Gene', (118, 122))	('PDE11A', 'Gene', '50940', (147, 153))	('patient', 'Species', '9606', (446, 453))	('SPRY4', 'Gene', (107, 112))	('KITLG', 'Gene', '4254', (100, 105))	('BAK1', 'Gene', '578', (118, 122))	('TGCT', 'Disease', (55, 59))	('PDE11A', 'Gene', (147, 153))	('SPRY4', 'Gene', '81848', (107, 112))	('copy number variations', 'Var', (349, 371))	('deletion', 'Var', (181, 189))	('variants', 'Var', (88, 96))	('contributing', 'Reg', (39, 51))	('KITLG', 'Gene', (100, 105))
3337	31296530	Patients with high residual platinum levels experienced greater Raynaud's phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, p = 0.07).	("Raynaud's phenomenon", 'Phenotype', 'HP:0030880', (64, 84))	('tinnitus', 'Disease', (211, 219))	("Raynaud's phenomenon", 'Disease', 'MESH:D011928', (64, 84))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	("Raynaud's phenomenon", 'Disease', (64, 84))	('tinnitus', 'Disease', 'MESH:D014012', (211, 219))	('tinnitus', 'Phenotype', 'HP:0000360', (211, 219))	('platinum', 'Chemical', 'MESH:D010984', (28, 36))
3403	31296530	Of the 1,010 TCS, 436 and 574 (43.2% and 56.8%, respectively) were treated with 300+-15 and 400+-15 mg/m2 cisplatin, respectively.	('300+-15', 'Var', (80, 87))	('TCS', 'Chemical', '-', (13, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('400+-15 mg/m2', 'Var', (92, 105))
3423	31296530	In considering the severity of the toxicity, a higher proportion of patients who experienced more severe toxicity was demonstrated in the high residual platinum value group when compared to the low or medium groups for CBM score (Figure 3A), peripheral sensory neuropathy (Figure 3B) and Raynaud's phenomenon (Figure 3C).	('peripheral sensory neuropathy', 'Disease', 'MESH:D010523', (242, 271))	('peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (242, 271))	('CBM score', 'Gene', (219, 228))	('platinum', 'Chemical', 'MESH:D010984', (152, 160))	('toxicity', 'Disease', 'MESH:D064420', (35, 43))	('neuropathy', 'Phenotype', 'HP:0009830', (261, 271))	('toxicity', 'Disease', (35, 43))	("Raynaud's phenomenon", 'Disease', (288, 308))	("Raynaud's phenomenon", 'Disease', 'MESH:D011928', (288, 308))	('patients', 'Species', '9606', (68, 76))	("Raynaud's phenomenon", 'Phenotype', 'HP:0030880', (288, 308))	('sensory neuropathy', 'Phenotype', 'HP:0000763', (253, 271))	('peripheral sensory neuropathy', 'Disease', (242, 271))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('high', 'Var', (138, 142))	('toxicity', 'Disease', (105, 113))
3424	31296530	In addition, patients with high residual platinum values were significantly more likely to have a higher CBM score (ORhigh/low = 1.26, p = 0.05), and peripheral sensory neuropathy (ORhigh/low = 1.61; p = 0.02, Supplemental Table 2), but not after adjusting for age (ORhigh/low = 1.13, p = 0.32 and ORhigh/low = 1.34; p = 0.17, respectively, Supplemental Table 3).	('CBM', 'Disease', (105, 108))	('peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (150, 179))	('sensory neuropathy', 'Phenotype', 'HP:0000763', (161, 179))	('patients', 'Species', '9606', (13, 21))	('peripheral sensory neuropathy', 'Disease', 'MESH:D010523', (150, 179))	('high', 'Var', (27, 31))	('higher', 'PosReg', (98, 104))	('platinum', 'Chemical', 'MESH:D010984', (41, 49))	('neuropathy', 'Phenotype', 'HP:0009830', (169, 179))	('peripheral sensory neuropathy', 'Disease', (150, 179))
3425	31296530	Patients with high residual platinum values were significantly more likely to have Raynaud's phenomenon (age-adjusted ORhigh/low = 1.46; p = 0.04, age and cisplatin dose-adjusted ORhigh/low = 1.45; p = 0.04).	("Raynaud's phenomenon", 'Disease', 'MESH:D011928', (83, 103))	("Raynaud's phenomenon", 'Disease', (83, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	("Raynaud's phenomenon", 'Phenotype', 'HP:0030880', (83, 103))	('platinum', 'Chemical', 'MESH:D010984', (28, 36))
3426	31296530	In regards to ototoxicity, patients with high residual platinum values had a higher likelihood of developing tinnitus (ORhigh/low = 1.69, p = 0.06), which remained marginally significant after adjusting for age at diagnosis (ORhigh/low = 1.68, p = 0.07), as well as age at diagnosis and cumulative cisplatin dose (ORhigh/low = 1.69, p = 0.07).	('tinnitus', 'Disease', (109, 117))	('ototoxicity', 'Disease', 'MESH:D006311', (14, 25))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('ototoxicity', 'Disease', (14, 25))	('tinnitus', 'Disease', 'MESH:D014012', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (298, 307))	('tinnitus', 'Phenotype', 'HP:0000360', (109, 117))	('platinum', 'Chemical', 'MESH:D010984', (55, 63))
3429	31296530	The SNP is in linkage disequilibrium with rs58754699 and rs113890379 (R2 = 1.0, p <0.0001), the next two most statistically significant genetic variants (p = 5.0x10-8 and 1.6x10-7, respectively).	('rs58754699', 'Mutation', 'rs58754699', (42, 52))	('rs113890379', 'Var', (57, 68))	('rs113890379', 'Mutation', 'rs113890379', (57, 68))	('rs58754699', 'Var', (42, 52))	('significant', 'Reg', (124, 135))
3441	31296530	Our data suggest that patients with high serum platinum levels are more susceptible to developing tinnitus and Raynaud's phenomenon than those with medium or low serum platinum levels, but does not provide robust associations with other toxicities, including cumulative burden of morbidity scores, hearing loss, and peripheral sensory neuropathy.	('tinnitus', 'Phenotype', 'HP:0000360', (98, 106))	('neuropathy', 'Phenotype', 'HP:0009830', (335, 345))	("Raynaud's phenomenon", 'Disease', 'MESH:D011928', (111, 131))	('patients', 'Species', '9606', (22, 30))	('peripheral sensory neuropathy', 'Phenotype', 'HP:0000763', (316, 345))	('hearing loss', 'Disease', (298, 310))	('peripheral sensory neuropathy', 'Disease', (316, 345))	('tinnitus', 'Disease', (98, 106))	('high', 'Var', (36, 40))	('platinum', 'Chemical', 'MESH:D010984', (168, 176))	('hearing loss', 'Phenotype', 'HP:0000365', (298, 310))	("Raynaud's phenomenon", 'Disease', (111, 131))	('toxicities', 'Disease', 'MESH:D064420', (237, 247))	('platinum', 'Chemical', 'MESH:D010984', (47, 55))	('peripheral sensory neuropathy', 'Disease', 'MESH:D010523', (316, 345))	('toxicities', 'Disease', (237, 247))	('sensory neuropathy', 'Phenotype', 'HP:0000763', (327, 345))	("Raynaud's phenomenon", 'Phenotype', 'HP:0030880', (111, 131))	('hearing loss', 'Disease', 'MESH:D034381', (298, 310))	('tinnitus', 'Disease', 'MESH:D014012', (98, 106))
3454	31296530	Further, multinomial regression indicated that patients with high levels of serum platinum were more likely to develop tinnitus, suggesting these individuals are at an increased risk of developing this off-target toxicity.	('patients', 'Species', '9606', (47, 55))	('toxicity', 'Disease', 'MESH:D064420', (213, 221))	('develop', 'PosReg', (111, 118))	('toxicity', 'Disease', (213, 221))	('tinnitus', 'Disease', (119, 127))	('high levels', 'Var', (61, 72))	('platinum', 'Chemical', 'MESH:D010984', (82, 90))	('tinnitus', 'Disease', 'MESH:D014012', (119, 127))	('tinnitus', 'Phenotype', 'HP:0000360', (119, 127))
3457	31296530	It is plausible that there are differences in the pathophysiology underlying cisplatin-induced hearing loss and tinnitus, as recent studies have indicated the development of tinnitus is more dependent on disruptions in the balance of excitatory and inhibitory nerve transmission within central auditory structures than pathology in the cochlea.	('tinnitus', 'Phenotype', 'HP:0000360', (112, 120))	('tinnitus', 'Phenotype', 'HP:0000360', (174, 182))	('hearing loss and tinnitus', 'Disease', 'MESH:D014012', (95, 120))	('hearing loss', 'Phenotype', 'HP:0000365', (95, 107))	('tinnitus', 'Disease', (112, 120))	('tinnitus', 'Disease', (174, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('tinnitus', 'Disease', 'MESH:D014012', (112, 120))	('tinnitus', 'Disease', 'MESH:D014012', (174, 182))	('disruptions', 'Var', (204, 215))
3471	31296530	Interestingly, a mutation in MYH14 has previously been associated with an autosomal dominant disorder of peripheral neuropathy, myopathy, hoarseness, and hearing loss, indicating that the gene could also potentially influence two prominent cisplatin-induced toxicities (peripheral neuropathy and hearing loss).	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (105, 126))	('MYH14', 'Gene', (29, 34))	('hearing loss', 'Disease', 'MESH:D034381', (154, 166))	('peripheral neuropathy', 'Disease', (270, 291))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (270, 291))	('hearing loss', 'Disease', 'MESH:D034381', (296, 308))	('mutation', 'Var', (17, 25))	('myopathy', 'Disease', 'MESH:D009135', (128, 136))	('neuropathy', 'Phenotype', 'HP:0009830', (116, 126))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (270, 291))	('hoarseness', 'Disease', (138, 148))	('associated with', 'Reg', (55, 70))	('hearing loss', 'Disease', (154, 166))	('hoarseness', 'Phenotype', 'HP:0001609', (138, 148))	('hearing loss', 'Disease', (296, 308))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (105, 126))	('neuropathy', 'Phenotype', 'HP:0009830', (281, 291))	('peripheral neuropathy', 'Disease', (105, 126))	('autosomal dominant disorder of peripheral neuropathy', 'Disease', 'MESH:D010523', (74, 126))	('toxicities', 'Disease', 'MESH:D064420', (258, 268))	('hearing loss', 'Phenotype', 'HP:0000365', (154, 166))	('influence', 'Reg', (216, 225))	('myopathy', 'Phenotype', 'HP:0003198', (128, 136))	('myopathy', 'Disease', (128, 136))	('hearing loss', 'Phenotype', 'HP:0000365', (296, 308))	('toxicities', 'Disease', (258, 268))
3482	31296530	In addition, our GWAS identified rs1377817 (p=4.6x10-8), a SNP intronic to MYH14, to be associated with residual platinum values, suggesting that genetic variation may predispose certain patients to high residual platinum values for years after treatment has been completed.	('predispose', 'Reg', (168, 178))	('patients', 'Species', '9606', (187, 195))	('rs1377817', 'Var', (33, 42))	('platinum', 'Chemical', 'MESH:D010984', (113, 121))	('associated', 'Reg', (88, 98))	('rs1377817', 'Mutation', 'rs1377817', (33, 42))	('platinum', 'Chemical', 'MESH:D010984', (213, 221))
3483	31296530	BEP bleomycin, etoposide, and cisplatin CBC cisplatin-based chemotherapy CBM cumulative burden of morbidity EP etoposide and cisplatin GWAS genome-wide association study LDL low-density lipoprotein cholesterol LH luteinizing hormone QC quality control SNP single nucleotide polymorphism TCS testicular cancer survivors VeIP vinblastine, ifosfamide, and cisplatin VIP etoposide, ifosfamide, and cisplatin AUC area under the concentration-time curve Although curative in many settings, cisplatin can elicit severe, often irreversible toxicities that impact long-term survivors' quality of life.	('etoposide', 'Chemical', 'MESH:D005047', (111, 120))	('testicular cancer', 'Phenotype', 'HP:0010788', (291, 308))	('etoposide', 'Chemical', 'MESH:D005047', (15, 24))	('BEP', 'Chemical', 'MESH:C038328', (0, 3))	('cisplatin', 'Var', (484, 493))	('LH', 'Chemical', 'MESH:D007986', (210, 212))	('VIP', 'Gene', '7432', (363, 366))	('cancer', 'Disease', (302, 308))	('cisplatin', 'Chemical', 'MESH:D002945', (484, 493))	('vinblastine', 'Chemical', 'MESH:D014747', (324, 335))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('LDL low', 'Phenotype', 'HP:0003563', (170, 177))	('VIP', 'Gene', (363, 366))	('VeIP', 'Chemical', '-', (319, 323))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('toxicities', 'Disease', 'MESH:D064420', (532, 542))	('impact', 'Reg', (548, 554))	('etoposide', 'Chemical', 'MESH:D005047', (367, 376))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('toxicities', 'Disease', (532, 542))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (394, 403))	('bleomycin', 'Chemical', 'MESH:D001761', (4, 13))	('TCS', 'Chemical', '-', (287, 290))	('ifosfamide', 'Chemical', 'MESH:D007069', (378, 388))	('ifosfamide', 'Chemical', 'MESH:D007069', (337, 347))	('elicit', 'Reg', (498, 504))	('quality of life', 'CPA', (576, 591))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (353, 362))
3490	24451139	Genetic Variants of GPER/GPR30, a Novel Estrogen-Related G Protein Receptor, Are Associated with Human Seminoma Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years.	('germ cell tumor', 'Phenotype', 'HP:0100728', (123, 138))	('GPER', 'Gene', '2852', (20, 24))	('Testicular germ cell tumors', 'Disease', (112, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('solid cancers', 'Disease', (168, 181))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('men', 'Species', '9606', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Human Seminoma', 'Disease', 'MESH:D018239', (97, 111))	('GPER', 'Gene', (20, 24))	('Associated', 'Reg', (81, 91))	('germ cell tumors', 'Phenotype', 'HP:0100728', (123, 139))	('GPR30', 'Gene', (25, 30))	('GPR30', 'Gene', '2852', (25, 30))	('Variants', 'Var', (8, 16))	('Testicular germ cell tumors', 'Disease', 'MESH:C563236', (112, 139))	('solid cancers', 'Disease', 'MESH:D009369', (168, 181))	('Human Seminoma', 'Disease', (97, 111))
3494	24451139	Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351) was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172-3.277) and 7.000 (2.747-17.840); p < 0.01).	('rs3808351', 'Mutation', 'rs3808351', (148, 157))	('rs3808351', 'Var', (148, 157))	('non-seminomas', 'Disease', (201, 214))	('seminomas', 'Disease', 'MESH:D018239', (180, 189))	('seminomas', 'Disease', (180, 189))	('GPER', 'Gene', '2852', (128, 132))	('seminomas', 'Disease', 'MESH:D018239', (205, 214))	('seminomas', 'Disease', (205, 214))	('rs3808350', 'Mutation', 'rs3808350', (134, 143))	('GPER', 'Gene', (128, 132))	('non-seminomas', 'Disease', 'MESH:D018239', (201, 214))	('rs3808350', 'Var', (134, 143))
3495	24451139	These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis.	('overexpression', 'PosReg', (37, 51))	('testicular carcinogenesis', 'Disease', 'MESH:D063646', (162, 187))	('GPER', 'Gene', '2852', (146, 150))	('polymorphisms', 'Var', (6, 19))	('testicular carcinogenesis', 'Disease', (162, 187))	('men', 'Species', '9606', (139, 142))	('GPER', 'Gene', '2852', (32, 36))	('GPER', 'Gene', (146, 150))	('GPER', 'Gene', (32, 36))
3504	24451139	Indeed, E2-BSA was able to promote JKT-1 cell proliferation in vitro by activating PKA and MAP kinases pathways due to a rapid phosphorylation of CREB transcription factor, involving a membrane G protein-coupled receptor (GPCR).	('E2-BSA', 'Var', (8, 14))	('phosphorylation', 'MPA', (127, 142))	('G protein-coupled receptor', 'Gene', (194, 220))	('GPCR', 'Gene', (222, 226))	('JKT-1 cell proliferation', 'CPA', (35, 59))	('G protein-coupled receptor', 'Gene', '151', (194, 220))	('JKT-1', 'CellLine', 'CVCL:T011', (35, 40))	('promote', 'PosReg', (27, 34))	('activating', 'PosReg', (72, 82))	('CREB', 'Gene', (146, 150))	('rat', 'Species', '10116', (53, 56))	('MAP kinases pathways', 'Pathway', (91, 111))	('CREB', 'Gene', '1385', (146, 150))	('GPCR', 'Gene', '151', (222, 226))
3516	24451139	As we previously reported, the co-localization of GPER with E2-BSA-FITC, which does not cross the membrane, strongly supported the membrane location of GPER in JKT-1 seminoma-derived cells.	('E2-BSA-FITC', 'Var', (60, 71))	('seminoma', 'Disease', 'MESH:D018239', (166, 174))	('FITC', 'Chemical', 'MESH:D016650', (67, 71))	('GPER', 'Gene', '2852', (152, 156))	('GPER', 'Gene', '2852', (50, 54))	('seminoma', 'Disease', (166, 174))	('JKT-1', 'CellLine', 'CVCL:T011', (160, 165))	('GPER', 'Gene', (152, 156))	('GPER', 'Gene', (50, 54))
3520	24451139	After 24-h exposure at a physiological intra-testicular concentration of 10-9 M, E2 induced a significant decrease in cell proliferation, whereas E2-BSA, at the same concentration, stimulated JKT-1 cell proliferation.	('rat', 'Species', '10116', (173, 176))	('E2-BSA', 'Var', (146, 152))	('JKT-1', 'CellLine', 'CVCL:T011', (192, 197))	('decrease', 'NegReg', (106, 114))	('rat', 'Species', '10116', (130, 133))	('cell proliferation', 'CPA', (118, 136))	('stimulated', 'PosReg', (181, 191))	('rat', 'Species', '10116', (210, 213))	('rat', 'Species', '10116', (63, 66))	('JKT-1 cell proliferation', 'CPA', (192, 216))
3521	24451139	As we previously reported, this E2-BSA specific effect was not inhibited by ICI-182,780, a pure ER antagonist, but was reversed by Pertussis toxin, a G protein inhibitor, we hypothesized that E2-BSA directly interacted with GPER to induce JKT-1 cell proliferation (Figure 2).	('GPER', 'Gene', '2852', (224, 228))	('interacted', 'Interaction', (208, 218))	('GPER', 'Gene', (224, 228))	('rat', 'Species', '10116', (257, 260))	('E2-BSA', 'Var', (192, 198))	('JKT-1', 'CellLine', 'CVCL:T011', (239, 244))	('JKT-1 cell proliferation', 'CPA', (239, 263))	('induce', 'PosReg', (232, 238))
3531	24451139	One explanation for this overexpression could be single nucleotide polymorphisms (SNPs), which are the most frequent genetic variations in genomic sequences and are widely associated with human diseases and TGCTs.	('single nucleotide polymorphisms', 'Var', (49, 80))	('human', 'Species', '9606', (188, 193))	('associated', 'Reg', (172, 182))
3533	24451139	NM_001039966), only four were reported to be associated with human neoplasms, according to the internet database The first of these four SNPs has been reported in gastric cancer and creates an alternative splice site that produces a frameshift protein with no cellular relevance.	('gastric cancer', 'Disease', (163, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (67, 76))	('SNPs', 'Var', (137, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('neoplasms', 'Disease', 'MESH:D009369', (67, 76))	('human', 'Species', '9606', (61, 66))	('neoplasms', 'Disease', (67, 76))	('produces', 'Reg', (222, 230))	('reported', 'Reg', (151, 159))
3535	24451139	These three SNPs have higher biological relevance, with two of them being located in the 5' region of the GPER gene (SNP rs3808350 located in the 5'-regulatory region and SNP rs3808351 located in the 5'-untranslated region and containing the gene promoter), which might affect its expression levels (Figure 5).	('rs3808350', 'Mutation', 'rs3808350', (121, 130))	('GPER', 'Gene', '2852', (106, 110))	('SNP rs3808351', 'Var', (171, 184))	('GPER', 'Gene', (106, 110))	('affect', 'Reg', (270, 276))	('SNP rs3808350', 'Var', (117, 130))	('rs3808351', 'Mutation', 'rs3808351', (175, 184))	('expression levels', 'MPA', (281, 298))
3536	24451139	The third SNP results in an amino acid exchange (p.Pro16Leu) in the only coding exon (exon 3) of the GPER gene, which might alter GPER protein structure and function.	('GPER', 'Gene', '2852', (130, 134))	('function', 'MPA', (157, 165))	('amino acid exchange', 'Var', (28, 47))	('GPER', 'Gene', (130, 134))	('GPER', 'Gene', '2852', (101, 105))	('p.Pro16Leu', 'Mutation', 'rs11544331', (49, 59))	('alter', 'Reg', (124, 129))	('GPER', 'Gene', (101, 105))	('results in', 'Reg', (14, 24))
3540	24451139	Due to this degradation, genotyping could only be performed in 89 patients for SNP rs3808350 (81 seminomas and eight non-seminomas, respectively), 100 patients for SNP rs3808351 (91 and nine) and 123 patients for SNP rs11544331 (115 and eight), leading to genotyping success rates of 61.8%, 69.5%, and 87.8% for seminomas and 42.1%, 47.3%, and 42.3% for non-seminomas, respectively.	('seminomas', 'Disease', 'MESH:D018239', (358, 367))	('SNP rs3808351', 'Var', (164, 177))	('seminomas', 'Disease', (358, 367))	('rat', 'Species', '10116', (275, 278))	('rs3808350', 'Mutation', 'rs3808350', (83, 92))	('rs3808351', 'Mutation', 'rs3808351', (168, 177))	('seminomas', 'Disease', 'MESH:D018239', (312, 321))	('seminomas', 'Disease', (312, 321))	('patients', 'Species', '9606', (66, 74))	('seminomas', 'Disease', 'MESH:D018239', (121, 130))	('patients', 'Species', '9606', (200, 208))	('seminomas', 'Disease', 'MESH:D018239', (97, 106))	('seminomas', 'Disease', (97, 106))	('non-seminomas', 'Disease', (117, 130))	('non-seminomas', 'Disease', (354, 367))	('seminomas', 'Disease', (121, 130))	('patients', 'Species', '9606', (151, 159))	('SNP rs3808350', 'Var', (79, 92))	('non-seminomas', 'Disease', 'MESH:D018239', (354, 367))	('rs11544331', 'Mutation', 'rs11544331', (217, 227))	('non-seminomas', 'Disease', 'MESH:D018239', (117, 130))
3542	24451139	We first analyzed a missense SNP (rs11544331; (c.47 C > T), located in the only coding exon (exon 3) of GPER gene, which leads to an amino-acid (p.Pro16Leu) exchange.	('c.47 C > T', 'Mutation', 'rs11544331', (47, 57))	('GPER', 'Gene', '2852', (104, 108))	('rs11544331;', 'Var', (34, 45))	('leads to', 'Reg', (121, 129))	('rs11544331', 'Mutation', 'rs11544331', (34, 44))	('GPER', 'Gene', (104, 108))	('p.Pro16Leu', 'Mutation', 'rs11544331', (145, 155))	('amino-acid', 'MPA', (133, 143))
3543	24451139	Such an exchange might alter GPER protein structure and its function, but not its expression.	('GPER', 'Gene', (29, 33))	('alter', 'Reg', (23, 28))	('GPER', 'Gene', '2852', (29, 33))	('exchange', 'Var', (8, 16))	('function', 'MPA', (60, 68))
3548	24451139	The homozygous AA genotype of the SNP rs3808350 in the 5'-untranslated region and the SNP rs3808351 in the 5'-regulatory region were both significantly more common in seminoma patients than in the control population, suggesting that homozygous ancestral genotype GG could exert relative protective effects on tumor development.	('patients', 'Species', '9606', (176, 184))	('seminoma', 'Disease', 'MESH:D018239', (167, 175))	('tumor', 'Disease', (309, 314))	('SNP', 'Var', (86, 89))	('rs3808351', 'Mutation', 'rs3808351', (90, 99))	('seminoma', 'Disease', (167, 175))	('SNP rs3808350', 'Var', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('men', 'Species', '9606', (322, 325))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('common', 'Reg', (157, 163))	('rs3808350', 'Mutation', 'rs3808350', (38, 47))
3553	24451139	We found no difference from the control population for SNP rs3808350 (genotype AG), but an homozygous carriage of minor allele A for SNP rs3808351, as more frequently observed in the tumoral samples; this genotype could also explain GPER expression in germ cell tumors.	('SNP rs3808351', 'Var', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('GPER', 'Gene', '2852', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (262, 268))	('GPER', 'Gene', (233, 237))	('rs3808351', 'Mutation', 'rs3808351', (137, 146))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('germ cell tumors', 'Phenotype', 'HP:0100728', (252, 268))	('rs3808350', 'Mutation', 'rs3808350', (59, 68))	('tumoral', 'Disease', (183, 190))	('tumoral', 'Disease', 'MESH:D009369', (183, 190))	('germ cell tumor', 'Phenotype', 'HP:0100728', (252, 267))
3587	24451139	Allele-specific PCR product sizes were as follows: 205/294 bp (A/G) for SNP rs3808350, 231/196 bp (A/G) for SNP rs3808351, and 198/231 bp (C/T) for SNP rs11544331.	('rs11544331', 'Mutation', 'rs11544331', (152, 162))	('rs3808350', 'Mutation', 'rs3808350', (76, 85))	('rs3808351', 'Mutation', 'rs3808351', (112, 121))	('SNP rs11544331', 'Var', (148, 162))	('SNP rs3808350', 'Var', (72, 85))	('SNP rs3808351', 'Var', (108, 121))
3588	24451139	SNP frequencies were compared with genotype frequencies determined in the HapMap project and reported on the internet database as follows: for SNP rs3808350, genotype frequencies are 0.366 (AA), 0.491 (AG), and 0.143 (GG), and allele frequencies are 0.612 (A) and 0.388 (G); for SNP rs3808351, genotype frequencies are 0.054 (AA), 0.514 (AG), and 0.432 (GG), and allele frequencies are 0.311 (A) and 0.689 (G); and for SNP rs11544331, genotype frequencies are 0.650 (CC), 0.302 (CT), and 0.048 (TT), and allele frequencies are 0.801 (C) and 0.199 (T).	('SNP rs11544331', 'Var', (419, 433))	('0.311', 'Var', (386, 391))	('rs3808351', 'Mutation', 'rs3808351', (283, 292))	('SNP rs3808351', 'Var', (279, 292))	('0.302', 'Var', (472, 477))	('rs11544331', 'Mutation', 'rs11544331', (423, 433))	('rs3808350', 'Mutation', 'rs3808350', (147, 156))
3593	24451139	One can suppose that the presence of such polymorphisms represent a genetic factor of susceptibility able to increase the risk of endocrine disruption, for example foetal exposure to bisphenol A, which seems to carry a high affinity for GPR30 expressed by germ stem cells.	('endocrine', 'MPA', (130, 139))	('foetal exposure', 'Phenotype', 'HP:0031437', (164, 179))	('GPR30', 'Gene', '2852', (237, 242))	('increase', 'PosReg', (109, 117))	('bisphenol A', 'Chemical', 'MESH:C006780', (183, 194))	('polymorphisms', 'Var', (42, 55))	('presence', 'Var', (25, 33))	('GPR30', 'Gene', (237, 242))
3600	20047465	The mutant line develops spontaneous testicular tumors at a median age of 7 months, and pedigree analysis indicates dominant inheritance of the germ cell tumor susceptibility trait.	('germ cell tumor', 'Phenotype', 'HP:0100728', (144, 159))	('tumor', 'Disease', (48, 53))	('mutant', 'Var', (4, 10))	('testicular tumors', 'Disease', 'MESH:D013736', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('testicular tumors', 'Phenotype', 'HP:0010788', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('testicular tumor', 'Phenotype', 'HP:0010788', (37, 53))	('testicular tumors', 'Disease', (37, 54))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (154, 159))
3605	20047465	In humans, aberrations in germ cell development are linked to gonadal dysgenesis, infertility and germ cell tumors.	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (62, 80))	('aberrations', 'Var', (11, 22))	('linked', 'Reg', (52, 58))	('infertility', 'Disease', (82, 93))	('gonadal dysgenesis', 'Disease', (62, 80))	('germ cell tumors', 'Disease', 'MESH:D009373', (98, 114))	('germ cell tumors', 'Phenotype', 'HP:0100728', (98, 114))	('germ cell tumor', 'Phenotype', 'HP:0100728', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (62, 80))	('germ cell development', 'CPA', (26, 47))	('humans', 'Species', '9606', (3, 9))	('germ cell tumors', 'Disease', (98, 114))	('men', 'Species', '9606', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('infertility', 'Disease', 'MESH:D007247', (82, 93))	('aberrations in germ cell', 'Phenotype', 'HP:0012862', (11, 35))	('infertility', 'Phenotype', 'HP:0000789', (82, 93))
3618	20047465	Germinomas and non-germinomas appear to arise from a common precursor, the carcinoma in situ cell, share common chromosomal aberrations including isochromosome 12p and are frequently found together in mixed tumors.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (112, 135))	('isochromosome 12p', 'Var', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('carcinoma', 'Disease', 'MESH:D002277', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('non-germinomas', 'Disease', (15, 29))	('Germinomas', 'Disease', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (75, 92))	('tumors', 'Disease', (207, 213))	('Germinomas', 'Disease', 'MESH:D018237', (0, 10))	('non-germinomas', 'Disease', 'MESH:D018237', (15, 29))	('carcinoma', 'Disease', (75, 84))
3638	20047465	Here we describe the identification, through an ENU-based forward-genetic approach, of a mutant zebrafish line that spontaneously develops highly penetrant testicular germ cell tumors at an average age of 7 months.	('germ cell tumors', 'Disease', 'MESH:D009373', (167, 183))	('germ cell tumor', 'Phenotype', 'HP:0100728', (167, 182))	('zebrafish', 'Species', '7955', (96, 105))	('germ cell tumors', 'Disease', (167, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutant', 'Var', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('develops', 'PosReg', (130, 138))	('germ cell tumors', 'Phenotype', 'HP:0100728', (167, 183))
3639	20047465	The GCT-susceptibility trait was identified in carriers of the shortstop cell proliferation mutation, but we show that the trait is not linked to shortstop.	('shortstop', 'Gene', (146, 155))	('shortstop', 'Gene', '286832', (63, 72))	('mutation', 'Var', (92, 100))	('shortstop', 'Gene', '286832', (146, 155))	('shortstop', 'Gene', (63, 72))	('GCT-susceptibility', 'Disease', (4, 22))
3646	20047465	The forward genetic screen for cell proliferation and cancer susceptibility mutants has been described elsewhere.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('mutants', 'Var', (76, 83))	('cell', 'CPA', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
3657	20047465	Previously, we described a genetic screen to identify mutations that altered embryonic cell proliferation in the progeny of ENU-mutagenized zebrafish.	('zebrafish', 'Species', '7955', (140, 149))	('mutations', 'Var', (54, 63))	('altered', 'Reg', (69, 76))	('embryonic cell proliferation', 'CPA', (77, 105))
3658	20047465	Using whole-mount immunohistochemistry with anti-phosphohistone H3 to evaluate cell proliferation, seven mutant lines were identified including lamc1cz61, sfdcz213, mybl2cz226, espl1cz280, llgcz3322, sdscz319 and slhcz333 (ref.).	('espl1', 'Gene', '797406', (177, 182))	('sdscz319', 'Var', (200, 208))	('sfdcz213', 'Var', (155, 163))	('espl1', 'Gene', (177, 182))	('mybl2', 'Gene', '445390', (165, 170))	('lamc1', 'Gene', (144, 149))	('lamc1', 'Gene', '286832', (144, 149))	('mybl2', 'Gene', (165, 170))
3659	20047465	One of the goals of the screen was to identify mutations that increased cancer susceptibility in adult zebrafish.	('increased', 'PosReg', (62, 71))	('zebrafish', 'Species', '7955', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
3660	20047465	As all the lines were homozygous embryonic lethal, we investigated the incidence of cancer in heterozygote carriers of the cell proliferation mutations.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
3663	20047465	The carcinogens used were 7,12-Dimethylbenz[a]anthracene (DMBA) and N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), both of which had been shown to potently induce tumors in zebrafish.	('zebrafish', 'Species', '7955', (171, 180))	('induce', 'PosReg', (154, 160))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	("N-Methyl-N'-Nitro-N-Nitrosoguanidine", 'Var', (68, 104))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('DMBA', 'Chemical', 'MESH:D015127', (58, 62))	("N-Methyl-N'-Nitro-N-Nitrosoguanidine", 'Chemical', 'MESH:D008769', (68, 104))	('7,12-Dimethylbenz[a]anthracene', 'Chemical', 'MESH:D015127', (26, 56))	('MNNG', 'Chemical', 'MESH:D008769', (106, 110))
3667	20047465	Fish developing tumors were not genotyped in this analysis, and heterozygous carriers of the mutations and wild-type siblings are considered together.	('tumors', 'Disease', (16, 22))	('mutations', 'Var', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
3675	20047465	The mybl2cz226 line carries a loss-of-function mutation in the mybl2 gene.	('loss-of-function', 'NegReg', (30, 46))	('mutation', 'Var', (47, 55))	('mybl2', 'Gene', '445390', (4, 9))	('mybl2', 'Gene', (4, 9))	('mybl2', 'Gene', '445390', (63, 68))	('mybl2', 'Gene', (63, 68))
3676	20047465	We genotyped 20 fish that developed GCTs from this line and found that 10 carried the mybl2cz226 mutation, and 10 were wild type at the mybl2 locus.	('mybl2', 'Gene', (86, 91))	('mutation', 'Var', (97, 105))	('GCTs', 'Phenotype', 'HP:0100728', (36, 40))	('mybl2', 'Gene', '445390', (136, 141))	('mybl2', 'Gene', '445390', (86, 91))	('mybl2', 'Gene', (136, 141))
3681	20047465	The shortstop mutation causes a characteristic morphologic defect in homozygous mutant progeny, allowing the identification of heterozygote carrier parents after genetic incrosses.	('shortstop', 'Gene', '286832', (4, 13))	('mutation', 'Var', (14, 22))	('shortstop', 'Gene', (4, 13))	('mutant', 'Var', (80, 86))
3691	20047465	After two generations of outcrossing, five different carriers of the shortstop/lamc1cz61 cell proliferation mutation (identified via phenotyping of incross embryos) were tested for ability to transmit the TGCT trait in outcrosses to a wildtype strain.	('shortstop', 'Gene', '286832', (69, 78))	('lamc1', 'Gene', '286832', (79, 84))	('TGCT', 'Gene', (205, 209))	('mutation', 'Var', (108, 116))	('transmit', 'Reg', (192, 200))	('lamc1', 'Gene', (79, 84))	('shortstop', 'Gene', (69, 78))
3694	20047465	Initial possible linkage to four different chromosomes was obtained by carrying out bulk segregant mapping with a pool of 20 phenotypically wildtype and 20 shortstop mutant embryos against a panel of 250 microsatellite markers, as described.	('shortstop', 'Gene', '286832', (156, 165))	('mutant', 'Var', (166, 172))	('shortstop', 'Gene', (156, 165))
3695	20047465	Using a further panel of 88 mutant embryos we assigned shortstop to zebrafish chromosome 2 near the microsatellite markers Z8448 and Z21490 (18/88 and 12/88 recombinants, respectively).	('zebrafish', 'Species', '7955', (68, 77))	('mutant', 'Var', (28, 34))	('shortstop', 'Gene', (55, 64))	('Z8448', 'Var', (123, 128))	('shortstop', 'Gene', '286832', (55, 64))	('Z21490', 'Var', (133, 139))
3700	20047465	We prepared and sequenced lamc1 cDNA from shortstop mutant embryos and found that shortstop lamc1 contains an 11 bp insertion in exon 27 of the coding sequence, leading to the aberrant insertion of the sequence Phe-Phe-Ser-STOP in the predicted lamc1 protein sequence.	('insertion in', 'Var', (116, 128))	('shortstop', 'Gene', '286832', (42, 51))	('Ser', 'Chemical', 'MESH:D012694', (219, 222))	('mutant', 'Var', (52, 58))	('lamc1', 'Gene', '286832', (245, 250))	('lamc1', 'Gene', '286832', (92, 97))	('lamc1', 'Gene', (245, 250))	('lamc1', 'Gene', (92, 97))	('lamc1', 'Gene', '286832', (26, 31))	('insertion', 'Var', (185, 194))	('shortstop', 'Gene', (82, 91))	('lamc1', 'Gene', (26, 31))	('shortstop', 'Gene', '286832', (82, 91))	('Phe', 'Chemical', 'MESH:D010649', (211, 214))	('Phe', 'Chemical', 'MESH:D010649', (215, 218))	('shortstop', 'Gene', (42, 51))
3701	20047465	Further analysis showed that shortstop mutants contain a T>A mutation at nucleotide 80 of the 91 bp intron 26-27, creating a cryptic splice acceptor site and leading to the 11 bp insertion.	('shortstop', 'Gene', (29, 38))	('11 bp', 'MPA', (173, 178))	('leading to', 'Reg', (158, 168))	('shortstop', 'Gene', '286832', (29, 38))	('T>A mutation', 'Var', (57, 69))
3734	20047465	In mice, mutations in oncogenes and tumor-suppressor genes often exhibit effects on embryonic cell proliferation.	('embryonic cell proliferation', 'CPA', (84, 112))	('effects', 'Reg', (73, 80))	('mutations', 'Var', (9, 18))	('oncogenes', 'Gene', (22, 31))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
3735	20047465	Therefore, one of the goals of the zebrafish screen was to determine whether adult zebrafish carrying cell-proliferation mutations (including lamc1cz61, sfdcz213, mybl2cz226, espl1cz280, llgcz3322, sdscz319 and slhcz333) showed increased cancer susceptibility.	('mybl2', 'Gene', '445390', (163, 168))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('zebrafish', 'Species', '7955', (83, 92))	('slhcz333', 'Gene', (211, 219))	('mybl2', 'Gene', (163, 168))	('sdscz319', 'Var', (198, 206))	('zebrafish', 'Species', '7955', (35, 44))	('llgcz3322', 'Var', (187, 196))	('espl1', 'Gene', '797406', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('lamc1', 'Gene', '286832', (142, 147))	('sfdcz213', 'Var', (153, 161))	('espl1', 'Gene', (175, 180))	('lamc1', 'Gene', (142, 147))
3737	20047465	Zebrafish heterozygous for loss-of-function mutations in mybl2 and espl1 were more susceptible to neoplasia than their wild-type siblings, identifying these genes as haploinsufficient tumor suppressors.	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (166, 189))	('susceptible', 'CPA', (83, 94))	('haploinsufficient tumor', 'Disease', (166, 189))	('mybl2', 'Gene', '445390', (57, 62))	('espl1', 'Gene', '797406', (67, 72))	('loss-of-function', 'NegReg', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('mybl2', 'Gene', (57, 62))	('neoplasia', 'Disease', (98, 107))	('espl1', 'Gene', (67, 72))	('mutations', 'Var', (44, 53))	('neoplasia', 'Disease', 'MESH:D009369', (98, 107))	('neoplasia', 'Phenotype', 'HP:0002664', (98, 107))	('Zebrafish', 'Species', '7955', (0, 9))
3741	20047465	Using microsatellite mapping and a candidate gene approach, we identified a splice-site mutation in lamc1 in shortstop.	('shortstop', 'Gene', (109, 118))	('splice-site mutation', 'Var', (76, 96))	('shortstop', 'Gene', '286832', (109, 118))	('lamc1', 'Gene', '286832', (100, 105))	('lamc1', 'Gene', (100, 105))
3744	20047465	The F1 progeny of ENU-mutagenized males typically contain 100-200 different mutations, making it very likely that the GCT trait arose due to a second-site mutation that was transmitted to the original lamc1cz61 female.	('lamc1', 'Gene', '286832', (201, 206))	('lamc1', 'Gene', (201, 206))	('mutations', 'Var', (76, 85))
3757	20047465	The increased incidence of testicular germ cell tumors in older fish may result from the accumulation of mutations, or alternatively from age-related changes in steroid hormones or other cell signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('germ cell tumor', 'Phenotype', 'HP:0100728', (38, 53))	('changes', 'Reg', (150, 157))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('germ cell tumors', 'Phenotype', 'HP:0100728', (38, 54))	('germ cell tumors', 'Disease', 'MESH:D009373', (38, 54))	('mutations', 'Var', (105, 114))	('steroid hormones', 'Chemical', 'MESH:D013256', (161, 177))	('result', 'Reg', (73, 79))	('germ cell tumors', 'Disease', (38, 54))
3758	20047465	The frequency of testicular GCTs after carcinogenesis suggests that multiple targets exist in which somatic mutations lead to a germ cell tumor phenotype.	('lead to', 'Reg', (118, 125))	('tumor', 'Disease', (138, 143))	('mutations', 'Var', (108, 117))	('testicular GCTs', 'Disease', (17, 32))	('germ', 'Disease', (128, 132))	('germ cell tumor', 'Phenotype', 'HP:0100728', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('GCTs', 'Phenotype', 'HP:0100728', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
3764	20047465	The tumors in the zebrafish GCT-susceptible mutant shares important features with human testicular GCT, particularly seminomas and spermatocytic seminomas, including the accumulation of primitive, undifferentiated germ cells, the profound defect in spermatocytic differentiation and (in the case of seminomas) the sensitivity to radiation treatment.	('spermatocytic differentiation', 'CPA', (249, 278))	('men', 'Species', '9606', (344, 347))	('zebrafish', 'Species', '7955', (18, 27))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('accumulation', 'PosReg', (170, 182))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (131, 154))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (131, 154))	('seminomas', 'Disease', (299, 308))	('seminomas', 'Disease', 'MESH:D018239', (299, 308))	('seminomas', 'Disease', 'MESH:D018239', (117, 126))	('seminomas', 'Disease', (117, 126))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (314, 338))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('defect', 'NegReg', (239, 245))	('testicular GCT', 'Disease', (88, 102))	('spermatocytic seminomas', 'Disease', (131, 154))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (4, 10))	('seminomas', 'Disease', 'MESH:D018239', (145, 154))	('seminomas', 'Disease', (145, 154))	('mutant', 'Var', (44, 50))	('human', 'Species', '9606', (82, 87))
3848	20737560	Several papers have described paraneoplastic limbic encephalitis in men with testicular cancer associated with anti-Ma and anti-Ta antibodies.	('anti-Ma', 'Var', (111, 118))	('testicular cancer', 'Phenotype', 'HP:0010788', (77, 94))	('testicular cancer', 'Disease', 'MESH:D013736', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('men', 'Species', '9606', (68, 71))	('encephalitis', 'Phenotype', 'HP:0002383', (52, 64))	('testicular cancer', 'Disease', (77, 94))	('associated', 'Reg', (95, 105))	('anti-Ta antibodies', 'Var', (123, 141))	('paraneoplastic limbic encephalitis', 'Disease', (30, 64))	('paraneoplastic limbic encephalitis', 'Disease', 'MESH:D020363', (30, 64))
3871	23420531	Association between polymorphisms in the aryl hydrocarbon receptor repressor gene and disseminated testicular germ cell cancer In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('germ cell cancer', 'Phenotype', 'HP:0100728', (110, 126))	('TGCC', 'Chemical', '-', (178, 182))	('malignancy', 'Disease', 'MESH:D009369', (203, 213))	('men', 'Species', '9606', (223, 226))	('cancer', 'Disease', (170, 176))	('malignancy', 'Disease', (203, 213))	('polymorphisms', 'Var', (20, 33))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('germ cell cancer', 'Phenotype', 'HP:0100728', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('aryl hydrocarbon receptor repressor', 'Gene', '57491', (41, 76))	('Association', 'Interaction', (0, 11))	('aryl hydrocarbon receptor repressor', 'Gene', (41, 76))
3876	23420531	The aim of the present study was to identify whether AHR-related polymorphisms were associated with risk as well as histological and clinical features of TGCC in 367 patients and 537 controls.	('TGCC', 'Disease', (154, 158))	('polymorphisms', 'Var', (65, 78))	('associated', 'Reg', (84, 94))	('patients', 'Species', '9606', (166, 174))	('TGCC', 'Chemical', '-', (154, 158))
3877	23420531	Haplotype-tagging single-nucleotide polymorphisms (SNPs) were genotyped in genes encoding AHR and AHR repressor (AHRR).	('AHRR', 'Gene', '57491', (113, 117))	('single-nucleotide polymorphisms', 'Var', (18, 49))	('AHR repressor', 'Gene', (98, 111))	('AHRR', 'Gene', (113, 117))	('AHR repressor', 'Gene', '57491', (98, 111))
3879	23420531	Four SNPs in AHRR demonstrated a significant allele association with risk to develop metastases (rs2466287: OR = 0.43, 95% CI 0.21-0.90; rs2672725: OR = 0.49, 95% CI: 0.25-0.94; rs6879758: OR = 0.27, 95% CI: 0.08-0.92; rs6896163: OR = 0.34, 95% CI: 0.12-0.98).	('rs2672725', 'Var', (137, 146))	('rs2672725', 'Mutation', 'rs2672725', (137, 146))	('AHRR', 'Gene', '57491', (13, 17))	('rs2466287', 'Mutation', 'rs2466287', (97, 106))	('rs6879758', 'Mutation', 'rs6879758', (178, 187))	('rs6879758', 'Var', (178, 187))	('rs6896163', 'Var', (219, 228))	('metastases', 'Disease', (85, 95))	('rat', 'Species', '10116', (25, 28))	('AHRR', 'Gene', (13, 17))	('rs6896163', 'Mutation', 'rs6896163', (219, 228))	('metastases', 'Disease', 'MESH:D009362', (85, 95))
3893	23420531	Therefore, we aimed to analyze the association between polymorphic variants of genes encoding AHR and AHRR and the risk as well as histological and clinical features of TGCC.	('AHR', 'Gene', (94, 97))	('AHRR', 'Gene', '57491', (102, 106))	('polymorphic variants', 'Var', (55, 75))	('TGCC', 'Chemical', '-', (169, 173))	('association', 'Interaction', (35, 46))	('AHRR', 'Gene', (102, 106))
3921	23420531	For four SNPs in AHRR a significant allele association with the occurrence of disseminated disease was observed (Table 2).	('disseminated disease', 'Disease', (78, 98))	('allele', 'Var', (36, 42))	('AHRR', 'Gene', '57491', (17, 21))	('AHRR', 'Gene', (17, 21))
3922	23420531	Patients with metastatic disease had significantly lower frequencies of the minor rs2466287 G, rs2672725 G, rs6879758 C, and rs6896163 G alleles compared to patients with localized disease (5 vs 10%, 6 vs 11%, 2 vs 5%, and 2 vs 6%, respectively), which were associated with 57, 51, 73, and 66%, reduced per allele OR for developing metastatic TGCC, respectively.	('rs2466287 G', 'Var', (82, 93))	('localized disease', 'Disease', (171, 188))	('rs6879758 C', 'Var', (108, 119))	('rs6896163', 'Mutation', 'rs6896163', (125, 134))	('localized disease', 'Disease', 'MESH:D012594', (171, 188))	('rs2672725', 'Mutation', 'rs2672725', (95, 104))	('patients', 'Species', '9606', (157, 165))	('lower', 'NegReg', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('rs6879758', 'Mutation', 'rs6879758', (108, 117))	('rs2672725 G', 'Var', (95, 106))	('metastatic disease', 'Disease', (14, 32))	('TGCC', 'Chemical', '-', (343, 347))	('rs2466287', 'Mutation', 'rs2466287', (82, 91))	('rs6896163 G', 'Var', (125, 136))
3923	23420531	Heterozygous carriers of AHRR variants rs6879758 and rs6896163 had a 74 and 67% reduced risk of developing metastatic TGCC, respectively.	('rs6879758', 'Var', (39, 48))	('rs6896163', 'Var', (53, 62))	('TGCC', 'Chemical', '-', (118, 122))	('reduced', 'NegReg', (80, 87))	('variants rs6879758', 'Var', (30, 48))	('AHRR', 'Gene', '57491', (25, 29))	('rs6896163', 'Mutation', 'rs6896163', (53, 62))	('AHRR', 'Gene', (25, 29))	('rs6879758', 'Mutation', 'rs6879758', (39, 48))
3924	23420531	Due to very low frequencies, or even absence, of homozygous carriers of the AHRR variants the OR could not be calculated for these groups of patients.	('AHRR', 'Gene', '57491', (76, 80))	('patients', 'Species', '9606', (141, 149))	('AHRR', 'Gene', (76, 80))	('variants', 'Var', (81, 89))
3926	23420531	Polymorphisms in AHRR did not show a significant association with risk of TGCC or histological subtype, which was also the case for SNPs in AHR.	('TGCC', 'Disease', (74, 78))	('Polymorphisms', 'Var', (0, 13))	('AHRR', 'Gene', '57491', (17, 21))	('TGCC', 'Chemical', '-', (74, 78))	('AHRR', 'Gene', (17, 21))
3928	23420531	LD analysis demonstrated a high correlation between rs2466287 and rs2672725 as well as between rs6879758 and rs6896163 (Table 3).	('rs2466287', 'Var', (52, 61))	('rs6879758', 'Mutation', 'rs6879758', (95, 104))	('rs6879758', 'Var', (95, 104))	('rs6896163', 'Var', (109, 118))	('rs2466287', 'Mutation', 'rs2466287', (52, 61))	('rat', 'Species', '10116', (19, 22))	('rs2672725', 'Var', (66, 75))	('rs2672725', 'Mutation', 'rs2672725', (66, 75))	('rs6896163', 'Mutation', 'rs6896163', (109, 118))
3929	23420531	In this study we have analyzed associations between SNPs in genes encoding AHR and AHRR and the risk of developing TGCC, histological subtype, and the occurrence of metastasis.	('AHRR', 'Gene', (83, 87))	('AHR', 'Gene', (75, 78))	('TGCC', 'Chemical', '-', (115, 119))	('AHRR', 'Gene', '57491', (83, 87))	('TGCC', 'Disease', (115, 119))	('SNPs', 'Var', (52, 56))
3930	23420531	Whereas no associations were found with SNPs in AHR, four variants in AHRR associated significantly with the occurrence of metastatic disease.	('variants', 'Var', (58, 66))	('AHRR', 'Gene', (70, 74))	('metastatic disease', 'Disease', (123, 141))	('AHRR', 'Gene', '57491', (70, 74))	('associated', 'Reg', (75, 85))
3938	23420531	While SNPs in either AHR or AHRR did not associate with the risk of TGCC, it is interesting that an association was observed between AHRR and dissemination of TGCC, since AHR signaling is indeed known to contribute to the control of cell adhesion and migration.	('TGCC', 'Disease', (68, 72))	('AHRR', 'Gene', (28, 32))	('TGCC', 'Gene', (159, 163))	('association', 'Interaction', (100, 111))	('AHRR', 'Gene', '57491', (133, 137))	('TGCC', 'Chemical', '-', (159, 163))	('SNPs', 'Var', (6, 10))	('dissemination', 'CPA', (142, 155))	('TGCC', 'Chemical', '-', (68, 72))	('AHRR', 'Gene', '57491', (28, 32))	('AHRR', 'Gene', (133, 137))	('rat', 'Species', '10116', (254, 257))
3941	23420531	An interaction between AHR signaling and steroid or gonadotropic hormones could therefore be an alternative mechanism underlying the association between AHRR polymorphisms and metastatic TGCC.	('association', 'Interaction', (133, 144))	('polymorphisms', 'Var', (158, 171))	('steroid', 'Chemical', 'MESH:D013256', (41, 48))	('TGCC', 'Chemical', '-', (187, 191))	('AHRR', 'Gene', (153, 157))	('metastatic TGCC', 'Disease', (176, 191))	('AHRR', 'Gene', '57491', (153, 157))
3951	29036324	We further performed survival analysis and identified 22 212 eQTLs associated with patient overall survival.	('associated', 'Reg', (67, 77))	('patient', 'Species', '9606', (83, 90))	('eQTLs', 'Var', (61, 66))
3952	29036324	PancanQTL could help the research community understand the effects of inherited variants in tumorigenesis and development.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('development', 'CPA', (110, 121))	('variants', 'Var', (80, 88))	('tumor', 'Disease', (92, 97))
3954	29036324	Genome-wide association studies (GWAS) identified more than 10 000 SNPs associated with susceptibility of human traits or diseases.	('SNPs', 'Var', (67, 71))	('associated', 'Reg', (72, 82))	('human', 'Species', '9606', (106, 111))
3958	29036324	Collectively, systematic and large-scale investigations of both cis- and trans-eQTLs in multiple cancer types would provide the research community with a further understanding of inherited variant effects in tumorigenesis and development.	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('development', 'CPA', (226, 237))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (208, 213))	('variant', 'Var', (189, 196))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
3968	29036324	Many genes are associated with cancer prognoses, and eQTLs may influence the prognosis by altering gene expression.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gene expression', 'MPA', (99, 114))	('eQTLs', 'Var', (53, 58))	('prognosis', 'CPA', (77, 86))	('associated', 'Reg', (15, 25))	('altering', 'Reg', (90, 98))	('influence', 'Reg', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
3980	29036324	The number of trans-eQTLs ranged from five in lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) and uterine carcinosarcoma (UCS) to 20 466 in BRCA, while the number of egenes ranged from two in UCS to 6013 in BRCA (Table 1).	('UCS', 'Phenotype', 'HP:0002891', (199, 202))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (105, 127))	('BRCA', 'Gene', (214, 218))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (78, 93))	('BRCA', 'Gene', '672', (147, 151))	('lymphoid neoplasm', 'Disease', (46, 63))	('B-cell lymphoma', 'Disease', (78, 93))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (46, 63))	('BRCA', 'Gene', (147, 151))	('carcinosarcoma', 'Disease', (113, 127))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('BRCA', 'Phenotype', 'HP:0003002', (147, 151))	('UCS', 'Phenotype', 'HP:0002891', (129, 132))	('carcinosarcoma', 'Disease', 'MESH:D002296', (113, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('trans-eQTLs', 'Var', (14, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('BRCA', 'Gene', '672', (214, 218))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (78, 93))
3988	29036324	When the user selects a specific cancer type or enters a gene or SNP ID, the table will be rebuilt to display the query results.	('gene', 'Var', (57, 61))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
3989	29036324	For example, our analysis showed that ERAP2 expression in individuals carrying the homozygote rs2351010 aa is significantly higher than that in individuals carrying the homozygote rs2351010 AA and heterozygous rs2351010 Aa (P-value = 2.37 x 10-302) (Figure 2C).	('expression', 'MPA', (44, 54))	('ERAP2', 'Gene', (38, 43))	('rs2351010 aa', 'Var', (94, 106))	('ERAP2', 'Gene', '64167', (38, 43))	('rs2351010', 'Mutation', 'rs2351010', (210, 219))	('rs2351010', 'Mutation', 'rs2351010', (180, 189))	('rs2351010', 'Mutation', 'rs2351010', (94, 103))	('higher', 'PosReg', (124, 130))
3991	29036324	For example, our analysis showed that patients with the rs1824937 aa genotype have worse prognoses than other breast cancer patients (P-value = 6.3 x 10-7) (Figure 2D).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs1824937', 'Var', (56, 65))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('patients', 'Species', '9606', (38, 46))	('rs1824937', 'Mutation', 'rs1824937', (56, 65))	('breast cancer', 'Disease', (110, 123))	('patients', 'Species', '9606', (124, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
3992	29036324	We systematically identified cis-eQTLs, trans-eQTLs, survival-associated eQTLs and GWAS-related eQTLs in 33 cancer types.	('trans-eQTLs', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cis-eQTLs', 'Var', (29, 38))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
3994	29036324	PancanQTL could also contribute to understanding the effects of inherited variants in tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('PancanQTL', 'Gene', (0, 9))	('tumor', 'Disease', (86, 91))	('development', 'CPA', (104, 115))	('variants', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
4016	28893722	Widely used solvents such as toluene, trichloroethylene, and perchloroethylene have possible endocrine disrupting properties, and might also interact with the masculinization process in utero.	('trichloroethylene', 'Var', (38, 55))	('perchloroethylene', 'Var', (61, 78))	('toluene', 'Chemical', 'MESH:D014050', (29, 36))	('endocrine disrupting', 'MPA', (93, 113))	('masculinization process', 'CPA', (159, 182))	('trichloroethylene', 'Chemical', 'MESH:D014241', (38, 55))	('perchloroethylene', 'Chemical', 'MESH:D013750', (61, 78))	('interact', 'Reg', (141, 149))
4043	28893722	The lowest correlation was found between toluene and perchloroethylene, whereas the highest was found for trichloroethylene and 1,1,1-trichloroethane in maternal exposures and for toluene and benzene in paternal exposures.	('toluene', 'Chemical', 'MESH:D014050', (180, 187))	('trichloroethylene', 'Chemical', 'MESH:D014241', (106, 123))	('1,1,1-trichloroethane', 'Chemical', 'MESH:C024566', (128, 149))	('benzene', 'Chemical', 'MESH:D001554', (192, 199))	('correlation', 'Interaction', (11, 22))	('toluene', 'Chemical', 'MESH:D014050', (41, 48))	('lowest', 'NegReg', (4, 10))	('trichloroethylene', 'Var', (106, 123))	('perchloroethylene', 'Chemical', 'MESH:D013750', (53, 70))	('maternal exposure', 'Phenotype', 'HP:0031437', (153, 170))
4066	28893722	The mechanisms underlying a potential effect of paternal exposure to solvents on TGCT in offspring is unclear, but a plausible pathway has been hypothesized; notably an effect on sperm DNA, producing mutations or chromosomal abnormalities.	('mutations', 'Var', (200, 209))	('effect', 'Reg', (169, 175))	('chromosomal abnormalities', 'Disease', (213, 238))	('sperm DNA', 'CPA', (179, 188))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (213, 238))
4107	22675250	Inhibiting NF-kB and thereby iNOS using antioxidants has already proved to be effective in attenuating the CIS-induced testicular injury.	('NF-kB', 'Gene', (11, 16))	('Inhibiting', 'Var', (0, 10))	('NF-kB', 'Gene', '309165', (11, 16))	('testicular injury', 'Disease', (119, 136))	('attenuating', 'NegReg', (91, 102))	('testicular injury', 'Disease', 'MESH:D013736', (119, 136))	('CIS', 'Gene', (107, 110))	('CIS', 'Gene', '83681', (107, 110))
4219	29444652	found that strenuous physical activity more than five times per week during teenage years more than doubled the risk of TC development later in life (adjusted OR: 2.58, 95% CI 1.14-5.85), but when asked the same questions regarding the two-year period prior to the interview, this association effectively disappeared (adjusted OR: 1.18, 95% CI 0.52-2.65).	('strenuous', 'Var', (11, 20))	('men', 'Species', '9606', (130, 133))	('TC development', 'CPA', (120, 134))
4253	29444652	Assuming that large-scale genomic studies will identify one or more genetic variants that predispose an individual to undertake high levels of physical activity, future studies (such as those driven by the Testicular Cancer Consortium, or TECAC) should permit the examination of whether loci linked to physical activity are also associated with testicular cancer.	('associated', 'Reg', (329, 339))	('Testicular Cancer', 'Phenotype', 'HP:0010788', (206, 223))	('Testicular Cancer', 'Disease', (206, 223))	('Testicular Cancer', 'Disease', 'MESH:D013736', (206, 223))	('testicular cancer', 'Disease', (345, 362))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('variants', 'Var', (76, 84))	('testicular cancer', 'Phenotype', 'HP:0010788', (345, 362))	('testicular cancer', 'Disease', 'MESH:D013736', (345, 362))
4438	29023373	Characteristic peaks of PEI, such as stretching vibration of C-H (2810 cm-1) and bending vibration of N-H group (1586 cm-1), were found in nanostructured hybrid, slightly shifted at 2834 cm-1 (nu C-H) and 1546 cm-1 (delta N-H), respectively.	('2834 cm-1', 'Var', (182, 191))	('and 1', 'Gene', '218973', (201, 206))	('PEI', 'Chemical', 'MESH:D011094', (24, 27))	('bending', 'MPA', (81, 88))	('and 1', 'Gene', (201, 206))
4451	29023373	As illustrated in Figure A2 and Supplemental Movie 1, cell proliferation was not affected by the presence of NPs and Fe-PEI NPs rapidly accumulated onto the cell surface and assembled into micron-level aggregates upon interaction with cells.	('cell proliferation', 'CPA', (54, 72))	('Fe-PEI', 'Var', (117, 123))	('Fe-PEI', 'Chemical', '-', (117, 123))	('assembled', 'Reg', (174, 183))	('interaction', 'Interaction', (218, 229))
4455	29023373	It is worth noting that aggregation of Fe-PEI NPs was produced in culture medium both in tissue culture-treated plates (in conditions favoring cell adhesion), as well as in ultra-low adherence (ULA) plates (in conditions not-favoring cell adhesion), and in both cases adhesive aggregates were produced.	('aggregation', 'CPA', (24, 35))	('Fe-PEI', 'Chemical', '-', (39, 45))	('Fe-PEI', 'Var', (39, 45))
4472	29023373	As revealed in Figure 3d, DeltaPsim was almost completely lost after 24-h exposure of MSCs to valinomycin-Fe-PEI aggregates, to a similar extent to MSCs exposed to the same dose of valinomycin given as such.	('valinomycin-Fe-PEI', 'Var', (94, 112))	('valinomycin', 'Chemical', 'MESH:D014634', (94, 105))	('Fe-PEI', 'Chemical', '-', (106, 112))	('DeltaPsim', 'MPA', (26, 35))	('lost', 'NegReg', (58, 62))	('valinomycin', 'Chemical', 'MESH:D014634', (181, 192))
4481	29023373	The survival curve of U87 cells in the presence of increasing concentrations of Cisplatin (ranging from 0.2 to 50 microM) showed that at concentrations less than 1 microM Cisplatin, U87 viability and proliferation were not affected (Figure A3).	('Cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('proliferation', 'CPA', (200, 213))	('U87 viability', 'CPA', (182, 195))	('Cisplatin', 'Var', (171, 180))	('Cisplatin', 'Chemical', 'MESH:D002945', (171, 180))
4486	29023373	However, for Fe-PEI NPs doses at which the viability of U87 cells was not affected, only Cis-Fe-PEI, but not Fe-PEI+Cis, significantly decreased cell viability (Figure 4d).	('Fe-PEI', 'Chemical', '-', (109, 115))	('Fe-PEI', 'Chemical', '-', (13, 19))	('cell viability', 'CPA', (145, 159))	('Fe-PEI', 'Chemical', '-', (93, 99))	('decreased', 'NegReg', (135, 144))	('Cis-Fe-PEI', 'Var', (89, 99))	('Cis-Fe-PEI', 'Chemical', '-', (89, 99))
4487	29023373	This data confirmed that Fe-PEI NPs increased the efficiency of intracellular delivery of cisplatin when the latter was incorporated during hydrothermal synthesis process.	('Fe-PEI NPs', 'Var', (25, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('intracellular delivery of cisplatin', 'MPA', (64, 99))	('Fe-PEI', 'Chemical', '-', (25, 31))	('increased', 'PosReg', (36, 45))
4495	29023373	The results showed that administration of 50 microL Cis-Fe-PEI NPs (containing a very small dose of cisplatin, corresponding to 4 ng cisplatin/kg body weight, which is 105 times lower than the dose usually used in vivo for therapeutic purposes) showed a tendency to reduce the onset of tumor progression at early time points in vivo (Figure 4f).	('Cis-Fe-PEI', 'Var', (52, 62))	('reduce', 'NegReg', (266, 272))	('Cis-Fe-PEI', 'Chemical', '-', (52, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (286, 291))
4498	29023373	By concluding, the results presented here demonstrate that the incorporation of cisplatin into Fe-PEI NPs during hydrothermal synthesis is associated with the preservation of the biological activity of the molecule that can be further transferred into the target cells by direct contact.	('Fe-PEI', 'Chemical', '-', (95, 101))	('incorporation', 'Var', (63, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('biological activity of the', 'MPA', (179, 205))
4573	22315593	Within these subgroups, patients, with gonadal dysgenesis (GD) and hypovirilization with presence of part of the Y chromosome (i.e., GBY), are known to have an increased risk to develop carcinoma in situ (CIS) or gonadoblastoma (GB), the precursor lesions of seminoma(SE)/dysgerminoma(DG) and nonseminoma, referred to as malignant type II germ cell tumors (GCTs) (, for review).	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('carcinoma in situ', 'Disease', (186, 203))	('GCTs', 'Phenotype', 'HP:0100728', (357, 361))	('gonadoblastoma', 'Disease', (213, 227))	('GD', 'Disease', 'MESH:D005776', (59, 61))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('presence', 'Var', (89, 97))	('DG', 'Phenotype', 'HP:0100621', (285, 287))	('dysgerminoma', 'Phenotype', 'HP:0100621', (272, 284))	('malignant type II germ cell tumors', 'Disease', 'MESH:D009373', (321, 355))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (186, 203))	('GD', 'Phenotype', 'HP:0000133', (59, 61))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (39, 57))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (39, 57))	('carcinoma in situ', 'Disease', 'MESH:D002278', (186, 203))	('germ cell tumors', 'Phenotype', 'HP:0100728', (339, 355))	('CIS', 'Gene', (205, 208))	('nonseminoma', 'Disease', (293, 304))	('nonseminoma', 'Disease', 'None', (293, 304))	('malignant type II germ cell tumors', 'Disease', (321, 355))	('develop', 'PosReg', (178, 185))	('gonadoblastoma', 'Phenotype', 'HP:0000150', (213, 227))	('GB', 'Phenotype', 'HP:0000150', (229, 231))	('CIS', 'Gene', '1154', (205, 208))	('CIS', 'Phenotype', 'HP:0030075', (205, 208))	('seminoma(SE)/dysgerminoma', 'Disease', 'MESH:D004407', (259, 284))	('GB', 'Phenotype', 'HP:0000150', (133, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('gonadal dysgenesis', 'Disease', (39, 57))	('patients', 'Species', '9606', (24, 32))	('gonadoblastoma', 'Disease', 'MESH:D018238', (213, 227))
4575	22315593	Hypovirilization is caused by defects in androgen-dependent target tissues, errors in testosterone biosynthesis, and testicular unresponsiveness to stimulation from the pituitary, leading to underdevelopment of the male differentiation lineage.	('Hypovirilization', 'Disease', (0, 16))	('errors', 'Var', (76, 82))	('testosterone', 'Chemical', 'MESH:D013739', (86, 98))	('caused by', 'Reg', (20, 29))	('leading to', 'Reg', (180, 190))
4584	22315593	However, genetic factors, especially a limited number of single nucleotide polymorphisms (SNPs) are also recognized to play a role in development of this type of cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('play', 'Reg', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('single nucleotide polymorphisms', 'Var', (57, 88))	('role', 'Reg', (126, 130))
4633	22315593	The presence of CIS initiated reexamination of the biopsy taken at the age of three years.	('CIS', 'Gene', '1154', (16, 19))	('presence', 'Var', (4, 12))	('CIS', 'Phenotype', 'HP:0030075', (16, 19))	('CIS', 'Gene', (16, 19))
4642	22315593	Presence of GB, known to be associated with DSD, besides CIS, as precursor in these patients, triggered review of their clinical history.	('patients', 'Species', '9606', (84, 92))	('associated', 'Reg', (28, 38))	('CIS', 'Gene', '1154', (57, 60))	('CIS', 'Phenotype', 'HP:0030075', (57, 60))	('CIS', 'Gene', (57, 60))	('DSD', 'Disease', (44, 47))	('GB', 'Phenotype', 'HP:0000150', (12, 14))	('Presence', 'Var', (0, 8))
4646	22315593	DSD patients can be diagnosed early in life based on various characteristics, including sexual ambiguity, family history, discordant karyotype and genital appearance, and aberrant male and female genitalia.	('genitalia', 'Disease', (196, 205))	('aberrant', 'Var', (171, 179))	('genitalia', 'Disease', 'MESH:D012734', (196, 205))	('patients', 'Species', '9606', (4, 12))	('DSD', 'Disease', (0, 3))
4658	22315593	Of interest in this context is the linkage of specific single nucleotide polymorphisms with development of type II GCTs in the general Caucasian population, including involvement of SCF.	('linkage', 'Interaction', (35, 42))	('GCTs', 'Phenotype', 'HP:0100728', (115, 119))	('single nucleotide polymorphisms', 'Var', (55, 86))	('SCF', 'Gene', '4254', (182, 185))	('SCF', 'Gene', (182, 185))	('type II GCTs', 'Disease', (107, 119))
4664	22315593	All patients showed a SRY mutation, inherited from the father, being mosaic.	('SRY', 'Gene', '6736', (22, 25))	('SRY', 'Gene', (22, 25))	('patients', 'Species', '9606', (4, 12))	('mutation', 'Var', (26, 34))
4693	20535292	After a median 10-year follow-up, more radiotherapy patients had suffered a cardiac event (9.6%) than those treated with chemotherapy (6.7%) or orchidectomy alone (3.7%).	('cardiac', 'Disease', (76, 83))	('suffered', 'Reg', (65, 73))	('radiotherapy', 'Var', (39, 51))	('patients', 'Species', '9606', (52, 60))
4698	20535292	Overall acute toxicity was lower in the PA strip group and oligospermia recovered more quickly.	('PA strip', 'Var', (40, 48))	('PA', 'Chemical', '-', (40, 42))	('lower', 'NegReg', (27, 32))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('oligospermia', 'Phenotype', 'HP:0000798', (59, 71))	('toxicity', 'Disease', (14, 22))	('oligospermia', 'Disease', 'MESH:D009845', (59, 71))	('oligospermia', 'Disease', (59, 71))
4700	20535292	The second MRC trial in conjunction with the EORTC (TE18/EORTC 30942) looked at the efficacy and morbidity of a reduction in dose to 20Gy compared with the control of 30Gy.	('20Gy', 'Var', (133, 137))	('MRC', 'CellLine', 'CVCL:0440', (11, 14))	('dose', 'MPA', (125, 129))	('reduction', 'NegReg', (112, 121))
4752	20535292	A margin of 1-1.5 cm on diseased nodes is advised with dose prescriptions of 30Gy in IIA and 36Gy in IIB disease.	('IIB disease', 'Disease', (101, 112))	('IIB disease', 'Disease', 'MESH:C536043', (101, 112))	('36Gy', 'Var', (93, 97))	('IIA', 'Disease', (85, 88))
4753	20535292	Extension to the contralateral iliac, inguinal or scrotal region is not recommended (even with T3/T4 tumors, prior testicular mal-descent, scrotal or inguinal surgery) due to a lack of evidence base.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('men', 'Species', '9606', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('T3/T4', 'Var', (95, 100))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
4755	20535292	There is, however, significant acute toxicity and rare but serious additional late toxicities such as cardiovascular disease from cisplatin and the risk of leukemia from etoposide.	('toxicity', 'Disease', (37, 45))	('cardiovascular disease', 'Disease', 'MESH:D002318', (102, 124))	('etoposide', 'Chemical', 'MESH:D005047', (170, 179))	('toxicities', 'Disease', (83, 93))	('cisplatin', 'Var', (130, 139))	('leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('leukemia', 'Disease', 'MESH:D007938', (156, 164))	('cardiovascular disease', 'Disease', (102, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('toxicities', 'Disease', 'MESH:D064420', (83, 93))	('leukemia', 'Disease', (156, 164))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (102, 124))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
4780	20535292	Bleomycin is associated with pulmonary toxicity which can be fatal.	('Bleomycin', 'Chemical', 'MESH:D001761', (0, 9))	('associated', 'Reg', (13, 23))	('Bleomycin', 'Var', (0, 9))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (29, 47))	('pulmonary toxicity', 'Disease', (29, 47))
4790	20535292	Low blood counts do not necessarily require dose reductions unless they are associated with febrile neutropenia or other significant complications.	('febrile neutropenia', 'Disease', (92, 111))	('febrile neutropenia', 'Disease', 'MESH:D009503', (92, 111))	('neutropenia', 'Phenotype', 'HP:0001875', (100, 111))	('Low', 'Var', (0, 3))
4825	32178360	Seasonal reproduction can be categorized as long-day (LD) breeders and short-day (SD) breeders, of which sheep are short-day breeders, and reducing the day length promotes the seasonal onset of the cycling activity.	('seasonal', 'MPA', (176, 184))	('cycling activity', 'MPA', (198, 214))	('reducing', 'Var', (139, 147))	('sheep', 'Species', '9940', (105, 110))
4869	32178360	A total of thirteen genes, including six mRNAs (LHB, PRL, ATP1A2, ATP1A3, CGA, and AKT2) related to reproduction and seven random lncRNAs (MSTRG.273909, MSTRG.87497, MSTRG.378494, MSTRG.229415, MSTRG.353354, MSTRG.371055, and MSTRG.138183), were selected for qRT-PCR verification.	('LHB', 'Gene', '443395', (48, 51))	('MSTRG.229415', 'Var', (180, 192))	('MSTRG.138183', 'Var', (226, 238))	('ATP1A2', 'Gene', '101118148', (58, 64))	('MSTRG.273909', 'Var', (139, 151))	('PRL', 'Gene', '443317', (53, 56))	('ATP1A2', 'Gene', (58, 64))	('MSTRG.87497', 'Var', (153, 164))	('LHB', 'Gene', (48, 51))	('ATP1A3', 'Gene', '101103751', (66, 72))	('MSTRG.378494', 'Var', (166, 178))	('ATP1A3', 'Gene', (66, 72))	('MSTRG.371055', 'Var', (208, 220))	('AKT2', 'Gene', '101119242', (83, 87))	('MSTRG.353354', 'Var', (194, 206))	('PRL', 'Gene', (53, 56))	('AKT2', 'Gene', (83, 87))
4882	32178360	It has been reported that CGA expression has a robust photoperiodic response in melatonin-proficient CBA/N mice.	('photoperiodic response', 'MPA', (54, 76))	('expression', 'Var', (30, 40))	('mice', 'Species', '10090', (107, 111))	('CGA', 'Gene', (26, 29))	('melatonin', 'Chemical', 'MESH:D008550', (80, 89))
4894	32178360	For example, lncRNA MSTRG.94748 was predicted to act on SIX3 through cis-targeting.	('MSTRG.94748', 'Var', (20, 31))	('SIX3', 'Gene', '101111085', (56, 60))	('SIX3', 'Gene', (56, 60))
4896	32178360	In turn, lncRNA MSTRG.229415, MSTRG.247962, MSTRG.286057, MSTRG.371055, MSTRG.378494, MSTRG.420890, MSTRG.63350, and MSTRG.87497 were predicted to act on AKT2 through trans-targeting.	('MSTRG.286057', 'Var', (44, 56))	('MSTRG.229415', 'Var', (16, 28))	('MSTRG.87497', 'Var', (117, 128))	('MSTRG.371055', 'Var', (58, 70))	('MSTRG.63350', 'Var', (100, 111))	('AKT2', 'Gene', '101119242', (154, 158))	('MSTRG.420890', 'Var', (86, 98))	('AKT2', 'Gene', (154, 158))	('trans-targeting', 'MPA', (167, 182))	('MSTRG.378494', 'Var', (72, 84))	('MSTRG.247962', 'Var', (30, 42))	('act', 'Reg', (147, 150))
4898	32178360	The lncRNA MSTRG.137414 was predicted to act on TRHR through trans-targeting.	('act', 'Reg', (41, 44))	('MSTRG.137414', 'Var', (11, 23))	('TRHR', 'Gene', (48, 52))	('trans-targeting', 'MPA', (61, 76))	('TRHR', 'Gene', '443425', (48, 52))
4900	32178360	Mitogen-activated Protein Kinase Kinase Kinase 2 (MAP3K2) is an upstream MAPK kinase of the MAPK signaling pathway that is targeted by oar_circ_0001714 and plays a critical role in cell proliferation, differentiation, and cell migration.	('cell proliferation', 'CPA', (181, 199))	('MAP3K2', 'Gene', '101109858', (50, 56))	('Mitogen-activated Protein Kinase Kinase Kinase 2', 'Gene', '101109858', (0, 48))	('differentiation', 'CPA', (201, 216))	('Mitogen-activated Protein Kinase Kinase Kinase 2', 'Gene', (0, 48))	('MAP3K2', 'Gene', (50, 56))	('oar_circ_0001714', 'Var', (135, 151))	('cell migration', 'CPA', (222, 236))
4928	30547014	Several genomewide studies suggested driver mutations in only three genes (KIT, KRAS, and NRAS) in 4-31% of seminoma, and up to 14% of non-seminoma patients.	('seminoma', 'Disease', (139, 147))	('patients', 'Species', '9606', (148, 156))	('non-seminoma', 'Disease', 'MESH:D018239', (135, 147))	('NRAS', 'Gene', (90, 94))	('KRAS', 'Gene', (80, 84))	('seminoma', 'Disease', 'MESH:D018239', (108, 116))	('NRAS', 'Gene', '4893', (90, 94))	('KIT', 'Gene', (75, 78))	('KRAS', 'Gene', '3845', (80, 84))	('mutations', 'Var', (44, 53))	('non-seminoma', 'Disease', (135, 147))	('seminoma', 'Disease', 'MESH:D018239', (139, 147))	('seminoma', 'Disease', (108, 116))
4950	30547014	High expression in tumor was associated with shorter PFS; however, the clinically more useful utility of plasmatic assessment failed to be prognostic in GCT.	('PFS', 'MPA', (53, 56))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('GCT', 'Phenotype', 'HP:0100728', (153, 156))	('tumor', 'Disease', (19, 24))
4959	30547014	Patients with low levels of PD-L1 expression had significantly better PFS (HR = 0.40; P = 0.008) and OS (HR = 0.43; P = 0.040).	('PD-L1', 'Gene', '29126', (28, 33))	('low levels', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (63, 69))	('PD-L1', 'Gene', (28, 33))	('PFS', 'CPA', (70, 73))
4961	30547014	Patients with high PD-L1 expression on TIL had significantly better prognosis than patients with low PD-L1 TIL.	('PD-L1', 'Gene', (19, 24))	('better', 'PosReg', (61, 67))	('expression', 'MPA', (25, 35))	('PD-L1', 'Gene', '29126', (101, 106))	('PD-L1', 'Gene', '29126', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (83, 91))	('PD-L1', 'Gene', (101, 106))
4971	30547014	reported numerous markers associated with poor prognosis in GCT, including low hemoglobin and albumin, high leukocytes, neutrophils, CRP, neutrophil to lymphocyte ratio, and SII.	('high leukocytes', 'Phenotype', 'HP:0001974', (103, 118))	('low', 'NegReg', (75, 78))	('neutrophils', 'CPA', (120, 131))	('low hemoglobin', 'Phenotype', 'HP:0001903', (75, 89))	('neutrophil', 'CPA', (138, 148))	('CRP', 'Gene', (133, 136))	('GCT', 'Phenotype', 'HP:0100728', (60, 63))	('CRP', 'Gene', '1401', (133, 136))	('high', 'Var', (103, 107))	('albumin', 'MPA', (94, 101))	('SII', 'Disease', 'None', (174, 177))	('GCT', 'Disease', (60, 63))	('SII', 'Disease', (174, 177))
4992	30547014	A global DNA hypermethylation was proposed as one of the acting mechanisms in cisplatin resistance, the most frustrating challenge for oncologists treating GCT patients.	('cisplatin resistance', 'MPA', (78, 98))	('patients', 'Species', '9606', (160, 168))	('GCT', 'Phenotype', 'HP:0100728', (156, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('hypermethylation', 'Var', (13, 29))
5030	29662516	Patients aged 15-24 years with T-GCTs had an improved OS, but not cancer-specific survival, than those aged 25-39 years.	('improved', 'PosReg', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('OS', 'Chemical', 'MESH:D009992', (54, 56))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('T-GCTs', 'Var', (31, 37))	('cancer', 'Disease', (66, 72))
5044	29662516	Even controlling for other factors, AYA status remains significantly associated with improved OS.	('OS', 'Chemical', 'MESH:D009992', (94, 96))	('improved', 'PosReg', (85, 93))	('AYA status', 'Var', (36, 46))
5087	29662516	Etoposide specifically carries a risk of developing a secondary leukemia that is highly resistant to available therapies.	('leukemia', 'Disease', (64, 72))	('Etoposide', 'Var', (0, 9))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('leukemia', 'Disease', 'MESH:D007938', (64, 72))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
5162	25044313	We classified TGCT as either seminoma or non-seminoma, with the International Classification of Disease for Oncology (ICD-O-3) morphology codes 9060-9062 and 9064 for seminoma, and 9065 and 9070-9102 for non-seminoma.	('seminoma', 'Disease', (29, 37))	('non-seminoma', 'Disease', 'MESH:D018239', (204, 216))	('seminoma', 'Disease', 'MESH:D018239', (45, 53))	('non-seminoma', 'Disease', (41, 53))	('TGCT', 'Disease', (14, 18))	('seminoma', 'Disease', (167, 175))	('seminoma', 'Disease', 'MESH:D018239', (29, 37))	('seminoma', 'Disease', (45, 53))	('seminoma', 'Disease', 'MESH:D018239', (208, 216))	('9060-9062', 'Var', (144, 153))	('non-seminoma', 'Disease', 'MESH:D018239', (41, 53))	('non-seminoma', 'Disease', (204, 216))	('Oncology', 'Phenotype', 'HP:0002664', (108, 116))	('seminoma', 'Disease', 'MESH:D018239', (167, 175))	('seminoma', 'Disease', (208, 216))
5218	27785439	Cancer risk factors include Y-chromosomal material and gonadal position, especially for streak gonads.	('Y-chromosomal material', 'Var', (28, 50))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('streak gonads', 'Disease', (88, 101))
5243	27785439	Cancer risk factors include Y-chromosomal material and gonadal position.	('Y-chromosomal material', 'Var', (28, 50))	('gonadal position', 'CPA', (55, 71))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
5256	27785439	However, men with Klinefelter Syndrome may be at substantially elevated risks for non-Hodgkin lymphoma, breast cancer, and possibly lung cancer:though the exact mechanisms remain unclear.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Klinefelter Syndrome', 'Var', (18, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (94, 102))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('men', 'Species', '9606', (9, 12))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (86, 102))	('breast cancer', 'Disease', (104, 117))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (82, 102))	('lung cancer', 'Disease', (132, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('non-Hodgkin lymphoma', 'Disease', (82, 102))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (82, 102))
5257	27785439	Juvenile granulosa cell tumor (JGCT), a tumor of sex cord-stromal cells, has been noted to occur in rare cases of sex-chromosomal mosaicism and ambiguous genitalia in the neonatal period.	('JGCT', 'Phenotype', 'HP:0031919', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Juvenile granulosa cell tumor', 'Disease', (0, 29))	('sex-chromosomal mosaicism', 'Var', (114, 139))	('genitalia in the neonatal period', 'Phenotype', 'HP:0000078', (154, 186))	('Juvenile granulosa cell tumor', 'Phenotype', 'HP:0031919', (0, 29))	('ambiguous genitalia', 'Disease', 'MESH:D012734', (144, 163))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Juvenile granulosa cell tumor', 'Disease', 'MESH:D006106', (0, 29))	('ambiguous genitalia', 'Phenotype', 'HP:0000062', (144, 163))	('ambiguous genitalia', 'Disease', (144, 163))	('GCT', 'Phenotype', 'HP:0100728', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor of sex cord-stromal cells', 'Phenotype', 'HP:0031918', (40, 71))
5298	27785439	Recent studies have demonstrated a possible role for WT1 (Wilms tumor 1) genotyping in 46 XY DSD, including patients with both hypospadias and uni- or bilateral undescended testes.	('Wilms tumor 1', 'Gene', '7490', (58, 71))	('Wilms tumor 1', 'Gene', (58, 71))	('WT1', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('46 XY DSD', 'Disease', (87, 96))	('patients', 'Species', '9606', (108, 116))	('undescended testes', 'Phenotype', 'HP:0000028', (161, 179))	('hypospadias', 'Phenotype', 'HP:0000047', (127, 138))	('Wilms tumor', 'Phenotype', 'HP:0002667', (58, 69))	('genotyping', 'Var', (73, 83))	('hypospadias', 'Disease', 'MESH:D007021', (127, 138))	('WT1', 'Gene', '7490', (53, 56))	('hypospadias', 'Disease', (127, 138))
5308	25294825	Mutations that constitutively activate the RAS/ERK pathway occur in one quarter of all tumors, including 95% of pancreatic cancers, 35% of lung cancers and 30% of melanomas.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('lung cancers', 'Disease', 'MESH:D008175', (139, 151))	('melanomas', 'Disease', 'MESH:D008545', (163, 172))	('pancreatic cancers', 'Disease', 'MESH:D010190', (112, 130))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancers', 'Disease', (139, 151))	('melanomas', 'Disease', (163, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('activate', 'PosReg', (30, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('tumors', 'Disease', (87, 93))	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (112, 130))	('RAS/ERK pathway', 'Pathway', (43, 58))	('occur', 'Reg', (59, 64))	('pancreatic cancers', 'Disease', (112, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))
5317	25294825	A deletion of ETS2 in mice results in a phenotype similar to a deletion of the RAS/ERK activator EGFR, and a deletion of both ETS1 and ETS2 in mouse embryonic fibroblasts inhibits HrasG12V transformation, but it is not known what cis-regulatory sequences mediate these effects.	('inhibits', 'NegReg', (171, 179))	('ETS1', 'Gene', (126, 130))	('deletion', 'Var', (109, 117))	('ETS2', 'Gene', (135, 139))	('mouse', 'Species', '10090', (143, 148))	('deletion', 'Var', (2, 10))	('HrasG12V transformation', 'CPA', (180, 203))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '13649', (97, 101))	('deletion', 'Var', (63, 71))	('results in', 'Reg', (27, 37))	('mice', 'Species', '10090', (22, 26))	('ETS2', 'Gene', (14, 18))
5331	25294825	PC3 cells were cultured in F12K medium (Mediatech-Cellgro) with 10% FBS.	('PC3', 'Gene', '3853', (0, 3))	('F12K', 'SUBSTITUTION', 'None', (27, 31))	('F12K', 'Var', (27, 31))	('FBS', 'Disease', 'MESH:D005198', (68, 71))	('PC3', 'Gene', (0, 3))	('FBS', 'Disease', (68, 71))
5338	25294825	Wild type and mutant ETS/AP-1 reporter plasmids were previously described.	('mutant', 'Var', (14, 20))	('AP-1', 'Gene', '2353', (25, 29))	('AP-1', 'Gene', (25, 29))
5343	25294825	Antibodies used in ChIP were from Santa Cruz Biotechnology: GABPA (sc-22810, lot #B2009), ETS1, (sc-350, lot #F2811 [DU145], lot #F1312 [PANC-1]), ELF1 (sc-631, lot #L2702), ELK4 (sc-13030, lot #G2711, JUND (sc-74, lot #K1111).	('GABPA', 'Gene', (60, 65))	('ELK4', 'Gene', '2005', (174, 178))	('sc-13030', 'Var', (180, 188))	('JUND', 'Gene', (202, 206))	('JUND', 'Gene', '3727', (202, 206))	('ELF1', 'Gene', '1997', (147, 151))	('lot #K1111', 'Var', (215, 225))	('GABPA', 'Gene', '2551', (60, 65))	('lot #F2811', 'Var', (105, 115))	('ELK4', 'Gene', (174, 178))	('PANC-1', 'CellLine', 'CVCL:0480', (137, 143))	('ELF1', 'Gene', (147, 151))	('DU145', 'CellLine', 'CVCL:0105', (117, 122))	('lot #B2009', 'Var', (77, 87))
5347	25294825	Total RNA for three independent biological replicates was isolated from DU145 cells transduced with lentiviral shRNA knockdown vectors (see above), or U0126 inhibition at 50 muM for 6 h (Cell Signaling) using the RNeasy mini kit (Qiagen) according to manufacturer's instructions.	('shRNA', 'Gene', (111, 116))	('U0126', 'Chemical', 'MESH:C113580', (151, 156))	('knockdown vectors', 'Var', (117, 134))	('inhibition', 'NegReg', (157, 167))	('U0126', 'Gene', (151, 156))	('DU145', 'CellLine', 'CVCL:0105', (72, 77))
5355	25294825	Multiple control sequences were tested to verify significance, including a sequence with a point mutation in the ETS sequence (mutETS/AP-1), and three sequences that reflect other known ETS partnerships: ETS/ETS, ETS/CRE and ETS/SP1.	('AP-1', 'Gene', '2353', (134, 138))	('ETS', 'Gene', (113, 116))	('ETS/SP1', 'Gene', '6667', (225, 232))	('AP-1', 'Gene', (134, 138))	('ETS/SP1', 'Gene', (225, 232))	('point mutation', 'Var', (91, 105))
5368	25294825	We used a shRNA knockdown approach to test cell migration roles of five candidate ETS proteins in DU145, a prostate cancer cell line that does not express high levels of oncogenic ETS proteins, but has an active RAS/ERK pathway due to a chromosomal rearrangement of KRAS.	('prostate cancer', 'Disease', (107, 122))	('DU145', 'CellLine', 'CVCL:0105', (98, 103))	('KRAS', 'Gene', (266, 270))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('active', 'PosReg', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('chromosomal rearrangement', 'Var', (237, 262))	('RAS/ERK pathway', 'Pathway', (212, 227))
5371	25294825	While depletion of ELF1, GABPA and ETV4 had no effect on cell migration, knockdown of ETS2, a close homolog of ETS1, actually increased cell migration (Figure 2B), without affecting proliferation (Supplementary Figure S2C), indicating a possible attenuating function for this factor.	('ETS2', 'Gene', (86, 90))	('GABPA', 'Gene', '2551', (25, 30))	('ELF1', 'Gene', '1997', (19, 23))	('ELF1', 'Gene', (19, 23))	('GABPA', 'Gene', (25, 30))	('ETV4', 'Gene', '2118', (35, 39))	('ETV4', 'Gene', (35, 39))	('increased', 'PosReg', (126, 135))	('cell migration', 'CPA', (136, 150))	('knockdown', 'Var', (73, 82))
5374	25294825	Mutation of the ETS binding sequences (ETSmut/AP-1) in the reporter decreased expression to a similar extent, indicating that binding of an ETS factor is required for RAS/ERK mediated activation.	('decreased', 'NegReg', (68, 77))	('expression', 'MPA', (78, 88))	('Mutation', 'Var', (0, 8))	('AP-1', 'Gene', '2353', (46, 50))	('AP-1', 'Gene', (46, 50))
5377	25294825	In DU145 cells, knockdown of ETS1, but not ETV4 or ELF1 decreased anchorage independent growth (Figure 2E).	('ETV4', 'Gene', '2118', (43, 47))	('anchorage independent growth', 'CPA', (66, 94))	('decreased', 'NegReg', (56, 65))	('knockdown', 'Var', (16, 25))	('DU145', 'CellLine', 'CVCL:0105', (3, 8))	('ETV4', 'Gene', (43, 47))	('ETS1', 'Gene', (29, 33))	('ELF1', 'Gene', '1997', (51, 55))	('ELF1', 'Gene', (51, 55))
5378	25294825	ETS1 knockdown also increased E-Cadherin and decreased Vimentin expression consistent with a role for ETS1 in promoting EMT (Figure 2F).	('increased', 'PosReg', (20, 29))	('Vimentin', 'Gene', (55, 63))	('E-Cadherin', 'Gene', (30, 40))	('Vimentin', 'Gene', '7431', (55, 63))	('knockdown', 'Var', (5, 14))	('ETS1', 'Gene', (0, 4))	('decreased', 'NegReg', (45, 54))	('promoting', 'PosReg', (110, 119))	('E-Cadherin', 'Gene', '999', (30, 40))	('EMT', 'CPA', (120, 123))
5379	25294825	Interestingly, an ETS2 knockdown reduced E-Cadherin expression, again indicating an opposite or attenuating function.	('ETS2', 'Gene', (18, 22))	('knockdown', 'Var', (23, 32))	('E-Cadherin', 'Gene', (41, 51))	('reduced', 'NegReg', (33, 40))	('E-Cadherin', 'Gene', '999', (41, 51))
5381	25294825	ERK can phosphorylate ETS1 at T38 and S41 residues and this promotes transactivation by increasing affinity for the co-activator CBP/p300.	('promotes', 'PosReg', (60, 68))	('CBP/p300', 'Gene', '1387;2033', (129, 137))	('transactivation', 'MPA', (69, 84))	('S41', 'Var', (38, 41))	('affinity', 'MPA', (99, 107))	('CBP/p300', 'Gene', (129, 137))	('T38', 'Var', (30, 33))	('increasing', 'PosReg', (88, 98))
5382	25294825	To test the role of these residues in the ETS1 cell migration function, a retroviral vector system was used to stably overexpress FLAG-tagged versions of either wild-type ETS1 or ETS1 with two alanine substitutions (ETS1 T38A/S41A) in DU145 cells.	('T38A', 'Mutation', 'rs757197855', (221, 225))	('DU145', 'CellLine', 'CVCL:0105', (235, 240))	('ETS1', 'Gene', (179, 183))	('ETS1', 'Gene', (171, 175))	('S41A', 'SUBSTITUTION', 'None', (226, 230))	('alanine', 'Chemical', 'MESH:D000409', (193, 200))	('S41A', 'Var', (226, 230))
5383	25294825	Overexpression of wild-type ETS1 increased migration of DU145 cells, but ETS1 T38A/S41A acted in a dominant negative fashion and decreased cell migration (Figure 2H).	('S41A', 'Var', (83, 87))	('ETS1', 'Gene', (73, 77))	('T38A', 'Mutation', 'rs757197855', (78, 82))	('negative', 'NegReg', (108, 116))	('cell migration', 'CPA', (139, 153))	('increased', 'PosReg', (33, 42))	('migration', 'CPA', (43, 52))	('S41A', 'SUBSTITUTION', 'None', (83, 87))	('decreased', 'NegReg', (129, 138))	('DU145', 'CellLine', 'CVCL:0105', (56, 61))
5384	25294825	ETS2 had a similar effect as ETS1 T38A/S41A, again pointing to a role for ETS2 in attenuating migration.	('migration', 'CPA', (94, 103))	('S41A', 'SUBSTITUTION', 'None', (39, 43))	('attenuating', 'NegReg', (82, 93))	('S41A', 'Var', (39, 43))	('T38A', 'Mutation', 'rs757197855', (34, 38))
5387	25294825	Similar to the cell migration results, wild-type ETS1 increased reporter expression, and ETS1 T38A/S41A decreased reporter expression (Figure 2I).	('T38A', 'Mutation', 'rs757197855', (94, 98))	('reporter expression', 'MPA', (114, 133))	('ETS1', 'Gene', (89, 93))	('decreased', 'NegReg', (104, 113))	('increased', 'PosReg', (54, 63))	('S41A', 'SUBSTITUTION', 'None', (99, 103))	('S41A', 'Var', (99, 103))	('reporter expression', 'MPA', (64, 83))
5390	25294825	In PC3 cells, depletion of ETV4 decreased cell migration, but depletion of ETS1 had no effect (Figure 3A and B), indicating no ETS1 role when RAS/ERK activity is low.	('cell migration', 'CPA', (42, 56))	('ETV4', 'Gene', (27, 31))	('ETV4', 'Gene', '2118', (27, 31))	('depletion', 'Var', (14, 23))	('PC3', 'Gene', (3, 6))	('decreased', 'NegReg', (32, 41))	('PC3', 'Gene', '3853', (3, 6))
5395	25294825	Consistent with this observation, depleting endogenous ETS1 from RWPE2 cells results in a significant loss of cell migration (Figure 3E).	('depleting', 'Var', (34, 43))	('RWPE2', 'CellLine', 'CVCL:3792', (65, 70))	('cell migration', 'CPA', (110, 124))	('ETS1', 'Gene', (55, 59))	('loss', 'NegReg', (102, 106))	('endogenous', 'MPA', (44, 54))
5396	25294825	In conclusion, the ability of ETS1 to transactivate through ETS/AP-1 sequences and drive cell migration requires RAS/ERK activation and the ERK phosphorylation residues T38 and S41.	('RAS/ERK', 'Protein', (113, 120))	('AP-1', 'Gene', '2353', (64, 68))	('AP-1', 'Gene', (64, 68))	('ETS1', 'Gene', (30, 34))	('drive', 'PosReg', (83, 88))	('T38', 'Var', (169, 172))	('S41', 'Var', (177, 180))	('cell migration', 'CPA', (89, 103))	('transactivate', 'MPA', (38, 51))
5422	25294825	RAS pathway activating mutations are more common in pancreatic cancer and lung cancer than in prostate cancer.	('lung cancer', 'Disease', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Disease', (52, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (52, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('mutations', 'Var', (23, 32))	('RAS pathway', 'Pathway', (0, 11))	('activating', 'PosReg', (12, 22))	('common', 'Reg', (42, 48))	('prostate cancer', 'Disease', (94, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
5429	25294825	Loss of ETS1 significantly decreased the migration of PANC1 cells (Figure 5D).	('PANC1', 'CellLine', 'CVCL:0480', (54, 59))	('migration', 'CPA', (41, 50))	('decreased', 'NegReg', (27, 36))	('Loss', 'Var', (0, 4))	('ETS1', 'Gene', (8, 12))	('PANC1', 'Gene', (54, 59))
5439	25294825	However, knockdown of ETS1 resulted in only a slight decrease in steady-state pERK levels (Figure 6D).	('pERK', 'Gene', '9451', (78, 82))	('ETS1', 'Gene', (22, 26))	('knockdown', 'Var', (9, 18))	('decrease', 'NegReg', (53, 61))	('pERK', 'Gene', (78, 82))
5457	25294825	In fact, loss of ETS1 causes lethality due to vascular rupture when combined with a hypomorphic allele of ETS2, indicating genetic redundancy in endothelial cells.	('ETS1', 'Gene', (17, 21))	('vascular rupture', 'Disease', 'MESH:D012421', (46, 62))	('loss', 'Var', (9, 13))	('vascular rupture', 'Phenotype', 'HP:0025019', (46, 62))	('lethality', 'MPA', (29, 38))	('vascular rupture', 'Disease', (46, 62))
5459	25294825	This is consistent with previous studies indicating that high ETS1 expression levels correlate with increased invasion and poor prognosis in breast and colon cancer, while ETS2 is tumor suppressive.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('increased', 'PosReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('high', 'Var', (57, 61))	('ETS1', 'Gene', (62, 66))	('tumor', 'Disease', (180, 185))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('breast and colon cancer', 'Disease', 'MESH:D001943', (141, 164))	('expression levels', 'MPA', (67, 84))	('invasion', 'CPA', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
5606	24457464	In a study of sections taken from patients with testicular germ cell cancer, using Ki67 as a marker of proliferation, 17.42% of intratubular germ cell neoplasia cells were found to be Ki67 positive.	('germ cell cancer', 'Phenotype', 'HP:0100728', (59, 75))	('testicular germ cell cancer', 'Disease', (48, 75))	('testicular germ cell cancer', 'Disease', 'MESH:D009373', (48, 75))	('neoplasia', 'Disease', 'MESH:D009369', (151, 160))	('neoplasia', 'Phenotype', 'HP:0002664', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('intratubular', 'Disease', (128, 140))	('patients', 'Species', '9606', (34, 42))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (141, 160))	('Ki67', 'Var', (184, 188))	('neoplasia', 'Disease', (151, 160))
5681	24198622	Furthermore, patients receiving radiotherapy are at a higher risk of developing a secondary malignancy versus no therapy at all (though the incidence of a secondary malignancy is very low).	('radiotherapy', 'Var', (32, 44))	('malignancy', 'Disease', 'MESH:D009369', (165, 175))	('patients', 'Species', '9606', (13, 21))	('malignancy', 'Disease', (165, 175))	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('malignancy', 'Disease', (92, 102))
5827	24198622	The term "complicated" RPLND (PCRPLND) applies to patients who have received more than induction chemotherapy only (salvage), have experienced a retroperitoneal recurrence after initial RPLND (redo), or have elevated serum TM or progression of disease during or immediately after chemotherapy (desperation).	('elevated', 'PosReg', (208, 216))	('patients', 'Species', '9606', (50, 58))	('RPLND', 'Var', (186, 191))	('serum TM', 'MPA', (217, 225))	('PC', 'Chemical', '-', (30, 32))	('elevated serum TM', 'Phenotype', 'HP:0002155', (208, 225))
5868	27315568	Disruptions in mitotic checkpoints contribute resistance to DNA-damaging agents in cancer.	('Disruptions', 'Var', (0, 11))	('mitotic checkpoints', 'Gene', (15, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('resistance', 'MPA', (46, 56))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
5878	27315568	MAD2 is an important activator of the mitotic spindle assembly checkpoint (SAC), which delays the onset of anaphase in response to microtubule disruption or misaligned or unattached kinetochores during mitosis.	('MAD2', 'Gene', (0, 4))	('response to microtubule disruption', 'MPA', (119, 153))	('MAD2', 'Gene', '4085', (0, 4))	('misaligned', 'Var', (157, 167))	('mitosis', 'Disease', (202, 209))	('mitosis', 'Disease', 'None', (202, 209))
5879	27315568	SAC impairment causes cells to prematurely enter anaphase, resulting in chromosome missegregation, aneuploidy or chromosome instability.	('aneuploidy', 'Disease', 'MESH:D000782', (99, 109))	('resulting in', 'Reg', (59, 71))	('impairment', 'Var', (4, 14))	('chromosome instability', 'Phenotype', 'HP:0040012', (113, 135))	('enter', 'Reg', (43, 48))	('aneuploidy', 'Disease', (99, 109))	('chromosome instability', 'CPA', (113, 135))	('chromosome missegregation', 'CPA', (72, 97))
5880	27315568	Aberrant MAD2 expression has been demonstrated to play a role in these chromosomal abnormalities in different types of cancerous cells, including those derived from testicular cancer, esophageal adenocarcinoma, ovarian cancer, colorectal cancer, cervical cancer, breast cancer, and gastric cancer, among others.	('cervical cancer', 'Disease', 'MESH:D002583', (246, 261))	('esophageal adenocarcinoma', 'Disease', (184, 209))	('breast cancer', 'Disease', (263, 276))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (71, 96))	('cervical cancer', 'Disease', (246, 261))	('gastric cancer', 'Phenotype', 'HP:0012126', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('colorectal cancer', 'Phenotype', 'HP:0003003', (227, 244))	('Aberrant', 'Var', (0, 8))	('ovarian cancer', 'Disease', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('testicular cancer', 'Disease', 'MESH:D013736', (165, 182))	('ovarian cancer', 'Phenotype', 'HP:0100615', (211, 225))	('gastric cancer', 'Disease', (282, 296))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('chromosomal abnormalities', 'Disease', (71, 96))	('MAD2', 'Gene', '4085', (9, 13))	('cancerous', 'Disease', 'MESH:D009369', (119, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (282, 296))	('breast cancer', 'Phenotype', 'HP:0003002', (263, 276))	('colorectal cancer', 'Disease', 'MESH:D015179', (227, 244))	('MAD2', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('testicular cancer', 'Disease', (165, 182))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (184, 209))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (184, 209))	('play', 'Reg', (50, 54))	('colorectal cancer', 'Disease', (227, 244))	('testicular cancer', 'Phenotype', 'HP:0010788', (165, 182))	('role', 'Reg', (57, 61))	('cancerous', 'Disease', (119, 128))	('breast cancer', 'Disease', 'MESH:D001943', (263, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (211, 225))
5886	27315568	In fact, several studies have demonstrated an association between aberrant MAD2 expression and resistance or sensitivity to DNA damage both in vitro and in vivo.	('sensitivity to DNA damage', 'MPA', (109, 134))	('MAD2', 'Gene', (75, 79))	('MAD2', 'Gene', '4085', (75, 79))	('resistance', 'MPA', (95, 105))	('aberrant', 'Var', (66, 74))	('expression', 'MPA', (80, 90))
5895	27315568	The ectopic expression of MAD2gamma in the SAC-competent colorectal cancer cell line HCT116 reduced the mitotic index, suggesting an impairment of the SAC.	('colorectal cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('MAD2', 'Gene', (26, 30))	('MAD2', 'Gene', '4085', (26, 30))	('HCT116', 'CellLine', 'CVCL:0291', (85, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('reduced', 'NegReg', (92, 99))	('mitotic index', 'CPA', (104, 117))	('ectopic expression', 'Var', (4, 22))
5898	27315568	These results highlight the importance of exploring the splice variants of different SAC components, which may compromise SAC signaling and the response to cancer chemotherapy.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('SAC signaling', 'MPA', (122, 135))	('splice variants', 'Var', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('compromise', 'NegReg', (111, 121))
5909	27315568	In contrast, MAD2gamma was expressed at lower levels in the following cell lines: SW48, HT29, SW480, HeLa, C33, and NT2-D1.	('HeLa', 'CellLine', 'CVCL:0030', (101, 105))	('MAD2', 'Gene', (13, 17))	('MAD2', 'Gene', '4085', (13, 17))	('SW480', 'Var', (94, 99))	('HT29', 'CellLine', 'CVCL:0320', (88, 92))	('SW480', 'CellLine', 'CVCL:0546', (94, 99))
5911	27315568	As indicated previously, aberrant levels of MAD2alpha or MAD2beta correlate with SAC impairment and chromosome missegregation.	('MAD2', 'Gene', (57, 61))	('MAD2', 'Gene', (44, 48))	('MAD2', 'Gene', '4085', (44, 48))	('MAD2', 'Gene', '4085', (57, 61))	('MAD2beta', 'Gene', (57, 65))	('chromosome missegregation', 'CPA', (100, 125))	('aberrant levels', 'Var', (25, 40))	('MAD2beta', 'Gene', '10459', (57, 65))	('SAC', 'Disease', (81, 84))
5924	27315568	A frameshift and a premature stop codon in both MAD2 isoforms generates a new C-terminal of 17 amino acids length that is not present in MAD2alpha (Fig.	('MAD2', 'Gene', (137, 141))	('MAD2', 'Gene', '4085', (137, 141))	('frameshift', 'Var', (2, 12))	('MAD2', 'Gene', (48, 52))	('MAD2', 'Gene', '4085', (48, 52))
5969	27315568	Interestingly, other spliced variants that compromise SAC activation have been reported, such as the MAD1 isoform MAD1beta, reported by Sze et al.	('compromise', 'NegReg', (43, 53))	('SAC activation', 'MPA', (54, 68))	('MAD1', 'Gene', (101, 105))	('variants', 'Var', (29, 37))	('MAD1', 'Gene', (114, 118))	('MAD1', 'Gene', '8379', (101, 105))	('MAD1', 'Gene', '8379', (114, 118))
5982	27315568	Thus, disruptions to the SAC in human cancers may contribute to resistance to both spindle inhibitors and DNA-damaging agents.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('contribute', 'Reg', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('resistance', 'MPA', (64, 74))	('disruptions', 'Var', (6, 17))	('human', 'Species', '9606', (32, 37))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
5992	27315568	Depletion of TPR shifted the localization of MAD2 from the NPC to the nucleus, which resulted in decreased binding of MAD2 to MAD1 and CDC20, premature induction of anaphase, and chromosome missegregation.	('MAD2', 'Gene', (118, 122))	('TPR', 'Gene', (13, 16))	('MAD1', 'Gene', (126, 130))	('MAD2', 'Gene', '4085', (118, 122))	('CDC20', 'Gene', (135, 140))	('CDC20', 'Gene', '991', (135, 140))	('TPR', 'Gene', '7175', (13, 16))	('anaphase', 'CPA', (165, 173))	('MAD1', 'Gene', '8379', (126, 130))	('MAD2', 'Gene', (45, 49))	('Depletion', 'Var', (0, 9))	('chromosome missegregation', 'CPA', (179, 204))	('decreased', 'NegReg', (97, 106))	('MAD2', 'Gene', '4085', (45, 49))	('binding', 'Interaction', (107, 114))
5998	27315568	demonstrated that osteosarcoma cells treated with mitomycin C modulated their response to DNA damage and survived by upregulating the splicing factor SRp55, which in turn shifted the splicing pattern of the FAS receptor gene (CD95) to favor expression of the soluble, pro-survival isoform (sFAS) over the membrane-bound, pro-apoptotic isoform (FAS).	('SRp55', 'Gene', (150, 155))	('CD95', 'Gene', '355', (226, 230))	('mitomycin', 'Var', (50, 59))	('osteosarcoma', 'Phenotype', 'HP:0002669', (18, 30))	('CD95', 'Gene', (226, 230))	('osteosarcoma', 'Disease', (18, 30))	('response', 'MPA', (78, 86))	('expression', 'MPA', (241, 251))	('osteosarcoma', 'Disease', 'MESH:D012516', (18, 30))	('favor', 'PosReg', (235, 240))	('upregulating', 'PosReg', (117, 129))	('SRp55', 'Gene', '6431', (150, 155))	('modulated', 'Reg', (62, 71))	('mitomycin C', 'Chemical', 'MESH:D016685', (50, 61))
6000	27315568	The inhibition of the splicing factor CDC5L, which modulates the splicing of a set of genes involved in mitosis and DNA damage response, induced dramatic mitotic arrest and sustained activation of the SAC, eventually leading to mitotic catastrophe.	('SAC', 'MPA', (201, 204))	('mitotic arrest', 'Disease', (154, 168))	('activation', 'PosReg', (183, 193))	('mitosis', 'Disease', 'None', (104, 111))	('CDC5L', 'Gene', '988', (38, 43))	('mitotic arrest', 'Disease', 'MESH:D006323', (154, 168))	('CDC5L', 'Gene', (38, 43))	('inhibition', 'Var', (4, 14))	('leading to', 'Reg', (217, 227))	('mitosis', 'Disease', (104, 111))	('mitotic catastrophe', 'CPA', (228, 247))
6004	27315568	Our results highlight the importance of identifying alternative splicing events that may compromise both SAC function and the response to cancer therapy.	('cancer', 'Disease', (138, 144))	('compromise', 'NegReg', (89, 99))	('SAC function', 'CPA', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('alternative splicing events', 'Var', (52, 79))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
6005	27315568	The following cancer cell lines were maintained in DMEM (Life Technologies, Inc., Massachusetts, USA): HeLa, SiHa, and C33A (cervical cancer); T24 and 1A6 (bladder cancer); NT2-D1 (testicular cancer); T47D (breast cancer); SW48 and SW480 (colon cancer); and U373 (glioblastoma).	('DMEM', 'Chemical', '-', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cervical cancer', 'Disease', 'MESH:D002583', (125, 140))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cervical cancer', 'Disease', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (214, 220))	('colon cancer', 'Phenotype', 'HP:0003003', (239, 251))	('cancer', 'Disease', (134, 140))	('SW48', 'Var', (223, 227))	('testicular cancer', 'Disease', 'MESH:D013736', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('glioblastoma', 'Disease', 'MESH:D005909', (264, 276))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('HeLa', 'CellLine', 'CVCL:0030', (103, 107))	('colon cancer', 'Disease', 'MESH:D015179', (239, 251))	('cancer', 'Disease', (245, 251))	('T47D', 'CellLine', 'CVCL:0553', (201, 205))	('SW480', 'Var', (232, 237))	('glioblastoma', 'Disease', (264, 276))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('SiHa', 'CellLine', 'CVCL:0032', (109, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (264, 276))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (14, 20))	('SW480', 'CellLine', 'CVCL:0546', (232, 237))	('testicular cancer', 'Disease', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('bladder cancer', 'Disease', (156, 170))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('colon cancer', 'Disease', (239, 251))	('testicular cancer', 'Phenotype', 'HP:0010788', (181, 198))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Disease', (207, 220))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))
6039	27315568	HPRT was used as a reference (Hs99999909_m1, Cat.	('HPRT', 'Gene', (0, 4))	('Hs99999909_m1', 'Var', (30, 43))	('HPRT', 'Gene', '3251', (0, 4))
6217	24098438	Cells were incubated overnight in 1% BSA/0.1% Triton X-100 in PBS at 4 C with the following primary antibodies: anti-E-cadherin (Santa Cruz Biotechnology, rabbit polyclonal sc-7870 1:50), anti-beta-catenin (Santa Cruz Biotechnology, mouse monoclonal sc-7963, 1:50 dilution), anti-connexin-43 (Sigma-Aldrich, rabbit polyclonal C6219, 1:50 dilution), and anti-p-Histone H3 (Santa Cruz Biotechnology, mouse monoclonal sc-374669, 1:50 dilution).	('PBS', 'Gene', (62, 65))	('PBS', 'Gene', '1131', (62, 65))	('mouse', 'Species', '10090', (398, 403))	('rabbit', 'Species', '9986', (155, 161))	('mouse', 'Species', '10090', (233, 238))	('connexin-43', 'Gene', '2697', (280, 291))	('beta-catenin', 'Gene', (193, 205))	('anti-p-Histone', 'Var', (353, 367))	('rabbit', 'Species', '9986', (308, 314))	('Triton X-100', 'Chemical', 'MESH:D017830', (46, 58))	('beta-catenin', 'Gene', '1499', (193, 205))	('connexin-43', 'Gene', (280, 291))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))
6252	24098438	Differences between treated and control samples were observed already at 10 minutes of incubation and TCam-2 cell spreading resulted faster in the presence of EW than in control cells in all the substrate culture condition considered (Figure 1B upper panel).	('TCam-2', 'Gene', (102, 108))	('faster', 'PosReg', (133, 139))	('presence', 'Var', (147, 155))	('TCam-2', 'CellLine', 'CVCL:T012', (102, 108))
6274	24098438	Interestingly E-cadherin knock-down was able to increase significantly the migratory ability of TCam-2 seminoma cells even in control condition and is able to completely rescue the migratory capability of EW treated sample.	('E-cadherin', 'Gene', '999', (14, 24))	('migratory ability', 'CPA', (75, 92))	('seminoma', 'Disease', 'MESH:D018239', (103, 111))	('TCam-2', 'CellLine', 'CVCL:T012', (96, 102))	('knock-down', 'Var', (25, 35))	('migratory capability', 'CPA', (181, 201))	('seminoma', 'Disease', (103, 111))	('E-cadherin', 'Gene', (14, 24))	('increase', 'PosReg', (48, 56))
6275	24098438	Also beta-catenin knock-down is able to rescue migratory behaviour of EW treated TCam-2 cells even if it does not reach the same level of negative control duplex EW untreated samples (Figure 9B).	('migratory behaviour', 'CPA', (47, 66))	('beta-catenin', 'Gene', (5, 17))	('knock-down', 'Var', (18, 28))	('rescue', 'PosReg', (40, 46))	('beta-catenin', 'Gene', '1499', (5, 17))	('TCam-2', 'CellLine', 'CVCL:T012', (81, 87))
6276	24098438	This result can be easily explained considering that beta-catenin knock-down in EW treated samples was less efficient than the E-cadherin knock-down in the same samples (Figure 9C).	('beta-catenin', 'Gene', (53, 65))	('knock-down', 'Var', (66, 76))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (127, 137))	('beta-catenin', 'Gene', '1499', (53, 65))
6287	24098438	Modulation of cell adhesion to substrates is a key-step during the early phases of metastatic progression, when individual or small groups of cancer cells may acquire the ability to detach from a primary tumour.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Disease', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (142, 148))
6298	24098438	The E-cadherin loss in tumours can be mainly ascribed to inactivating mutations, epigenetic silencing, proteolytic cleavage, and proteosomal degradation.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('epigenetic silencing', 'Var', (81, 101))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('loss', 'NegReg', (15, 19))	('tumours', 'Disease', (23, 30))	('E-cadherin', 'Gene', (4, 14))	('E-cadherin', 'Gene', '999', (4, 14))	('inactivating mutations', 'Var', (57, 79))	('proteolytic', 'MPA', (103, 114))
6333	32217837	Understanding of the molecular mechanisms that control the early steps of spermatogenesis is important as aberrant expression of signaling molecules may result in proliferating or differentiating defects.	('result in', 'Reg', (153, 162))	('aberrant', 'Var', (106, 114))	('rat', 'Species', '10116', (170, 173))	('differentiating defects', 'CPA', (180, 203))	('proliferating', 'CPA', (163, 176))	('expression', 'MPA', (115, 125))
6336	32217837	Notably, inhibition of sumoylation with the inhibitor Gingkolic acid (GA) arrested the G2/M1 transition in purified mouse spermatocytes in vitro.	('inhibition', 'Var', (9, 19))	('GA', 'Chemical', '-', (70, 72))	('G2/M1 transition', 'CPA', (87, 103))	('Gingkolic acid', 'Chemical', '-', (54, 68))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('mouse', 'Species', '10090', (116, 121))	('arrest', 'Disease', (74, 80))
6339	32217837	Inactivation of sumoylation machinery in mouse resulted in early embryonic lethality with severe disruptions in mitosis, a finding that supports the indispensable role of sumoylation in cell cycle progression.	('disruptions', 'NegReg', (97, 108))	('mouse', 'Species', '10090', (41, 46))	('embryonic lethality', 'Disease', 'MESH:D020964', (65, 84))	('embryonic lethality', 'Disease', (65, 84))	('mitosis', 'CPA', (112, 119))	('Inactivation', 'Var', (0, 12))
6361	32217837	The C18-4 cell line was grown in DMEM media with 5% fetal bovine serum (FBS; 16140-071; Thermo Fisher, Waltham, MA, USA), 5% bovine growth serum (SH30541.03, Thermo Fisher), 1% penicillin/streptomycin (15140-122, Thermo Fisher), and 0.5% Fungizone (15290-018, Thermo Fisher) at 37 C with 5% CO2.	('penicillin', 'Chemical', 'MESH:D010406', (177, 187))	('CO2', 'Chemical', 'MESH:D002245', (291, 294))	('15290-018', 'Var', (249, 258))	('Fungizone', 'Chemical', 'MESH:D000666', (238, 247))	('15140-122', 'Var', (202, 211))	('streptomycin', 'Chemical', 'MESH:D013307', (188, 200))	('DMEM media', 'Chemical', '-', (33, 43))
6390	32217837	The secondary antibodies used in this study included the following: anti-rabbit IgG horseradish peroxidase (HRP) linked (NA934V, GE Healthcare UK Limited) and goat anti-mouse IgG (H + L) HRP (AP308P, EMD Millipore Corporation, Sigma Aldrich).	('NA934V', 'Chemical', '-', (121, 127))	('mouse', 'Species', '10090', (169, 174))	('AP308P', 'Var', (192, 198))	('NA934V', 'Var', (121, 127))	('rat', 'Species', '10116', (219, 222))
6440	32217837	Notably, it has been shown that PCNA can be modified by SUMO at the replication fork, and that impairment of this modification facilitates formation of double-strand DNA breaks.	('PCNA', 'Gene', (32, 36))	('SUMO', 'MPA', (56, 60))	('facilitates', 'PosReg', (127, 138))	('men', 'Species', '9606', (101, 104))	('formation of double-strand DNA breaks', 'MPA', (139, 176))	('PCNA', 'Gene', '18538', (32, 36))	('impairment', 'Var', (95, 105))
6441	32217837	Therefore, aberrant sumoylation of PCNA can contribute to aberrant recombination events and development of cancer.	('aberrant', 'CPA', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('contribute', 'Reg', (44, 54))	('PCNA', 'Gene', '18538', (35, 39))	('aberrant', 'Var', (11, 19))	('sumoylation', 'MPA', (20, 31))	('men', 'Species', '9606', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('PCNA', 'Gene', (35, 39))	('cancer', 'Disease', (107, 113))
6446	32217837	Blocking SUMO modification of Top2 in mitotic cells prevented the dissociation of sister chromatids at the metaphase-anaphase transition, supporting the idea that SUMO conjugation is crucial for proper chromosome segregation.	('prevented', 'NegReg', (52, 61))	('Top2', 'Gene', (30, 34))	('Top2', 'Gene', '21973', (30, 34))	('modification', 'Var', (14, 26))
6476	32217837	To test whether changes in the level of sumoylated proteins affect the proliferation of C18-4 cell, a downregulation and overexpression of SUMO was performed using UBC9 (the SUMO conjugating enzyme) si-RNA and SUMO-2 plasmid, respectively.	('changes', 'Var', (16, 23))	('UBC9', 'Gene', (164, 168))	('SUMO-2', 'Gene', (210, 216))	('downregulation', 'NegReg', (102, 116))	('SUMO-2', 'Gene', '170930', (210, 216))	('UBC9', 'Gene', '22196', (164, 168))	('rat', 'Species', '10116', (78, 81))
6479	32217837	Using PCNA as a proliferative marker, the results of the experiments revealed that downregulation of sumoylation using si-RNA was not sufficient to significantly affect the level of cellular proliferation (Figure 6a).	('men', 'Species', '9606', (63, 66))	('PCNA', 'Gene', '18538', (6, 10))	('si-RNA', 'Var', (119, 125))	('rat', 'Species', '10116', (23, 26))	('downregulation', 'NegReg', (83, 97))	('PCNA', 'Gene', (6, 10))	('rat', 'Species', '10116', (198, 201))	('cellular proliferation', 'CPA', (182, 204))	('sumoylation', 'MPA', (101, 112))
6494	32217837	Further studies using overexpression of sumolylation in stem cells or its inactivation in cancerous cells, together with studies of specific SUMO targets identified in the current study, should provide a better understanding of the SUMO-mediated molecular control of events in normal and cancerous male germ cells.	('cancerous', 'Disease', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancerous', 'Disease', 'MESH:D009369', (90, 99))	('cancerous', 'Disease', (288, 297))	('sumolylation', 'Var', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancerous', 'Disease', 'MESH:D009369', (288, 297))
6561	28067779	In a Swedish, hospital-based study, higher blood levels of both trans-nonachlor (OR 4.1; 95% CI (1.5-11.0)) and cis-nonachlor (OR 3.1; 95% CI (1.2-7.8)) were detected among TC cases, in respect to healthy controls.	('cis-nonachlor', 'Var', (112, 125))	('higher', 'PosReg', (36, 42))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (112, 125))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (64, 79))	('blood levels', 'MPA', (43, 55))
6853	31730712	Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population.	('SMN', 'Gene', '6606', (94, 97))	('Radiotherapy', 'Var', (0, 12))	('SMN', 'Gene', (94, 97))	('higher', 'PosReg', (87, 93))
6861	31730712	Previous studies have shown that radiotherapy is associated with increased morbidity3, 4, 5, 6, 7 and mortality from second malignant neoplasms (SMNs).6, 7, 8 A recent study from our group observed that chemotherapy was associated with SMN incidence as well.9 Chemotherapy has been associated with increased cardiovascular disease (CVD) morbidity10, 11, 12, 13 and excess CVD mortality,6, 14, 15 but the data are less consistent.	('SMN', 'Gene', (145, 148))	('CVD', 'Disease', (372, 375))	('CVD', 'Phenotype', 'HP:0001626', (372, 375))	('cardiovascular disease', 'Disease', 'MESH:D002318', (308, 330))	('CVD', 'Disease', (332, 335))	('CVD', 'Disease', 'MESH:D002318', (372, 375))	('SMN', 'Gene', '6606', (145, 148))	('SMN', 'Gene', (236, 239))	('neoplasms', 'Phenotype', 'HP:0002664', (134, 143))	('Chemotherapy', 'Var', (260, 272))	('SMN', 'Gene', '6606', (236, 239))	('CVD', 'Phenotype', 'HP:0001626', (332, 335))	('cardiovascular disease', 'Disease', (308, 330))	('malignant neoplasms', 'Disease', 'MESH:D009369', (124, 143))	('CVD', 'Disease', 'MESH:D002318', (332, 335))	('malignant neoplasms', 'Disease', (124, 143))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (308, 330))
6923	31730712	Both colorectal (P trend = .006) and noncolorectal GI tract SMN mortality (P trend < .001) increased with a higher dose of cisplatin-containing chemotherapy, with the receipt of platinum-containing chemotherapy at 400 to 499 and >=500 mg/m2 being associated with 2.4 and 6.4 times increased noncolorectal GI cancer mortality, respectively, in comparison with patients not receiving platinum-containing chemotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('noncolorectal GI cancer', 'Phenotype', 'HP:0006719', (291, 314))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('>=500 mg/m2', 'Var', (229, 240))	('platinum', 'Chemical', 'MESH:D010984', (382, 390))	('colorectal', 'Disease', 'MESH:D015179', (5, 15))	('colorectal', 'Disease', (40, 50))	('SMN', 'Gene', (60, 63))	('GI cancer', 'Phenotype', 'HP:0007378', (305, 314))	('colorectal', 'Disease', (294, 304))	('increased', 'PosReg', (91, 100))	('SMN', 'Gene', '6606', (60, 63))	('increased', 'PosReg', (281, 290))	('cancer', 'Disease', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('patients', 'Species', '9606', (359, 367))	('colorectal', 'Disease', 'MESH:D015179', (40, 50))	('colorectal', 'Disease', 'MESH:D015179', (294, 304))	('colorectal', 'Disease', (5, 15))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))
6936	31730712	Both chemotherapy and radiotherapy have previously been associated with an increased risk of various solid SMNs, including GI and urologic malignancies.5, 6, 19, 26, 29, 30 Radiotherapy and chemotherapy were associated with SMN mortality (SMR for radiotherapy, 2.1; 95% CI, 1.8-2.5; SMR for chemotherapy, 2.5; 95% CI, 2.0-3.1).	('SMN', 'Gene', (107, 110))	('malignancies', 'Disease', (139, 151))	('SMN', 'Gene', '6606', (224, 227))	('SMN', 'Gene', '6606', (107, 110))	('associated', 'Reg', (208, 218))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('SMN', 'Gene', (224, 227))	('Radiotherapy', 'Var', (173, 185))
6938	31730712	In their study, BEP chemotherapy was associated with increased mortality from lung, esophageal, and bladder cancers, soft-tissue sarcomas, and myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('myeloid leukemia', 'Disease', 'MESH:D007951', (143, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('bladder cancers', 'Disease', 'MESH:D001749', (100, 115))	('esophageal', 'Disease', (84, 94))	('BEP', 'Chemical', 'MESH:C052613', (16, 19))	('BEP chemotherapy', 'Var', (16, 32))	('bladder cancers', 'Disease', (100, 115))	('soft-tissue sarcomas', 'Disease', 'MESH:D012509', (117, 137))	('-tissue sarcoma', 'Phenotype', 'HP:0030448', (121, 136))	('lung', 'Disease', (78, 82))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (117, 137))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (129, 137))	('myeloid leukemia', 'Disease', (143, 159))	('bladder cancers', 'Phenotype', 'HP:0009725', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (100, 114))	('soft-tissue sarcomas', 'Disease', (117, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
7020	31277621	The difference obtained was added to the value 1 to calculate the correction factor, as the number 1 is a neutral factor in multiplications: F = correction factor for chapter II (neoplasms); and D = difference between the redistributed deaths and those reported to SIM due to neoplasms, in relation to the number of deaths reported to SIM due to neoplasms.	('death', 'Disease', 'MESH:D003643', (236, 241))	('neoplasms', 'Phenotype', 'HP:0002664', (346, 355))	('neoplasms', 'Disease', 'MESH:D009369', (276, 285))	('neoplasms', 'Phenotype', 'HP:0002664', (179, 188))	('D =', 'Var', (195, 198))	('neoplasm', 'Phenotype', 'HP:0002664', (346, 354))	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('SIM', 'Gene', (265, 268))	('neoplasms', 'Disease', (276, 285))	('death', 'Disease', (316, 321))	('neoplasms', 'Disease', 'MESH:D009369', (346, 355))	('SIM', 'Gene', (335, 338))	('neoplasms', 'Disease', 'MESH:D009369', (179, 188))	('death', 'Disease', (236, 241))	('SIM', 'Gene', '6493', (265, 268))	('neoplasms', 'Disease', (346, 355))	('neoplasms', 'Phenotype', 'HP:0002664', (276, 285))	('SIM', 'Gene', '6493', (335, 338))	('neoplasms', 'Disease', (179, 188))	('neoplasm', 'Phenotype', 'HP:0002664', (276, 284))	('death', 'Disease', 'MESH:D003643', (316, 321))
7081	28428886	Similarly, we found that vaccination with the immunodominant p215-234 peptide of inhibin-alpha (Inalpha 215-234) inhibits the growth of autochthonous TSC tumors occurring in male SJL.AMH-SV40Tag transgenic mice.	('TSC tumors', 'Disease', 'MESH:C565346', (150, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('p215-234', 'Var', (61, 69))	('inhibin-alpha', 'Gene', '16322', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('inhibin-alpha', 'Gene', (81, 94))	('growth', 'MPA', (126, 132))	('TSC tumors', 'Disease', (150, 160))	('autochthonous', 'CPA', (136, 149))	('inhibits', 'NegReg', (113, 121))	('transgenic mice', 'Species', '10090', (195, 210))
7098	28428886	We also found that vaccination with the p215-234 immunodominant peptide of mouse inhibin-alpha (Inalpha 215-234) provides significant inhibition of autochthonous TSC tumor growth occurring spontaneously in SJL.AMH-SV40Tag transgenic mice.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('inhibin-alpha', 'Gene', '16322', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('inhibin-alpha', 'Gene', (81, 94))	('tumor', 'Disease', (166, 171))	('transgenic mice', 'Species', '10090', (222, 237))	('inhibition', 'NegReg', (134, 144))	('mouse', 'Species', '10090', (75, 80))	('p215-234', 'Var', (40, 48))
7099	28428886	Taken together, our data support the view that vaccination against inhibin-alpha has the potential to provide significant immunotherapy against TSC tumors that may prove useful in the adjuvant setting for control of this aggressive form of testicular cancer and for enhancing the overall survival of patients with these tumors.	('inhibin-alpha', 'Gene', (67, 80))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('patients', 'Species', '9606', (300, 308))	('testicular cancer', 'Disease', (240, 257))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('TSC tumors', 'Disease', 'MESH:C565346', (144, 154))	('testicular cancer', 'Phenotype', 'HP:0010788', (240, 257))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('inhibin-alpha', 'Gene', '16322', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('vaccination', 'Var', (47, 58))	('tumors', 'Disease', (148, 154))	('TSC tumors', 'Disease', (144, 154))	('enhancing', 'PosReg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumors', 'Disease', (320, 326))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('testicular cancer', 'Disease', 'MESH:D013736', (240, 257))
7157	28428886	After unmasking and blocking formalin-fixed 6 mum paraffin embedded tissues sections, antigens were detected using primary antibodies against luteinizing hormone receptor (LHR; Santa Cruz Biotechnology), AMH (Abcam, San Francisco, CA), SV40Tag (Santa Cruz Biotechnology), and mouse CD3 (Novacastra, Buffalo Grove, IL).	('formalin', 'Chemical', 'MESH:D005557', (29, 37))	('mouse', 'Species', '10090', (276, 281))	('LHR', 'Gene', (172, 175))	('CD3', 'Gene', (282, 285))	('LHR', 'Gene', '16867', (172, 175))	('paraffin', 'Chemical', 'MESH:D010232', (50, 58))	('SV40Tag', 'Var', (236, 243))	('luteinizing hormone receptor', 'Gene', '16867', (142, 170))	('luteinizing hormone receptor', 'Gene', (142, 170))	('CD3', 'Gene', '12501', (282, 285))
7172	28428886	Again, rmInalpha vaccination showed significant inhibition of tumor growth (P = 0.001) in rmInalpha vaccinated mice compared to control mice vaccinated with CFA alone (Fig.	('rmInalpha', 'Var', (90, 99))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mice', 'Species', '10090', (111, 115))	('inhibition', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
7196	28428886	TSC tumors from male SJL.AMH-SV40Tag transgenic mice also expressed the SV40Tag from the transgene (Fig.	('SV40Tag', 'Var', (72, 79))	('TSC tumors', 'Disease', 'MESH:C565346', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('transgenic mice', 'Species', '10090', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TSC tumors', 'Disease', (0, 10))
7204	28428886	To determine whether vaccination against Inalpha 215-234 could inhibit the growth of autochthonous TSC tumors, male SJL.AMH-SV40Tag mice were vaccinated at eight weeks of age with Inalpha 215-234 in CFA or with CFA alone as control.	('Inalpha 215-234', 'Var', (180, 195))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('growth', 'MPA', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('TSC tumors', 'Disease', (99, 109))	('mice', 'Species', '10090', (132, 136))	('inhibit', 'NegReg', (63, 70))	('TSC tumors', 'Disease', 'MESH:C565346', (99, 109))
7220	28428886	Experiments to determine how CD4+ T cells mediate inhibition of TSC tumor growth are ongoing as are experiments to determine whether antibodies mediate inhibition of TSC tumor growth by neutralization of inhibin-alpha or by complement-dependent cytotoxicity.	('tumor', 'Disease', (68, 73))	('men', 'Species', '9606', (230, 233))	('CD4', 'Gene', '12504', (29, 32))	('neutralization', 'Var', (186, 200))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TSC', 'Disease', (166, 169))	('inhibition', 'NegReg', (152, 162))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cytotoxicity', 'Disease', 'MESH:D064420', (245, 257))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('men', 'Species', '9606', (106, 109))	('CD4', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inhibin-alpha', 'Gene', '16322', (204, 217))	('inhibin-alpha', 'Gene', (204, 217))	('men', 'Species', '9606', (6, 9))	('cytotoxicity', 'Disease', (245, 257))
7228	28428886	In our prior studies we showed that inhibin-alpha vaccination of normal female mice resulted in antibody-mediated neutralization of inhibin-alpha that resulted in unregulated FSH release, enhanced litter numbers, early depletion of the ovarian reserve, and ultimately premature ovarian failure.	('inhibin-alpha', 'Gene', (36, 49))	('enhanced', 'PosReg', (188, 196))	('premature ovarian failure', 'Phenotype', 'HP:0008209', (268, 293))	('neutralization', 'Var', (114, 128))	('mice', 'Species', '10090', (79, 83))	('FSH', 'Gene', (175, 178))	('depletion of the ovarian reserve', 'MPA', (219, 251))	('FSH', 'Gene', '14308', (175, 178))	('litter numbers', 'CPA', (197, 211))	('premature ovarian failure', 'Disease', (268, 293))	('premature ovarian failure', 'Disease', 'MESH:D016649', (268, 293))	('inhibin-alpha', 'Gene', '16322', (132, 145))	('inhibin-alpha', 'Gene', '16322', (36, 49))	('inhibin-alpha', 'Gene', (132, 145))
7246	28428886	4e) thereby implying that both cell types may express AMH and that transgene expression of SV40Tag may predispose to creation of tumors of either cell type with Sertoli cell tumors predominating in the original AT-t94 transgenic mouse generated in the C57BL/6 (H-2b) background strain and Leydig cell tumors predominating when the AMH-SV40Tag transgene is expressed in the SJL/J (H-2s) background strain.	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (161, 180))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('transgenic', 'Species', '10090', (218, 228))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (289, 307))	('Sertoli cell tumors', 'Disease', 'MESH:D012707', (161, 180))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('Leydig cell tumors', 'Disease', (289, 307))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('mouse', 'Species', '10090', (229, 234))	('predispose to', 'Reg', (103, 116))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('SV40Tag', 'Var', (91, 98))	('creation of tumors', 'Disease', (117, 135))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('creation of tumors', 'Disease', 'MESH:D009369', (117, 135))	('Sertoli cell tumors', 'Disease', (161, 180))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (289, 307))
7256	20051947	Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (106, 111))	('TGCT', 'Phenotype', 'HP:0010788', (159, 163))	('testicular cancer', 'Phenotype', 'HP:0010788', (112, 129))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('malignant tumour', 'Disease', 'MESH:D009369', (184, 200))	('Testicular germ cell tumour', 'Disease', 'MESH:C563236', (130, 157))	('Testicular germ cell tumour', 'Phenotype', 'HP:0010788', (130, 157))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('malignant tumour', 'Disease', (184, 200))	('epigenetically', 'Var', (52, 66))	('cancer', 'Disease', (123, 129))	('Testicular germ cell tumour', 'Disease', (130, 157))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('germ cell tumour', 'Phenotype', 'HP:0100728', (141, 157))
7257	20051947	Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited number of genes are known to be epigenetically changed in TGCT.	('cancers', 'Disease', (79, 86))	('TGCT', 'Disease', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('implicated', 'Reg', (37, 47))	('TGCT', 'Phenotype', 'HP:0010788', (161, 165))	('aberrant', 'Var', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
7275	20051947	DNA mutation may be one of the causes of TGCT; however, accumulating information suggests a more prominent role for epigenetic alteration as a factor in tumourigenesis, including TGCT (Feinberg et al, 2006; Esteller, 2007).	('tumour', 'Disease', (153, 159))	('TGCT', 'Disease', (179, 183))	('epigenetic alteration', 'Var', (116, 137))	('TGCT', 'Phenotype', 'HP:0010788', (179, 183))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('TGCT', 'Phenotype', 'HP:0010788', (41, 45))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
7276	20051947	Previous reports on aberrant methylation of tumour-suppressor genes/oncogenes provide information of an epigenetic role in tumour development.	('genes/oncogenes', 'Gene', (62, 77))	('methylation', 'Var', (29, 40))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', (44, 50))	('tumour', 'Disease', (123, 129))	('aberrant methylation', 'Var', (20, 40))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
7279	20051947	These whole-genome approaches are powerful tools for the identification of differentially methylated genes that may be important in tumourigenesis.	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('tumour', 'Disease', (132, 138))	('differentially methylated genes', 'Var', (75, 106))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))
7282	20051947	Some miRNAs are epigenetically silenced in cancer cells as a result of cancer-specific hypermethylation (Han et al, 2007; Lujambio et al, 2008; Toyota et al, 2008).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('hypermethylation', 'Var', (87, 103))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
7314	20051947	We identified 22 452 hypermethylated and 12 756 hypomethylated DMRs in the cancer genome.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('DMRs', 'Chemical', '-', (63, 67))	('cancer', 'Disease', (75, 81))	('hypermethylated', 'Var', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
7323	20051947	However, a low percentage of DMRs, 1.9% (414) of hypermethylated and 2.3% (279) of hypomethylated DMRs, mapped to promoter regions of known genes (Figure 1A).	('hypermethylated', 'Var', (49, 64))	('DMRs', 'Chemical', '-', (29, 33))	('mapped', 'Reg', (104, 110))	('DMRs', 'Chemical', '-', (98, 102))
7328	20051947	For promoter-associated CpG islands, a number of them, including those of NTF3, FGF, OSR1, HOXA6, NPY and WT1, have previously been reported as differentially methylated in other cancer types (Mares et al, 2001; Bibikova et al, 2006; Oka et al, 2006; Houshdaran et al, 2007; Illingworth et al, 2008).	('NPY', 'Gene', '4852', (98, 101))	('WT1', 'Gene', '7490', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('HOXA6', 'Gene', (91, 96))	('differentially', 'Reg', (144, 158))	('WT1', 'Gene', (106, 109))	('NPY', 'Gene', (98, 101))	('OSR1', 'Gene', (85, 89))	('NTF3', 'Gene', (74, 78))	('OSR1', 'Gene', '130497', (85, 89))	('methylated', 'Var', (159, 169))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('NTF3', 'Gene', '4908', (74, 78))	('cancer', 'Disease', (179, 185))	('HOXA6', 'Gene', '3203', (91, 96))
7330	20051947	Previous studies have suggested that many genes, such as Oct-4 and Il2, lacked CpG islands in their promoters but were regulated by CpG methylation (Bruniquel and Schwartz, 2003; Hattori et al, 2004).	('methylation', 'Var', (136, 147))	('Il2', 'Gene', (67, 70))	('Oct-4', 'Gene', (57, 62))	('Oct-4', 'Gene', '5460', (57, 62))	('CpG methylation', 'Var', (132, 147))	('regulated', 'Reg', (119, 128))	('Il2', 'Gene', '3558', (67, 70))
7339	20051947	On the basis of DMR data, we identified novel hypermethylated candidate genes that might be potential epigenetic markers for TGCT.	('TGCT', 'Disease', (125, 129))	('TGCT', 'Phenotype', 'HP:0010788', (125, 129))	('DMR', 'Chemical', '-', (16, 19))	('hypermethylated', 'Var', (46, 61))
7340	20051947	We selected candidate genes on the basis of the following criteria: first, genes with hypermethylated promoters (Figure 3A); second, expression of genes that are downregulated and in which demethylation by 5-aza restored gene expression (Figure 2B); third, a biological role in testicular cancer was not previously described.	('testicular cancer', 'Disease', (278, 295))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('downregulated', 'NegReg', (162, 175))	('demethylation', 'Var', (189, 202))	('testicular cancer', 'Phenotype', 'HP:0010788', (278, 295))	('testicular cancer', 'Disease', 'MESH:D013736', (278, 295))	('5-aza', 'Chemical', 'MESH:D001374', (206, 211))	('gene expression', 'MPA', (221, 236))
7348	20051947	Among the candidate genes, hypermethylation of PCDH10 was implicated in other cancers (Ying et al, 2007; Yu et al, 2009).	('hypermethylation', 'Var', (27, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PCDH10', 'Gene', '57575', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('implicated', 'Reg', (58, 68))	('PCDH10', 'Gene', (47, 53))
7352	20051947	Hypermethylation of the APOLD1 promoter was confirmed in 71% (n=17) of TGCT specimens.	('TGCT', 'Disease', (71, 75))	('APOLD1', 'Gene', (24, 30))	('Hypermethylation', 'Var', (0, 16))	('TGCT', 'Phenotype', 'HP:0010788', (71, 75))	('APOLD1', 'Gene', '81575', (24, 30))
7356	20051947	The observations of hypermethylation and downregulation of APOLD1 in primary TGCT tissues suggest that DNA methylation has a crucial role in silencing this gene.	('silencing', 'NegReg', (141, 150))	('hypermethylation', 'Var', (20, 36))	('TGCT', 'Phenotype', 'HP:0010788', (77, 81))	('APOLD1', 'Gene', (59, 65))	('downregulation', 'NegReg', (41, 55))	('APOLD1', 'Gene', '81575', (59, 65))
7361	20051947	The loci of three miRNAs, namely hsa-mir-199a-2, hsa-mir-124a-2 and hsa-mir-184, were found to be linked to hypermethylated DMRs (Figure 4A).	('hsa-mir-124a-2', 'Gene', (49, 63))	('hsa-mir-199a-2', 'Gene', (33, 47))	('mir-184', 'Gene', (72, 79))	('mir-184', 'Gene', '406960', (72, 79))	('DMRs', 'Chemical', '-', (124, 128))	('hsa-mir-199a-2', 'Gene', '406977', (33, 47))	('hypermethylated', 'Var', (108, 123))	('hsa-mir-124a-2', 'Gene', '406908', (49, 63))	('linked', 'Reg', (98, 104))
7369	20051947	In addition to miRNA, we also mapped non-genic DMRs to snoRNA-LBME-db, and three snoRNAs, namely HBII-240, ACA33 and ACA8, were hypomethylated (Supplementary Figure 3A).	('ACA8', 'Gene', '654320', (117, 121))	('ACA33', 'Gene', (107, 112))	('ACA8', 'Gene', (117, 121))	('hypomethylated', 'Var', (128, 142))	('snoRNA', 'Gene', (81, 87))	('snoRNA', 'Gene', '84546', (55, 61))	('ACA33', 'Gene', '594839', (107, 112))	('HBII-240', 'Gene', '619564', (97, 105))	('snoRNA', 'Gene', '84546', (81, 87))	('snoRNA', 'Gene', (55, 61))	('HBII-240', 'Gene', (97, 105))	('DMRs', 'Chemical', '-', (47, 51))
7373	20051947	Aberrant DNA methylation is common in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Aberrant', 'Var', (0, 8))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
7381	20051947	Although the three miRNAs were hypermethylated, expression and 5-aza treatment experiments indicated that only hsa-mir-199a-2 was suppressed by hypermethylation.	('hypermethylation', 'Var', (144, 160))	('5-aza', 'Chemical', 'MESH:D001374', (63, 68))	('hsa-mir-199a-2', 'Gene', '406977', (111, 125))	('hsa-mir-199a-2', 'Gene', (111, 125))
7384	20051947	In this study, the identification of hypomethylation and enhanced expression of the three snoRNAs suggest a potential relationship between cancer and dysregulation of snoRNAs.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('snoRNA', 'Gene', '84546', (90, 96))	('snoRNA', 'Gene', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('hypomethylation', 'Var', (37, 52))	('expression', 'MPA', (66, 76))	('snoRNA', 'Gene', '84546', (167, 173))	('snoRNA', 'Gene', (90, 96))	('enhanced', 'PosReg', (57, 65))	('cancer', 'Disease', (139, 145))
7388	20051947	Expression of PCDH10 in these cell lines was suppressed by DNA hypermethylation (Ying et al, 2006).	('Expression', 'MPA', (0, 10))	('PCDH10', 'Gene', (14, 20))	('suppressed', 'NegReg', (45, 55))	('PCDH10', 'Gene', '57575', (14, 20))	('DNA hypermethylation', 'Var', (59, 79))
7397	20051947	We now use the MeDIP-chip for identifying aberrant methylation in malignant TGCT patient samples targeting for DMRs specific for cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('TGCT', 'Phenotype', 'HP:0010788', (76, 80))	('patient', 'Species', '9606', (81, 88))	('DMRs', 'Chemical', '-', (111, 115))	('cancer metastasis', 'Disease', (129, 146))	('aberrant methylation', 'Var', (42, 62))	('cancer metastasis', 'Disease', 'MESH:D009362', (129, 146))
7574	32957524	Particularly, GPER activation determines multiple intracellular events such as EGFR transactivation leading to rapid ERK1/2 activation, PLC and PI3K phosphorylation, AC stimulation, and intracellular calcium mobilization.	('activation', 'PosReg', (124, 134))	('intracellular calcium mobilization', 'MPA', (186, 220))	('ERK1/2', 'Gene', (117, 123))	('EGFR', 'Gene', (79, 83))	('calcium', 'Chemical', 'MESH:D002118', (200, 207))	('ERK1/2', 'Gene', '5595;5594', (117, 123))	('PLC', 'CPA', (136, 139))	('stimulation', 'PosReg', (169, 180))	('transactivation', 'Var', (84, 99))
7588	32957524	Alterations in the structure and distribution of various Leydig cell organelles after GPER blockage respect to control, were also observed.	('blockage', 'Var', (91, 99))	('distribution', 'MPA', (33, 45))	('structure', 'MPA', (19, 28))	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Reg', (0, 11))
7590	32957524	Moreover, the use of G15 determined a marked decrease in activity of mitochondria and cytoskeleton, cellular structures directly involved in steroid hormone production.	('steroid', 'Chemical', 'MESH:D013256', (141, 148))	('G15', 'Var', (21, 24))	('decrease', 'NegReg', (45, 53))	('activity', 'MPA', (57, 65))
7591	32957524	In addition, in both in vivo mice of different ages and in in vitro Leydig cells, G15 treatment determined an increase in ERalpha and ERbeta and aromatase mRNA expression.	('increase', 'PosReg', (110, 118))	('aromatase', 'Gene', (145, 154))	('aromatase', 'Gene', '1588', (145, 154))	('ERalpha', 'Protein', (122, 129))	('men', 'Species', '9606', (91, 94))	('G15', 'Var', (82, 85))	('mice', 'Species', '10090', (29, 33))	('mRNA expression', 'MPA', (155, 170))
7592	32957524	However, after GPER blockage, intratesticular androgen concentration significantly increased in immature mice, decreased in mature males and did not change in aged animals.	('mice', 'Species', '10090', (105, 109))	('increased', 'PosReg', (83, 92))	('decreased', 'NegReg', (111, 120))	('rat', 'Species', '10116', (33, 36))	('intratesticular androgen concentration', 'MPA', (30, 68))	('rat', 'Species', '10116', (62, 65))	('blockage', 'Var', (20, 28))
7597	32957524	In particular, a relationship between GPER activity and lipid metabolism derived from observation that GPER knockout mice developed visceral obesity and showed an increased level of low density lipoproteins.	('visceral obesity', 'Disease', (132, 148))	('visceral obesity', 'Disease', 'MESH:D056128', (132, 148))	('obesity', 'Phenotype', 'HP:0001513', (141, 148))	('increased', 'PosReg', (163, 172))	('visceral obesity', 'Phenotype', 'HP:0012743', (132, 148))	('developed', 'PosReg', (122, 131))	('lipid', 'Chemical', 'MESH:D008055', (56, 61))	('increased level of low density lipoproteins', 'Phenotype', 'HP:0003141', (163, 206))	('mice', 'Species', '10090', (117, 121))	('GPER', 'Gene', (103, 107))	('level', 'MPA', (173, 178))	('low density lipoproteins', 'MPA', (182, 206))	('knockout', 'Var', (108, 116))
7599	32957524	This study demonstrated that G15 induced protein expression changes of steroidogenic [LHR and 3beta-HSD] and lipid droplet [PLIN and LC3] markers.	('rat', 'Species', '10116', (18, 21))	('lipid', 'Chemical', 'MESH:D008055', (109, 114))	('LC3', 'Gene', (133, 136))	('3beta-HSD', 'Gene', '3283', (94, 103))	('LHR', 'Gene', '3973', (86, 89))	('changes', 'Reg', (60, 67))	('steroidogenic', 'MPA', (71, 84))	('protein expression', 'MPA', (41, 59))	('G15', 'Var', (29, 32))	('PLIN', 'Gene', '5346', (124, 128))	('LHR', 'Gene', (86, 89))	('PLIN', 'Gene', (124, 128))	('LC3', 'Gene', '84557', (133, 136))	('3beta-HSD', 'Gene', (94, 103))	('steroid', 'Chemical', 'MESH:D013256', (71, 78))
7604	32957524	Moreover, modified GPER-PPAR crosstalk was found in human LCTs, being a possible cause of LCTs development.	('cause', 'Reg', (81, 86))	('LCTs', 'Phenotype', 'HP:0100618', (58, 62))	('LCTs', 'Disease', (90, 94))	('LCTs', 'Phenotype', 'HP:0100618', (90, 94))	('human', 'Species', '9606', (52, 57))	('PPAR', 'Gene', '5465', (24, 28))	('modified', 'Var', (10, 18))	('PPAR', 'Gene', (24, 28))	('men', 'Species', '9606', (102, 105))
7614	32957524	In particular, the EXPO5 and DICER mRNA expressions were downregulated while the DROSHA and AGO2 mRNA expressions were significantly upregulated only by G15 plus BPA and TCBPA, respectively.	('downregulated', 'NegReg', (57, 70))	('DROSHA', 'Gene', '29102', (81, 87))	('BPA', 'Chemical', '-', (172, 175))	('DROSHA', 'Gene', (81, 87))	('upregulated', 'PosReg', (133, 144))	('AGO2', 'Gene', (92, 96))	('DICER', 'Gene', '23405', (29, 34))	('BPA', 'Chemical', '-', (162, 165))	('G15 plus BPA', 'Var', (153, 165))	('AGO2', 'Gene', '27161', (92, 96))	('TCBPA', 'Var', (170, 175))	('DICER', 'Gene', (29, 34))	('TCBPA', 'Chemical', '-', (170, 175))
7617	32957524	Interestingly, the same authors, inactivating GPER trough G15, demonstrated protein expression changes of telocytes functional markers such as CD34, c-kit, PDGFRalpha and beta, VEGF, and vimentin.	('VEGF', 'Gene', '7422', (177, 181))	('vimentin', 'Gene', '7431', (187, 195))	('changes', 'Reg', (95, 102))	('rat', 'Species', '10116', (70, 73))	('CD34', 'Gene', (143, 147))	('VEGF', 'Gene', (177, 181))	('inactivating', 'Var', (33, 45))	('protein expression', 'MPA', (76, 94))	('vimentin', 'Gene', (187, 195))	('CD34', 'Gene', '947', (143, 147))	('PDGFRalpha and beta', 'Gene', '5156', (156, 175))	('c-kit', 'Gene', '3815', (149, 154))	('c-kit', 'Gene', (149, 154))	('GPER', 'Gene', (46, 50))
7623	32957524	Surprisingly, melatonin concentration in these animals is regulated by GPER, decreasing in both LD and SD animals after G15 treatment.	('decreasing', 'NegReg', (77, 87))	('melatonin concentration', 'MPA', (14, 37))	('men', 'Species', '9606', (129, 132))	('melatonin', 'Chemical', 'MESH:D008550', (14, 23))	('G15', 'Var', (120, 123))	('rat', 'Species', '10116', (31, 34))
7640	32957524	In another study, it has been demonstrated that proliferation of mouse immature Sertoli cells TM4 can be stimulated by nanomolar concentrations of BPA, through a mechanism involving GPER.	('BPA', 'Chemical', '-', (147, 150))	('mouse', 'Species', '10090', (65, 70))	('proliferation', 'CPA', (48, 61))	('rat', 'Species', '10116', (37, 40))	('stimulated', 'PosReg', (105, 115))	('Sertoli cells', 'Phenotype', 'HP:0100619', (80, 93))	('TM4', 'Chemical', '-', (94, 97))	('nanomolar', 'Var', (119, 128))	('rat', 'Species', '10116', (136, 139))	('Sertoli cell', 'Phenotype', 'HP:0100619', (80, 92))	('rat', 'Species', '10116', (55, 58))
7651	32957524	The first report indicating estrogens' proliferative effects on testicular germ stem cells is attributed to Cobellis and colleagues, who, using a frog model characterized by slow progression of spermatogenesis, demonstrated that estradiol induced nuclear c-Fos activity, leading to spermatogonia multiplication.	('c-Fos', 'Gene', '2353', (255, 260))	('estradiol', 'Var', (229, 238))	('rat', 'Species', '10116', (46, 49))	('spermatogonia multiplication', 'CPA', (282, 310))	('estradiol', 'Chemical', 'MESH:D004958', (229, 238))	('rat', 'Species', '10116', (218, 221))	('leading to', 'Reg', (271, 281))	('c-Fos', 'Gene', (255, 260))
7668	32957524	However, only concomitant ERalpha and GPER silencing abolished E2-dependent effects on cell proliferation.	('rat', 'Species', '10116', (99, 102))	('cell proliferation', 'CPA', (87, 105))	('silencing', 'Var', (43, 52))	('E2', 'Chemical', 'MESH:D004958', (63, 65))	('GPER', 'Protein', (38, 42))
7705	32957524	On the other hand, E2 through ERbeta or G15 through GPER/ERK pathway, decreased cell proliferation.	('G15', 'Var', (40, 43))	('decreased', 'NegReg', (70, 79))	('ERK', 'Gene', '5594', (57, 60))	('rat', 'Species', '10116', (92, 95))	('cell proliferation', 'CPA', (80, 98))	('ERK', 'Gene', (57, 60))	('E2', 'Chemical', 'MESH:D004958', (19, 21))
7762	24159602	The correct maintenance and regulation of FGF signaling is evident from human and mouse genetic studies, which showed a variety of developmental disorders including dominant skeletal diseases, infertility, and cancer if some signaling mutations lead to the disruption of FGFs.	('developmental disorders', 'Disease', (131, 154))	('lead to', 'Reg', (245, 252))	('skeletal diseases', 'Disease', 'MESH:C538496', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('developmental disorders', 'Disease', 'MESH:D002658', (131, 154))	('mutations', 'Var', (235, 244))	('infertility', 'Disease', 'MESH:D007247', (193, 204))	('human', 'Species', '9606', (72, 77))	('infertility', 'Phenotype', 'HP:0000789', (193, 204))	('infertility', 'Disease', (193, 204))	('disruption', 'Var', (257, 267))	('skeletal diseases', 'Disease', (174, 191))	('FGFs', 'Gene', (271, 275))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('mouse', 'Species', '10090', (82, 87))	('cancer', 'Disease', (210, 216))
7816	24159602	Our study showed that the deletion of Fgf-21 gene does not affect testicular cell proliferation, but significantly increases the spontaneous incidence of testicular apoptosis accompanied with the increased ratio of Bax/Bcl2 expression.	('increased', 'PosReg', (196, 205))	('Bcl2', 'Gene', '12043', (219, 223))	('Bcl2', 'Gene', (219, 223))	('Fgf-21', 'Gene', (38, 44))	('Bax', 'Gene', (215, 218))	('Fgf-21', 'Gene', '56636', (38, 44))	('increases', 'PosReg', (115, 124))	('deletion', 'Var', (26, 34))	('ratio', 'MPA', (206, 211))	('rat', 'Species', '10116', (89, 92))	('expression', 'MPA', (224, 234))	('Bax', 'Gene', '12028', (215, 218))	('rat', 'Species', '10116', (206, 209))
7819	24159602	Deletion of Fgf-21 gene significantly enhances diabetes-induced testicular apoptosis along with the activation of mitochondrial-dependent apoptosis pathways, endoplasmic reticulum stress-dependent pathways, and oxidative damage but did not change the expression of cleaved caspase-3 and caspase-8, which was significantly prevented by the supplementation of exogenous FGF-21.	('diabetes', 'Disease', (47, 55))	('Fgf-21', 'Gene', '56636', (12, 18))	('mitochondrial-dependent apoptosis pathways', 'Pathway', (114, 156))	('diabetes', 'Disease', 'MESH:D003920', (47, 55))	('oxidative', 'CPA', (211, 220))	('endoplasmic reticulum stress-dependent pathways', 'Pathway', (158, 205))	('caspase-8', 'Gene', '12370', (287, 296))	('Fgf-21', 'Gene', (12, 18))	('caspase-8', 'Gene', (287, 296))	('activation', 'PosReg', (100, 110))	('enhances', 'PosReg', (38, 46))	('testicular apoptosis', 'CPA', (64, 84))	('Deletion', 'Var', (0, 8))
7849	24159602	Supplements of FGFs have a potential benefit in protecting testicular ischemia-reperfusion injury.	('ischemia-reperfusion injury', 'Disease', (70, 97))	('Supplements', 'Var', (0, 11))	('ischemia-reperfusion injury', 'Disease', 'MESH:D015427', (70, 97))	('FGFs', 'Gene', (15, 19))
7859	22740241	Applying the method to testicular cancer, we found a nominally significant MxM interaction between single nucleotide polymorphisms from C-Kit Ligand (KITLG) and Sex Hormone Binding Globulin (SHBG) using 210 families (relative risk 2.2, P = 0.03).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('C-Kit Ligand', 'Gene', '4254', (136, 148))	('SHBG', 'Gene', (191, 195))	('SHBG', 'Gene', '6462', (191, 195))	('testicular cancer', 'Phenotype', 'HP:0010788', (23, 40))	('testicular cancer', 'Disease', 'MESH:D013736', (23, 40))	('C-Kit Ligand', 'Gene', (136, 148))	('KITLG', 'Gene', '4254', (150, 155))	('KITLG', 'Gene', (150, 155))	('Sex Hormone Binding Globulin', 'Gene', '6462', (161, 189))	('MxM', 'MPA', (75, 78))	('testicular cancer', 'Disease', (23, 40))	('single nucleotide polymorphisms', 'Var', (99, 130))	('Sex Hormone Binding Globulin', 'Gene', (161, 189))	('MxM', 'Chemical', '-', (75, 78))
7869	22740241	For example, an association was found between craniofacial malformations and an interaction between maternal single nucleotide polymorphism (SNP) genotypes in folate and choline metabolism genes [, b].	('single nucleotide polymorphism', 'Var', (109, 139))	('craniofacial malformations', 'Disease', 'MESH:D019465', (46, 72))	('craniofacial malformations', 'Disease', (46, 72))	('interaction', 'Interaction', (80, 91))	('craniofacial malformations', 'Phenotype', 'HP:0004484', (46, 72))	('choline', 'Chemical', 'MESH:D002794', (170, 177))
7872	22740241	We and others have found that SNPs from KITLG are the most associated with TGCT in genome-wide association studies (GWAS) and it can be hypothesized that the disease-initiating events occur in the early embryonic development from an interplay between maternal estrogens and child or maternal KITLG.	('TGCT', 'Disease', (75, 79))	('child', 'Species', '9606', (274, 279))	('KITLG', 'Gene', '4254', (40, 45))	('associated', 'Reg', (59, 69))	('SNPs', 'Var', (30, 34))	('KITLG', 'Gene', (40, 45))	('KITLG', 'Gene', '4254', (292, 297))	('KITLG', 'Gene', (292, 297))	('men', 'Species', '9606', (220, 223))
7899	22740241	Although our primary focus is on the validity and power of the interactions tests, we also report as supplementary data the risk parameter estimates for the simulated models.	('tests', 'Reg', (76, 81))	('interactions', 'Var', (63, 75))	('men', 'Species', '9606', (107, 110))
7900	22740241	We applied two-locus log-linear models to 210 families (147 full trios and 63 case-mother pairs), testing the interactions between KITLG SNPs (rs1508595 and rs995030, each separately) and rs6259, a missense SNP from Sex Hormone Binding Globulin (SHBG; it binds estrogens and other sex hormones, regulating their availability).	('Sex Hormone Binding Globulin', 'Gene', (216, 244))	('KITLG', 'Gene', '4254', (131, 136))	('KITLG', 'Gene', (131, 136))	('binds', 'Interaction', (255, 260))	('regulating', 'Reg', (295, 305))	('SHBG', 'Gene', '6462', (246, 250))	('rs6259', 'Mutation', 'rs6259', (188, 194))	('rs6259', 'Var', (188, 194))	('Sex Hormone Binding Globulin', 'Gene', '6462', (216, 244))	('SHBG', 'Gene', (246, 250))	('interactions', 'Interaction', (110, 122))	('rs1508595', 'Mutation', 'rs1508595', (143, 152))	('rs995030', 'Mutation', 'rs995030', (157, 165))	('rs995030', 'Var', (157, 165))	('rs1508595', 'Var', (143, 152))
7921	22740241	Despite showing independent effects on TGCT in GWAS, we found that KITLG rs1508595 and rs995030 are in strong LD (D' = 0.91, r2 = 0.65, MAF = 0.17 and 0.14, respectively).	('rs995030', 'Mutation', 'rs995030', (87, 95))	('rs995030', 'Var', (87, 95))	('rs1508595', 'Var', (73, 82))	('KITLG', 'Gene', '4254', (67, 72))	('MAF', 'Gene', (136, 139))	('KITLG', 'Gene', (67, 72))	('MAF', 'Gene', '4094', (136, 139))	('rs1508595', 'Mutation', 'rs1508595', (73, 82))
7923	22740241	The second most significant effect was the MxM interaction involving rs1508595 and rs6259 (relative risk 2.2, P = 0.07, with a similar result when rs995030 was analyzed).	('MxM', 'Chemical', '-', (43, 46))	('rs995030', 'Mutation', 'rs995030', (147, 155))	('rs6259', 'Mutation', 'rs6259', (83, 89))	('rs1508595', 'Mutation', 'rs1508595', (69, 78))	('rs6259', 'Var', (83, 89))	('rs1508595', 'Var', (69, 78))
7924	22740241	In a model restricted to the two most prominent effects, the effect of inherited genotypes in KITLG is maintained, and the MxM interaction is also nominally significant between rs1508595 and rs6259 (P = 0.03).	('rs6259', 'Var', (191, 197))	('KITLG', 'Gene', '4254', (94, 99))	('KITLG', 'Gene', (94, 99))	('rs1508595', 'Mutation', 'rs1508595', (177, 186))	('MxM', 'Chemical', '-', (123, 126))	('rs1508595', 'Var', (177, 186))	('significant', 'Reg', (157, 168))	('rs6259', 'Mutation', 'rs6259', (191, 197))
7926	22740241	Overall findings of this study are that: (1) two-locus log-linear modeling is effective in detecting MxO and MxM interactions; (2) similar power can be achieved to detect MxO and MxM interactions of similar strengh; this power can be substantial, although lower than the power to detect the main effects; (3) MxO and MxM interactions are conditionally independent from paternal genotypes but are inflated by missing maternal genotypes; (4) in scenarios where HWE applies, its assumption increases the power to detect main effects but does not affect the interaction tests; (5) MxO and MxM tests are robust to the violation of mating symmetry assumption but, as has already been observed in single-locus models, the main maternal effect needs to be included in the model, although it is not itself robust to the violation of this assumption; (6) in testing for interaction effects, the method is insensitive to any inacurracy in the second locus genotype distribution, and specifying this distribution is as powerful as estimating it in the model; (7) if the second locus genotype distribution is well specified, the method is valid to test the main effect of the second locus; (8) the risk to testicular cancer may be increased by an interaction between maternal variants in KITLG and SHBG.	('testicular cancer', 'Disease', 'MESH:D013736', (1193, 1210))	('KITLG', 'Gene', (1275, 1280))	('KITLG', 'Gene', '4254', (1275, 1280))	('MxO', 'Chemical', '-', (309, 312))	('testicular cancer', 'Disease', (1193, 1210))	('MxM', 'Chemical', '-', (317, 320))	('MxO', 'Chemical', '-', (577, 580))	('increased', 'PosReg', (1218, 1227))	('MxM', 'Chemical', '-', (109, 112))	('testicular cancer', 'Phenotype', 'HP:0010788', (1193, 1210))	('variants', 'Var', (1263, 1271))	('SHBG', 'Gene', (1285, 1289))	('MxO', 'Chemical', '-', (101, 104))	('interaction', 'Interaction', (1234, 1245))	('MxM', 'Chemical', '-', (585, 588))	('MxO', 'Chemical', '-', (171, 174))	('SHBG', 'Gene', '6462', (1285, 1289))	('cancer', 'Phenotype', 'HP:0002664', (1204, 1210))	('MxM', 'Chemical', '-', (179, 182))
7929	22740241	The application of the method to TGCT confirmed the finding of two genome-wide studies: inherited KITLG variants (minor alleles) have a strong protective effect against the disease (relative risk 0.4, P = 2 x 10-4, assuming a dominant model).	('KITLG', 'Gene', '4254', (98, 103))	('protective', 'NegReg', (143, 153))	('KITLG', 'Gene', (98, 103))	('variants', 'Var', (104, 112))
7930	22740241	The method further detected a nominally significant MxM interaction between KITLG rs1508595 and SHBG rs6259 (reduced model relative risk = 2.2, P = 0.03).	('rs1508595', 'Mutation', 'rs1508595', (82, 91))	('KITLG', 'Gene', (76, 81))	('rs1508595', 'Var', (82, 91))	('SHBG', 'Gene', '6462', (96, 100))	('rs6259', 'Mutation', 'rs6259', (101, 107))	('MxM', 'Chemical', '-', (52, 55))	('SHBG', 'Gene', (96, 100))	('KITLG', 'Gene', '4254', (76, 81))	('rs6259', 'Var', (101, 107))
7940	19412439	Loss-of-function and gain-of-function mutations within Gsalpha-coding GNAS exons are found in various human disorders, including Albright's hereditary osteodystrophy, pseudohypoparathyroidism, fibrous dysplasia of bone, and some tumors of different origin.	("Albright's hereditary osteodystrophy", 'Disease', (129, 165))	('Loss-of-function', 'NegReg', (0, 16))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('fibrous dysplasia of bone', 'Disease', (193, 218))	('pseudohypoparathyroidism', 'Disease', 'MESH:D011547', (167, 191))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('mutations', 'Var', (38, 47))	('fibrous dysplasia of bone', 'Disease', 'MESH:D005357', (193, 218))	('gain-of-function', 'PosReg', (21, 37))	('fibrous dysplasia of bone', 'Phenotype', 'HP:0010734', (193, 218))	('GNAS', 'Gene', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('pseudohypoparathyroidism', 'Phenotype', 'HP:0000852', (167, 191))	('pseudohypoparathyroidism', 'Disease', (167, 191))	('tumors', 'Disease', (229, 235))	("Albright's hereditary osteodystrophy", 'Disease', 'MESH:C537045', (129, 165))	('human', 'Species', '9606', (102, 107))
7956	19412439	Mutagenesis experiments often lead to alteration in activity and/or subcellular distribution, indicating that changes are non-tolerable at many of the amino acid positions.	('tri', 'Chemical', '-', (83, 86))	('Mutagenesis', 'Var', (0, 11))	('activity', 'MPA', (52, 60))	('lead to alteration', 'Reg', (30, 48))	('subcellular distribution', 'MPA', (68, 92))	('rat', 'Species', '10116', (42, 45))
7957	19412439	Particularly, Arg201 and Gln227 are critical, since modifications of these residues, such as ADP-ribosylation of Arg201 that can be induced by cholera toxin or mutations at either residue, lead to inhibition of the GTPase activity and, therefore, render Gsalpha constitutively active.	('Arg201', 'Var', (113, 119))	('Gln227', 'Chemical', '-', (25, 31))	('mutations', 'Var', (160, 169))	('ADP-ribosylation', 'MPA', (93, 109))	('ADP', 'Chemical', 'MESH:D000244', (93, 96))	('Arg201', 'Chemical', '-', (113, 119))	('inhibition', 'NegReg', (197, 207))	('Arg201', 'Chemical', '-', (14, 20))	('activity', 'MPA', (222, 230))	('GTP', 'Chemical', 'MESH:D006160', (215, 218))	('GTPase', 'Enzyme', (215, 221))
7963	19412439	An important recent finding regarding the long and short Gsalpha forms is that, for the first time, an inactivating mutation in exon 3 has been identified in a patient with pseudohypoparathyroidism type-Ia, a disorder known to be caused by inactivating mutations in Gsalpha-coding GNAS exons (see below).	('caused', 'Reg', (230, 236))	('inactivating mutations', 'Var', (240, 262))	('Gsalpha-coding', 'Gene', (266, 280))	('pseudohypoparathyroidism', 'Phenotype', 'HP:0000852', (173, 197))	('pseudohypoparathyroidism type-Ia', 'Disease', (173, 205))	('pseudohypoparathyroidism type-Ia', 'Disease', 'MESH:D011547', (173, 205))	('patient', 'Species', '9606', (160, 167))
7974	19412439	The tissue-specific, imprinted expression of Gsalpha has important implications in the pathogenesis of diseases caused by mutations within GNAS, particularly pseudohypoparathyroidism (see below).	('pseudohypoparathyroidism', 'Disease', 'MESH:D011547', (158, 182))	('Gsalpha', 'Gene', (45, 52))	('mutations', 'Var', (122, 131))	('implications', 'Reg', (67, 79))	('caused', 'Reg', (112, 118))	('pseudohypoparathyroidism', 'Phenotype', 'HP:0000852', (158, 182))	('pseudohypoparathyroidism', 'Disease', (158, 182))	('GNAS', 'Gene', (139, 143))
7986	19412439	Although the role of this protein at the molecular level remains to be explored, the findings in the Nesp55 deficient mice appear to be consistent with the localization of this protein in specific parts of the central nervous system, particularly noradrenergic locus coeruleus.	('deficient', 'Var', (108, 117))	('mice', 'Species', '10090', (118, 122))	('Nesp55', 'Gene', (101, 107))
7999	19412439	Second, expression of an XLalphas mutant carrying the homolog of the Gsalpha Gln227 mutation results in elevated cAMP formation, indicating that XLalphas can stimulate adenylyl cyclase at least in the basal state.	('cAMP formation', 'MPA', (113, 127))	('cAMP', 'Chemical', 'MESH:D000242', (113, 117))	('stimulate', 'PosReg', (158, 167))	('XLalphas', 'Chemical', '-', (145, 153))	('Gsalpha', 'Gene', (69, 76))	('Gln227', 'Var', (77, 83))	('XLalphas', 'Chemical', '-', (25, 33))	('Gln227', 'Chemical', '-', (77, 83))	('elevated', 'PosReg', (104, 112))	('adenylyl cyclase', 'MPA', (168, 184))
8000	19412439	Third, XLalphas can mediate receptor-stimulated cAMP formation when overexpressed in opossum kidney cells that show endogenous Gsalpha expression and in mouse embryonic fibroblasts that endogenously lack Gsalpha and XLalphas due to homozygous disruption of Gnas exon 2.	('XLalphas', 'Chemical', '-', (7, 15))	('lack', 'NegReg', (199, 203))	('disruption', 'Var', (243, 253))	('mouse', 'Species', '10090', (153, 158))	('cAMP', 'Chemical', 'MESH:D000242', (48, 52))	('Gnas exon 2', 'Gene', (257, 268))	('XLalphas', 'Chemical', '-', (216, 224))
8001	19412439	Finally, mutations that impair Gsalpha activity have similar effects on XLalphas activity when introduced into the backbone of the latter].	('impair', 'NegReg', (24, 30))	('Gsalpha', 'Protein', (31, 38))	('XLalphas', 'Chemical', '-', (72, 80))	('mutations', 'Var', (9, 18))	('activity', 'MPA', (39, 47))	('XLalphas activity', 'MPA', (72, 89))
8008	19412439	Human XLalphas-N1 appears to have a subvariant produced by inclusion of sequences from two additional exons, A20 and A21, located immediately following exon XL.	('Human', 'Species', '9606', (0, 5))	('A21', 'Var', (117, 120))	('XLalphas', 'Chemical', '-', (6, 14))	('A20', 'Var', (109, 112))
8020	19412439	An insertion polymorphism within XLalphas mRNA, affecting both proteins, appears to impair this interaction, a finding that has been offered as an explanation as to why some individuals carrying this insertion polymorphism show elevated agonist-induced cAMP accumulation in platelets.	('agonist-induced cAMP accumulation in platelets', 'MPA', (237, 283))	('XLalphas mRNA', 'Gene', (33, 46))	('interaction', 'Interaction', (96, 107))	('cAMP', 'Chemical', 'MESH:D000242', (253, 257))	('elevated', 'PosReg', (228, 236))	('insertion polymorphism', 'Var', (3, 25))	('XLalphas', 'Chemical', '-', (33, 41))	('impair', 'NegReg', (84, 90))
8024	19412439	Exon XL has been disrupted in mice through introduction of a small deletion into the beginning part of both XLalphas and ALEX ORF; this disruption appears to preserve the imprinted expression of other Gnas transcripts.	('mice', 'Species', '10090', (30, 34))	('deletion', 'Var', (67, 75))	('imprinted', 'MPA', (171, 180))	('XLalphas', 'Chemical', '-', (108, 116))
8028	19412439	When crossed into the CD1 background, about 20% of the Gnasxl knockout animals survive with an apparently normal life-span.	('Gnasxl', 'Gene', (55, 61))	('CD1', 'Gene', (22, 25))	('Gnasxl', 'Gene', '14683', (55, 61))	('knockout', 'Var', (62, 70))	('CD1', 'Gene', '910', (22, 25))
8032	19412439	The genetic alteration in the Gnasxl knockout mice is predicted to disrupt not only XLalphas but also XLalphas-N1, ALEX, XXLalphas, XXLalphas-N1 and ALEXX.	('XLalphas', 'Disease', (84, 92))	('alteration', 'Var', (12, 22))	('rat', 'Species', '10116', (16, 19))	('Gnasxl', 'Gene', '14683', (30, 36))	('XLalphas', 'Chemical', '-', (84, 92))	('Gnasxl', 'Gene', (30, 36))	('mice', 'Species', '10090', (46, 50))	('disrupt', 'NegReg', (67, 74))	('XLalphas', 'Chemical', '-', (133, 141))	('ALEX', 'Disease', (115, 119))	('XLalphas', 'Chemical', '-', (102, 110))	('XLalphas', 'Chemical', '-', (122, 130))	('XLalphas-N1', 'Gene', (102, 113))
8034	19412439	Nonetheless, a similar phenotype is present in mice with paternal Gnas exon 2 disruption and in mice with a paternally inherited missense mutation in exon 6, thereby ruling out the involvement of ALEX, XLalphas-N1, and XXLalphas-N1 deficiency in the phenotypes of the Gnasxl knockout mice.	('Gnasxl', 'Gene', (268, 274))	('XLalphas', 'Chemical', '-', (220, 228))	('mice', 'Species', '10090', (96, 100))	('XLalphas', 'Chemical', '-', (202, 210))	('disruption', 'Var', (78, 88))	('XXLalphas-N1 deficiency', 'Disease', (219, 242))	('missense mutation', 'Var', (129, 146))	('Gnasxl', 'Gene', '14683', (268, 274))	('XXLalphas-N1 deficiency', 'Disease', 'MESH:D007153', (219, 242))	('mice', 'Species', '10090', (47, 51))	('mice', 'Species', '10090', (284, 288))	('Gnas exon 2', 'Gene', (66, 77))
8036	19412439	It is important to note that the phenotype of the Gnasxl knockout mice differs, by and large, from the phenotype of mice heterozygous for disruption of Gnas exon 1, in which Gsalpha, but not XLalphas, is ablated.	('mice', 'Species', '10090', (116, 120))	('Gnasxl', 'Gene', '14683', (50, 56))	('Gnas exon 1', 'Gene', (152, 163))	('Gnasxl', 'Gene', (50, 56))	('XLalphas', 'Chemical', '-', (191, 199))	('mice', 'Species', '10090', (66, 70))	('ablated', 'NegReg', (204, 211))	('disruption', 'Var', (138, 148))
8039	19412439	Findings that are reminiscent of those observed in Gnasxl knockout mice and the mice with paternal Gnas exon 2 disruption have been reported in two unrelated children with large paternal deletions of chromosome 20q13.3 that comprise the GNAS locus.	('Gnasxl', 'Gene', (51, 57))	('children', 'Species', '9606', (158, 166))	('Gnas exon 2', 'Gene', (99, 110))	('Gnasxl', 'Gene', '14683', (51, 57))	('mice', 'Species', '10090', (80, 84))	('disruption', 'Var', (111, 121))	('mice', 'Species', '10090', (67, 71))	('deletions', 'Var', (187, 196))
8048	19412439	Thus, it appears that the non-methylated A/B DMR and/or active A/B transcription is necessary for the tissue-specific paternal silencing of Gsalpha.	('DMR', 'Chemical', '-', (45, 48))	('paternal silencing', 'Var', (118, 136))	('Gsalpha', 'Gene', (140, 147))
8061	19412439	Second, mice with the paternal deletion exhibit a modest decrease in A/B expression combined with an increase in the methylation of the A/B promoter.	('decrease', 'NegReg', (57, 65))	('methylation', 'MPA', (117, 128))	('increase', 'PosReg', (101, 109))	('deletion', 'Var', (31, 39))	('A/B expression', 'MPA', (69, 83))	('mice', 'Species', '10090', (8, 12))
8063	19412439	Is it the derepression of Nesp55, the reduction of XLalphas expression, or the deletion of the genomic region containing the antisense promoter?	('XLalphas', 'Protein', (51, 59))	('Nesp55', 'Protein', (26, 32))	('XLalphas', 'Chemical', '-', (51, 59))	('reduction', 'NegReg', (38, 47))	('deletion', 'Var', (79, 87))	('derepression', 'NegReg', (10, 22))
8064	19412439	Consistent with the pivotal role of Gsalpha in multiple biological responses, mutations that affect the activity or expression of Gsalpha lead to human disease.	('expression', 'MPA', (116, 126))	('activity', 'MPA', (104, 112))	('human disease', 'Disease', (146, 159))	('mutations', 'Var', (78, 87))	('human', 'Species', '9606', (146, 151))	('lead to', 'Reg', (138, 145))	('Gsalpha', 'Gene', (130, 137))
8065	19412439	homozygous inactivating Gsalpha mutations, and this is consistent with the early embryonic lethality observed in mice with homozygous disruption of either Gnas exon 2 or Gnas exon 1.	('embryonic lethality', 'Disease', (81, 100))	('Gsalpha', 'Gene', (24, 31))	('mutations', 'Var', (32, 41))	('mice', 'Species', '10090', (113, 117))	('embryonic lethality', 'Disease', 'MESH:D020964', (81, 100))
8067	19412439	Accordingly, mutations that cause constitutive Gsalpha activity are found in various functionally active endocrine adenomas, including those that originate from pituitary somatotrophs.	('activity', 'MPA', (55, 63))	('Gsalpha', 'Gene', (47, 54))	('endocrine adenomas', 'Disease', 'MESH:D000236', (105, 123))	('endocrine adenomas', 'Disease', (105, 123))	('mutations', 'Var', (13, 22))
8068	19412439	In about 40% of patients with growth hormone secreting pituitary adenomas, constitutively activating Gsalpha missense mutations at either Arg201 or Gln227 have been identified in DNA from the tumor tissue, but not in DNA from peripheral blood.	('pituitary adenomas', 'Disease', 'MESH:D010911', (55, 73))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('missense mutations at', 'Var', (109, 130))	('growth hormone', 'Gene', (30, 44))	('patients', 'Species', '9606', (16, 24))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (55, 73))	('Arg201', 'Var', (138, 144))	('Gln227', 'Var', (148, 154))	('growth hormone', 'Gene', '2688', (30, 44))	('Gln227', 'Chemical', '-', (148, 154))	('activating', 'PosReg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Arg201', 'Chemical', '-', (138, 144))	('pituitary adenomas', 'Disease', (55, 73))	('Gsalpha', 'Gene', (101, 108))
8069	19412439	Since these mutant Gsalpha forms are identified in tumors and are present in one of the Gsalpha alleles only, they are referred to as the gsp oncogene.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutant', 'Var', (12, 18))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('gsp', 'Gene', '2778', (138, 141))	('Gsalpha', 'Gene', (19, 26))	('gsp', 'Gene', (138, 141))
8072	19412439	In a more recent study, 5 of 30 patients with clear cell renal carcinoma have been shown to carry constitutively activating Gsalpha mutations in the tumor tissue.	('activating', 'PosReg', (113, 123))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('renal carcinoma', 'Phenotype', 'HP:0005584', (57, 72))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (46, 72))	('Gsalpha', 'Gene', (124, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('clear cell renal carcinoma', 'Disease', (46, 72))
8077	19412439	Patients with the McCune-Albright syndrome (MAS) are mosaic for constitutively activating Gsalpha mutations that occur during early embryonic development.	('McCune-Albright syndrome', 'Disease', (18, 42))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (18, 42))	('activating', 'PosReg', (79, 89))	('mutations', 'Var', (98, 107))	('Patients', 'Species', '9606', (0, 8))	('Gsalpha', 'Gene', (90, 97))	('MAS', 'Disease', (44, 47))	('MAS', 'Disease', 'MESH:D005357', (44, 47))
8079	19412439	All identified mutations are at residue Arg201 (Cys or His), suggesting that changes in residue Gln227 may result in higher constitutive activity and are, therefore, less viable.	('Arg201', 'Chemical', '-', (40, 46))	('Gln227', 'Var', (96, 102))	('changes', 'Var', (77, 84))	('constitutive activity', 'MPA', (124, 145))	('Gln227', 'Chemical', '-', (96, 102))	('His', 'Chemical', 'MESH:D006639', (55, 58))	('higher', 'PosReg', (117, 123))	('Cys', 'Chemical', 'MESH:D003545', (48, 51))
8080	19412439	Because of the mosaicism, patients with MAS show significant variation in their clinical presentation.	('MAS', 'Disease', (40, 43))	('patients', 'Species', '9606', (26, 34))	('mosaicism', 'Var', (15, 24))	('MAS', 'Disease', 'MESH:D005357', (40, 43))
8082	19412439	It is important to note that some patients with the constitutively activating Gsalpha mutations present with fibrous dysplasia alone, affecting either a single bone or multiple bones.	('mutations', 'Var', (86, 95))	('present', 'Reg', (96, 103))	('Gsalpha', 'Gene', (78, 85))	('fibrous dysplasia', 'Disease', 'MESH:D005357', (109, 126))	('fibrous dysplasia', 'Disease', (109, 126))	('patients', 'Species', '9606', (34, 42))	('activating', 'PosReg', (67, 77))
8084	19412439	As in patients with MAS, nearly all isolated cases of fibrous dysplasia are associated with GNAS mutations at Arg201; however, a study using a mutation-specific restriction enzyme digest assay has recently identified three Gln227 (to Leu) mutations among a total of 56 samples.	('GNAS', 'Gene', (92, 96))	('Leu', 'Chemical', 'MESH:D007930', (234, 237))	('MAS', 'Disease', 'MESH:D005357', (20, 23))	('MAS', 'Disease', (20, 23))	('Gln227', 'Chemical', '-', (223, 229))	('fibrous dysplasia', 'Disease', (54, 71))	('mutations at Arg201', 'Var', (97, 116))	('fibrous dysplasia', 'Disease', 'MESH:D005357', (54, 71))	('associated', 'Reg', (76, 86))	('patients', 'Species', '9606', (6, 14))	('Gln227 (to Leu', 'Var', (223, 237))	('Arg201', 'Chemical', '-', (110, 116))	('tri', 'Chemical', '-', (164, 167))
8103	19412439	Inactivating Gsalpha mutations found in PHP-Ia patients are also present in patients who lack hormone resistance but present with AHO features, a condition referred to as pseudopseudohypoparathyroidism (PPHP).	('pseudopseudohypoparathyroidism', 'Disease', (171, 201))	('PHP-Ia', 'Disease', (40, 46))	('patients', 'Species', '9606', (76, 84))	('PHP', 'Phenotype', 'HP:0000852', (40, 43))	('pseudohypoparathyroidism', 'Phenotype', 'HP:0000852', (177, 201))	('Gsalpha', 'Gene', (13, 20))	('patients', 'Species', '9606', (47, 55))	('pseudopseudohypoparathyroidism', 'Disease', 'MESH:D011556', (171, 201))	('Inactivating', 'Var', (0, 12))	('PHP-Ia', 'Disease', 'MESH:D011547', (40, 46))	('PHP', 'Phenotype', 'HP:0000852', (204, 207))	('mutations', 'Var', (21, 30))
8109	19412439	Gsalpha haploinsufficiency has been demonstrated in the growth plate of mice chimeric for wild-type cells and cells heterozygous for disruption of either the maternal or the paternal Gnas exon 2.	('Gsalpha haploinsufficiency', 'Disease', 'MESH:D058495', (0, 26))	('rat', 'Species', '10116', (43, 46))	('disruption', 'Var', (133, 143))	('mice', 'Species', '10090', (72, 76))	('Gsalpha haploinsufficiency', 'Disease', (0, 26))
8110	19412439	In the chimeric setting, the mutant chondrocytes undergo hypertrophic differentiation sooner than wild-type chondrocytes, and because this finding is qualitatively similar to (albeit far less severe than) that observed in chondrocytes with homozygous Gsalpha ablation under the same conditions, it indicates Gsalpha haploinsufficiency.	('hypertrophic', 'Disease', (57, 69))	('mutant', 'Var', (29, 35))	('undergo', 'Reg', (49, 56))	('hypertrophic', 'Disease', 'MESH:D006984', (57, 69))	('Gsalpha haploinsufficiency', 'Disease', (308, 334))	('Gsalpha haploinsufficiency', 'Disease', 'MESH:D058495', (308, 334))
8113	19412439	It is also possible that disruption of other imprinted GNAS gene products contribute to the pathogenesis of AHO.	('contribute', 'Reg', (74, 84))	('disruption', 'Var', (25, 35))	('AHO', 'Disease', (108, 111))	('tri', 'Chemical', '-', (77, 80))
8114	19412439	Supporting this hypothesis, chondrocytes with paternal Gnas exon 2 disruption exhibit a slightly, but significantly, higher degree of Gsalpha haploinsufficiency than chondrocytes with maternal Gnas exon 2 disruption.	('disruption', 'Var', (67, 77))	('Gnas exon 2', 'Gene', (55, 66))	('higher', 'PosReg', (117, 123))	('Gsalpha haploinsufficiency', 'Disease', (134, 160))	('Gsalpha haploinsufficiency', 'Disease', 'MESH:D058495', (134, 160))
8115	19412439	More detailed characterization of the different AHO features between patients with paternally and maternally inherited Gsalpha mutations are likely to provide further insights into the understanding of the mechanisms underlying AHO.	('patients', 'Species', '9606', (69, 77))	('mutations', 'Var', (127, 136))	('Gsalpha', 'Gene', (119, 126))
8117	19412439	Heterozygous inactivation mutations within the Gsalpha coding GNAS exons have also been identified in patients with POH.	('Gsalpha', 'Gene', (47, 54))	('POH', 'Disease', (116, 119))	('patients', 'Species', '9606', (102, 110))	('Heterozygous inactivation mutations', 'Var', (0, 35))	('identified', 'Reg', (88, 98))
8118	19412439	In fact, some of those mutations are identical to those found in patients with PHP-Ia or PPHP.	('PPHP', 'Disease', (89, 93))	('PHP', 'Phenotype', 'HP:0000852', (79, 82))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (65, 73))	('PHP-Ia', 'Disease', (79, 85))	('PHP', 'Phenotype', 'HP:0000852', (90, 93))	('PHP-Ia', 'Disease', 'MESH:D011547', (79, 85))
8124	19412439	Unlike in PHP-Ia, Gsalpha activity is typically normal in easily accessible cells from these patients, thus excluding mutations within Gsalpha coding GNAS exons.	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (118, 127))	('PHP-Ia', 'Disease', (10, 16))	('PHP', 'Phenotype', 'HP:0000852', (10, 13))	('Gsalpha', 'Gene', (135, 142))	('PHP-Ia', 'Disease', 'MESH:D011547', (10, 16))
8126	19412439	Expressed in HEK293 cells, an embryonic kidney derived cell line, this Gsalpha mutant was shown to affect the signaling of PTH, but not of TSH, LH, or isoproterenol, thus explaining the isolated PTH resistance.	('embryonic kidney', 'Disease', (30, 46))	('HEK293', 'CellLine', 'CVCL:0045', (13, 19))	('mutant', 'Var', (79, 85))	('TSH', 'Chemical', 'MESH:D013972', (139, 142))	('LH', 'Chemical', 'MESH:D007986', (144, 146))	('embryonic kidney', 'Disease', 'MESH:D007674', (30, 46))	('signaling', 'MPA', (110, 119))	('PTH', 'Chemical', 'MESH:D010281', (123, 126))	('affect', 'Reg', (99, 105))	('isoproterenol', 'Chemical', 'MESH:D007545', (151, 164))	('PTH', 'Chemical', 'MESH:D010281', (195, 198))	('Gsalpha', 'Gene', (71, 78))	('PTH', 'MPA', (123, 126))
8127	19412439	The selective effect of this mutation on PTH signaling, however, could not be verified in a subsequent study, and it is possible that the discrepancy between the two studies stems from the use of different cell types and/or assays; the second study used mouse embryonic fibroblasts null for endogenous Gsalpha.	('mutation', 'Var', (29, 37))	('mouse', 'Species', '10090', (254, 259))	('Gsalpha', 'Gene', (302, 309))	('PTH', 'Chemical', 'MESH:D010281', (41, 44))	('PTH signaling', 'MPA', (41, 54))
8129	19412439	Since the urinary cAMP response to exogenously administered PTH is blunted in PHP-Ib patients, defects in the gene encoding PTHR1 seemed like a good candidate at the time.	('PTH', 'Chemical', 'MESH:D010281', (124, 127))	('blunted', 'NegReg', (67, 74))	('PHP-Ib', 'Gene', (78, 84))	('PHP', 'Phenotype', 'HP:0000852', (78, 81))	('urinary cAMP response to exogenously administered', 'MPA', (10, 59))	('PTH', 'Chemical', 'MESH:D010281', (60, 63))	('patients', 'Species', '9606', (85, 93))	('PTHR1', 'Gene', (124, 129))	('defects', 'Var', (95, 102))	('cAMP', 'Chemical', 'MESH:D000242', (18, 22))	('PTHR1', 'Gene', '5745', (124, 129))
8135	19412439	Flanked by two 391-bp repeats, the 3-kb microdeletion removes exons 4-6 of STX16, the gene encoding syntaxin-16.	('removes', 'NegReg', (54, 61))	('STX16', 'Gene', (75, 80))	('syntaxin-16', 'Gene', (100, 111))	('microdeletion', 'Var', (40, 53))	('syntaxin-16', 'Gene', '8675', (100, 111))
8136	19412439	These mutations cause disease only after maternal inheritance, and each affected individual carrying either of these mutations displays an isolated loss of exon A/B imprinting, thereby indicating that the mutations disrupt a cis-acting element that controls imprinting at the exon A/B DMR.	('DMR', 'Chemical', '-', (285, 288))	('loss', 'NegReg', (148, 152))	('mutations', 'Var', (205, 214))	('disease', 'Disease', (22, 29))	('disrupt', 'NegReg', (215, 222))	('mutations', 'Var', (6, 15))	('cause', 'Reg', (16, 21))
8138	19412439	Two unrelated familial cases with such GNAS imprinting abnormalities have been shown to carry maternally inherited deletions of the entire NESP55 DMR including exons 3 and 4 of the antisense transcript, revealing the putative location of another control element required for the imprinting of the entire maternal GNAS allele (Fig.	('DMR', 'Chemical', '-', (146, 149))	('NESP55 DMR', 'Gene', (139, 149))	('deletions', 'Var', (115, 124))
8139	19412439	The presence of similarly large deletions at the NESP55 DMR has been excluded in a number of sporadic PHP-Ib cases.	('deletions', 'Var', (32, 41))	('PHP', 'Phenotype', 'HP:0000852', (102, 105))	('DMR', 'Chemical', '-', (56, 59))	('NESP55 DMR', 'Gene', (49, 59))	('PHP-Ib', 'Disease', (102, 108))
8142	19412439	Leading to the diagnosis were PTH-resistance and mild TSH resistance in the absence of typical AHO findings, although the patient had additional abnormalities, including developmental delay and craniosynostosis, which may have resulted from either disrupted expression of other imprinted genes or from unmasking of recessive defects present on paternal chromosome 20q.	('mild TSH resistance', 'Disease', (49, 68))	('developmental delay', 'Phenotype', 'HP:0001263', (170, 189))	('developmental delay', 'Disease', 'MESH:D002658', (170, 189))	('developmental delay', 'Disease', (170, 189))	('additional abnormalities', 'Disease', (134, 158))	('TSH', 'Chemical', 'MESH:D013972', (54, 57))	('patient', 'Species', '9606', (122, 129))	('craniosynostosis', 'Disease', 'MESH:D003398', (194, 210))	('craniosynostosis', 'Phenotype', 'HP:0001363', (194, 210))	('craniosynostosis', 'Disease', (194, 210))	('PTH', 'Chemical', 'MESH:D010281', (30, 33))	('additional abnormalities', 'Disease', 'MESH:D000014', (134, 158))	('PTH-resistance', 'Disease', (30, 44))	('disrupted', 'Var', (248, 257))
8150	19412439	Mild short-stature has been recently reported in some patients who show PTH-resistance and GNAS imprinting defects, consistent with GHRH resistance and resultant growth hormone deficiency.	('PTH-resistance', 'Gene', (72, 86))	('GNAS imprinting', 'Gene', (91, 106))	('growth hormone deficiency', 'Phenotype', 'HP:0000824', (162, 187))	('growth hormone deficiency', 'Disease', 'MESH:C537404', (162, 187))	('PTH', 'Chemical', 'MESH:D010281', (72, 75))	('patients', 'Species', '9606', (54, 62))	('defects', 'Var', (107, 114))	('Mild short-stature', 'Disease', (0, 18))	('imprinting', 'Gene', (96, 106))	('GHRH', 'Gene', '2691', (132, 136))	('growth hormone deficiency', 'Disease', (162, 187))	('short-stature', 'Phenotype', 'HP:0004322', (5, 18))	('GHRH', 'Gene', (132, 136))
8154	19412439	Supporting this notion, ablation of the paternal exon A/B region derepresses Gsalpha in cis in tissues where this signaling protein is paternally silenced and, furthermore, rescues the PTH resistance phenotype observed in mice with a point mutation in maternal Gnas exon 6.	('mice', 'Species', '10090', (222, 226))	('derepresses', 'NegReg', (65, 76))	('point mutation', 'Var', (234, 248))	('PTH', 'Chemical', 'MESH:D010281', (185, 188))	('PTH resistance phenotype', 'MPA', (185, 209))	('rescues', 'PosReg', (173, 180))	('ablation', 'Var', (24, 32))	('Gsalpha', 'Gene', (77, 84))
8157	19412439	As explained above, mice with paternal disruption of Gnas exon 2 have severe defects that are similar to those seen in mice with paternal disruption of Gnasxl, including reduced adiposity, which is not seen in patients with paternally inherited inactivating Gsalpha mutations (PPHP); these patients are typically overweight.	('Gnasxl', 'Gene', '14683', (152, 158))	('mice', 'Species', '10090', (119, 123))	('patients', 'Species', '9606', (290, 298))	('Gnasxl', 'Gene', (152, 158))	('mice', 'Species', '10090', (20, 24))	('adiposity', 'MPA', (178, 187))	('reduced', 'NegReg', (170, 177))	('PHP', 'Phenotype', 'HP:0000852', (278, 281))	('paternal disruption', 'Var', (30, 49))	('patients', 'Species', '9606', (210, 218))	('overweight', 'Phenotype', 'HP:0025502', (313, 323))	('reduced adiposity', 'Phenotype', 'HP:0040063', (170, 187))	('Gnas', 'Gene', (53, 57))
8163	19412439	Hence, although the findings resulted from the disruption of exon 2 are rather complicated due to the use of this exon by not only Gsalpha but also several other GNAS products (particularly XLalphas), this animal model is able to phenocopy PHP-Ia to a significant extent.	('rat', 'Species', '10116', (72, 75))	('phenocopy PHP-Ia', 'Disease', (230, 246))	('disruption', 'Var', (47, 57))	('XLalphas', 'Chemical', '-', (190, 198))	('PHP', 'Phenotype', 'HP:0000852', (240, 243))	('phenocopy PHP-Ia', 'Disease', 'MESH:D011547', (230, 246))
8164	19412439	have independently generated another model of PHP-Ia through targeted disruption of Gnas exon 1.	('Gnas exon 1', 'Gene', (84, 95))	('PHP-Ia', 'Disease', 'MESH:D011547', (46, 52))	('rat', 'Species', '10116', (23, 26))	('disruption', 'Var', (70, 80))	('PHP-Ia', 'Disease', (46, 52))	('PHP', 'Phenotype', 'HP:0000852', (46, 49))
8165	19412439	In addition to early embryonic lethality observed upon homozygous inheritance of exon 1 disruption, even the heterozygous disruption is associated with some pre-weaning mortality regardless of the parental origin.	('associated', 'Reg', (136, 146))	('embryonic lethality', 'Disease', 'MESH:D020964', (21, 40))	('embryonic lethality', 'Disease', (21, 40))	('exon 1', 'Gene', (81, 87))	('disruption', 'Var', (88, 98))
8168	19412439	In humans with inactivating Gsalpha mutations it is accepted that obesity develops regardless of the parent-of-origin of the introduced mutation, but recent evidence indicates that patients with PHP-Ia exhibit more prominent obesity than patients with PPHP.	('PHP', 'Phenotype', 'HP:0000852', (253, 256))	('obesity', 'Disease', (225, 232))	('PHP-Ia', 'Disease', (195, 201))	('obesity', 'Phenotype', 'HP:0001513', (66, 73))	('PHP-Ia', 'Disease', 'MESH:D011547', (195, 201))	('mutations', 'Var', (36, 45))	('PHP', 'Phenotype', 'HP:0000852', (195, 198))	('obesity', 'Disease', 'MESH:D009765', (66, 73))	('Gsalpha', 'Gene', (28, 35))	('humans', 'Species', '9606', (3, 9))	('patients', 'Species', '9606', (181, 189))	('obesity', 'Phenotype', 'HP:0001513', (225, 232))	('obesity', 'Disease', (66, 73))	('patients', 'Species', '9606', (238, 246))	('obesity', 'Disease', 'MESH:D009765', (225, 232))
8169	19412439	Consistent with this recent observation, mice with the maternal Gnas exon 1 disruption is more obese than the paternal disruption.	('mice', 'Species', '10090', (41, 45))	('obese', 'Disease', (95, 100))	('obese', 'Disease', 'MESH:D009765', (95, 100))	('disruption', 'Var', (76, 86))
8170	19412439	In contrast to these similarities between the mouse models of exon 1 ablation and PHP-Ia/PPHP, the serum PTH level seems to be moderately elevated in mice with paternal Gnas exon 1 ablation, suggesting the presence of PTH-resistance.	('mice', 'Species', '10090', (150, 154))	('rat', 'Species', '10116', (131, 134))	('PHP', 'Phenotype', 'HP:0000852', (82, 85))	('PHP-Ia', 'Disease', (82, 88))	('PHP-Ia', 'Disease', 'MESH:D011547', (82, 88))	('mouse', 'Species', '10090', (46, 51))	('PTH', 'Chemical', 'MESH:D010281', (105, 108))	('serum PTH level', 'MPA', (99, 114))	('PTH', 'Chemical', 'MESH:D010281', (218, 221))	('ablation', 'Var', (181, 189))	('PHP', 'Phenotype', 'HP:0000852', (90, 93))	('elevated', 'PosReg', (138, 146))
8173	19412439	Since a 3-kb deletion removing exons 4-6 of the STX16 locus has been identified in numerous familial PHP-Ib cases, and since this locus, with its exon-intron structure and its proximity to the GNAS locus, is similar in mice and humans, an attempt at generating a PHP-Ib mouse model has been made through targeted deletion of Stx16 exons 4-6.	('PHP', 'Phenotype', 'HP:0000852', (263, 266))	('humans', 'Species', '9606', (228, 234))	('mice', 'Species', '10090', (219, 223))	('mouse', 'Species', '10090', (270, 275))	('deletion', 'Var', (13, 21))	('STX16', 'Gene', (48, 53))	('Stx16', 'Gene', '228960', (325, 330))	('PHP', 'Phenotype', 'HP:0000852', (101, 104))	('deletion', 'Var', (313, 321))	('Stx16', 'Gene', (325, 330))	('rat', 'Species', '10116', (254, 257))
8175	19412439	More important, regardless of the parental origin of the deletion, the mutant mice fail to phenocopy the epigenetic abnormalities found in patients with familial PHP-Ib.	('patients', 'Species', '9606', (139, 147))	('deletion', 'Var', (57, 65))	('familial PHP-Ib', 'Disease', (153, 168))	('phenocopy the epigenetic abnormalities', 'Disease', (91, 129))	('mutant', 'Var', (71, 77))	('phenocopy the epigenetic abnormalities', 'Disease', 'MESH:C580174', (91, 129))	('PHP', 'Phenotype', 'HP:0000852', (162, 165))	('mice', 'Species', '10090', (78, 82))
8177	19412439	Thus, the nearly exact change in the mouse Stx16 gene is not sufficient to disrupt Gnas imprinting and to result in PTH resistance, ruling out a disrupted STX16 mRNA and/or protein as the molecular cause of familial PHP-Ib.	('disrupted', 'Var', (145, 154))	('PHP', 'Phenotype', 'HP:0000852', (216, 219))	('familial PHP-Ib', 'Disease', (207, 222))	('result in', 'Reg', (106, 115))	('PTH resistance', 'MPA', (116, 130))	('mouse', 'Species', '10090', (37, 42))	('Stx16', 'Gene', '228960', (43, 48))	('PTH', 'Chemical', 'MESH:D010281', (116, 119))	('STX16', 'Gene', (155, 160))	('Stx16', 'Gene', (43, 48))
8180	19412439	Several human disorders are caused by heterozygous mutations that affect Gsalpha expression and/or activity, and consistent with the tissue-specific paternal silencing of Gsalpha expression, these disorders are inherited in a parent-of-origin specific manner.	('affect', 'Reg', (66, 72))	('mutations', 'Var', (51, 60))	('human disorders', 'Disease', (8, 23))	('Gsalpha', 'Protein', (73, 80))	('caused by', 'Reg', (28, 37))	('human', 'Species', '9606', (8, 13))	('activity', 'MPA', (99, 107))	('expression', 'MPA', (81, 91))
8181	19412439	Depending on their parental origin, mutations that affect the Gsalpha transcript also disrupt some of the additional GNAS transcripts, such as XLalphas.	('disrupt', 'NegReg', (86, 93))	('mutations', 'Var', (36, 45))	('Gsalpha', 'Gene', (62, 69))	('XLalphas', 'Disease', (143, 151))	('GNAS', 'Gene', (117, 121))	('XLalphas', 'Chemical', '-', (143, 151))
8182	19412439	It is likely that the disruption of these additional gene products or alterations in the balance between the expression of Gsalpha and these proteins contributes to disease pathogenesis.	('Gsalpha', 'Protein', (123, 130))	('alterations', 'Reg', (70, 81))	('expression', 'MPA', (109, 119))	('contributes', 'Reg', (150, 161))	('disruption', 'Var', (22, 32))	('balance', 'MPA', (89, 96))	('rat', 'Species', '10116', (74, 77))	('tri', 'Chemical', '-', (153, 156))
8314	29508384	TGCT was classified using the Danish modified version of the ICD 7th edition codes for seminoma (378) and nonseminoma (278, 478, 578), and the ICD for Oncology, 3rd edition morphology codes for seminoma (9060-9062, 9064) and nonseminoma (9065-9102).	('seminoma', 'Disease', (109, 117))	('9060-9062', 'Var', (204, 213))	('9065-9102', 'Var', (238, 247))	('seminoma', 'Disease', 'MESH:D018239', (87, 95))	('seminoma', 'Disease', 'MESH:D018239', (109, 117))	('Oncology', 'Phenotype', 'HP:0002664', (151, 159))	('ICD', 'Disease', 'OMIM:252500', (143, 146))	('nonseminoma', 'Disease', (225, 236))	('nonseminoma', 'Disease', 'None', (225, 236))	('nonseminoma', 'Disease', (106, 117))	('seminoma', 'Disease', (228, 236))	('nonseminoma', 'Disease', 'None', (106, 117))	('ICD', 'Disease', (61, 64))	('seminoma', 'Disease', 'MESH:D018239', (228, 236))	('seminoma', 'Disease', (194, 202))	('TGCT', 'Disease', (0, 4))	('ICD', 'Disease', 'OMIM:252500', (61, 64))	('seminoma', 'Disease', 'MESH:D018239', (194, 202))	('seminoma', 'Disease', (87, 95))	('ICD', 'Disease', (143, 146))
8340	29508384	Two of the SNPs evaluated were found to be associated with risk of TGCT (rs6060373 and rs143384).	('rs6060373', 'Var', (73, 82))	('rs6060373', 'Mutation', 'rs6060373', (73, 82))	('rs143384', 'Var', (87, 95))	('rs143384', 'Mutation', 'rs143384', (87, 95))	('TGCT', 'Disease', (67, 71))
8352	29508384	In conclusion, childhood height was associated with an increased risk of TGCT, but growth during childhood was not.	('child', 'Species', '9606', (97, 102))	('childhood height', 'Var', (15, 31))	('child', 'Species', '9606', (15, 20))	('TGCT', 'Disease', (73, 77))
8371	27853490	Computerized tomography (CT) scanning revealed a structural alteration in the L3 soma that was a frank pathological fracture (Figure 1).	('fracture', 'Disease', (116, 124))	('structural alteration', 'Var', (49, 70))	('pathological fracture', 'Phenotype', 'HP:0002756', (103, 124))	('fracture', 'Disease', 'MESH:D050723', (116, 124))
8422	27235586	miRNAs regulate the expression levels of their target genes, which are identified by partial complementarity of binding sites.	('miRNAs', 'Var', (0, 6))	('regulate', 'Reg', (7, 15))	('men', 'Species', '9606', (99, 102))	('expression levels', 'MPA', (20, 37))
8448	27235586	The dimension of miRNA and mRNA matrices are [1046x52] and [20531x52], respectively.	('[1046x52]', 'Var', (45, 54))	('[20531x52]', 'Var', (59, 69))	('men', 'Species', '9606', (6, 9))
8496	27235586	Similarly, GO:0030235 is related to the activity of nitric oxide synthase.	('nitric oxide synthase', 'Gene', (52, 73))	('nitric oxide synthase', 'Gene', '4843', (52, 73))	('activity', 'MPA', (40, 48))	('GO:0030235', 'Var', (11, 21))
8502	27235586	The protein kinase gene family is the most frequently mutated in human cancer and the role of mutated protein kinases in development of TGCT has been previously reported.	('mutated', 'Var', (94, 101))	('human', 'Species', '9606', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('men', 'Species', '9606', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
8517	27235586	Finally, AMP-activated protein kinase (AMPK) in "AMPK signaling pathway", can act as a physiological cellular energy sensor and strongly suppresses cell proliferation in both nonmalignant and tumor cells.	('AMP-activated', 'Var', (9, 22))	('tumor', 'Disease', (192, 197))	('cell proliferation in', 'CPA', (148, 169))	('suppresses', 'NegReg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
8529	27235586	None of the other "RP" genes are involved in any enriched pathways and all of them have direct physical interaction with estrogen genes, except for RPS19 which has a common significant GO term, GO:0017134 with FGFR3, one of the TGCT genes.	('GO:0017134', 'Var', (194, 204))	('FGFR3', 'Gene', '2261', (210, 215))	('FGFR3', 'Gene', (210, 215))	('RPS19', 'Gene', '6223', (148, 153))	('RPS19', 'Gene', (148, 153))
8538	27235586	Identification of miRNAs involved in a disease, such as TGCT, can facilitate the development of new therapies to control and treat the disease by designing Anti-miRNA Oligonucleotides (AMOs).	('Anti-miRNA', 'Var', (156, 166))	('TGCT', 'Disease', (56, 60))	('men', 'Species', '9606', (88, 91))
8573	26847433	EDCs can also affect hormone receptor expression, e.g.	('EDCs', 'Var', (0, 4))	('hormone receptor', 'Gene', '3164', (21, 37))	('affect', 'Reg', (14, 20))	('hormone receptor', 'Gene', (21, 37))
8581	26847433	The evidence that EDCs alter development is further supported by findings that EDCs can affect small non-coding RNAs that are implicated in development.	('alter', 'Reg', (23, 28))	('affect', 'Reg', (88, 94))	('development', 'MPA', (29, 40))	('men', 'Species', '9606', (36, 39))	('EDCs', 'Var', (79, 83))	('EDCs', 'Var', (18, 22))	('men', 'Species', '9606', (147, 150))	('small non-coding RNAs', 'Protein', (95, 116))
8582	26847433	In particular, microRNAs (miR) are involved in proper differentiation of primordial germ cells (PGCs) and have been shown to be dysregulated in testicular germ cell tumors.	('cell tumors', 'Disease', 'MESH:D005935', (160, 171))	('PGC', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('microRNAs', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('germ cell tumors', 'Phenotype', 'HP:0100728', (155, 171))	('involved', 'Reg', (35, 43))	('cell tumors', 'Disease', (160, 171))	('PGC', 'Gene', '109820', (96, 99))
8595	26847433	The role of biomechanical cues in tissue development is only recently being explored in different tissue systems such as the developing lung, heart, kidney and the MG. Hormones can also provide biomechanical cues; for example, estrogen has been shown to affect the biomechanical properties of cells isolated from the cornea, endothelium and the anterior cruciate ligament.	('men', 'Species', '9606', (48, 51))	('biomechanical properties of cells', 'CPA', (265, 298))	('affect', 'Reg', (254, 260))	('men', 'Species', '9606', (367, 370))	('estrogen', 'Var', (227, 235))
8597	26847433	Although the hypothesis that EDCs change the biomechanical properties of target tissues has yet to be tested, there is evidence that EDCs affect structural protein expression in the extracellular environment.	('affect', 'Reg', (138, 144))	('EDCs', 'Var', (133, 137))	('men', 'Species', '9606', (203, 206))
8599	26847433	While the phenotypes of affected tissues might be different, it is clear that EDCs act in a systemic manner, a conclusion also supported by reports that EDCs can trigger inflammatory responses in several target tissues.	('man', 'Species', '9606', (101, 104))	('EDCs', 'Var', (153, 157))	('inflammatory responses', 'CPA', (170, 192))	('trigger', 'Reg', (162, 169))
8602	26847433	Under the tenets of the currently prevailing theory of carcinogenesis, namely the Somatic Mutation Theory (SMT), carcinogenesis is a two-step process that occurs within a single normal cell, which, after accumulating somatic mutations, proliferates uncontrollably, and gives rise to a tumor.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mutations', 'Var', (225, 234))	('rat', 'Species', '10116', (243, 246))	('tumor', 'Disease', (285, 290))	('accumulating', 'PosReg', (204, 216))	('carcinogenesis', 'Disease', (113, 127))	('gives rise to', 'Reg', (269, 282))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('carcinogenesis', 'Disease', (55, 69))
8618	26847433	All these changes, when taken in the context of hormonal action during puberty, disrupt the MG environment.	('disrupt', 'Reg', (80, 87))	('changes', 'Var', (10, 17))	('men', 'Species', '9606', (102, 105))	('MG environment', 'MPA', (92, 106))
8625	26847433	Similarly, female CD-1 mice exposed in utero to either DES or methoxychlor (organochlorine pesticide), followed up by an estradiol challenge in adulthood, showed increased uterine weight at lower doses of DES or methoxychlor compared to those exposed to higher doses of both EDCs, thus confirming the non-monotonic dose response (NMDR) of EDCs.	('uterine weight', 'CPA', (172, 186))	('methoxychlor', 'Chemical', 'MESH:D008731', (62, 74))	('increased', 'PosReg', (162, 171))	('DES', 'Var', (205, 208))	('estradiol', 'Chemical', 'MESH:D004958', (121, 130))	('DES', 'Chemical', 'MESH:D004054', (205, 208))	('organochlorine', 'Chemical', 'MESH:D006843', (76, 90))	('mice', 'Species', '10090', (23, 27))	('CD-1', 'Gene', '111334', (18, 22))	('methoxychlor', 'Var', (212, 224))	('increased uterine weight', 'Phenotype', 'HP:0100878', (162, 186))	('methoxychlor', 'Chemical', 'MESH:D008731', (212, 224))	('CD-1', 'Gene', (18, 22))	('DES', 'Chemical', 'MESH:D004054', (55, 58))
8661	26847433	While this may suggest that some estrogens directly attenuate prostatic hyperplasia and metastasis, it is equally possible that genistein triggers a negative feedback response through the pituitary gland resulting in reduced androgen synthesis.	('androgen synthesis', 'MPA', (225, 243))	('prostatic hyperplasia', 'Disease', 'MESH:D011470', (62, 83))	('metastasis', 'CPA', (88, 98))	('attenuate', 'NegReg', (52, 61))	('genistein', 'Var', (128, 137))	('genistein', 'Chemical', 'MESH:D019833', (128, 137))	('negative feedback response', 'MPA', (149, 175))	('reduced androgen synthesis', 'Phenotype', 'HP:0008226', (217, 243))	('reduced', 'NegReg', (217, 224))	('prostatic hyperplasia', 'Disease', (62, 83))
8662	26847433	found that BPA increased the expression of genes associated with self-renewal and maintenance of non-differentiated phenotypes.	('BPA', 'Var', (11, 14))	('BPA', 'Chemical', 'MESH:C006780', (11, 14))	('increased', 'PosReg', (15, 24))	('self-renewal', 'CPA', (65, 77))	('expression of genes', 'MPA', (29, 48))
8681	26847433	Following exposure to PCBs, male rodents showed reduced ventral prostate weight, possibly resulting from their dual action on sex hormone receptors in the prostate.	('ventral prostate weight', 'CPA', (56, 79))	('hormone receptor', 'Gene', (130, 146))	('hormone receptor', 'Gene', '3164', (130, 146))	('reduced', 'NegReg', (48, 55))	('reduced ventral prostate', 'Phenotype', 'HP:0008687', (48, 72))	('PCBs', 'Var', (22, 26))	('PCBs', 'Chemical', 'MESH:D011078', (22, 26))
8685	26847433	The most common risk factor for testicular cancer (TC) is improper testicular development, further strengthening the notion that cancers represent "development gone awry", a notion that is implicit in the TOFT, and made explicit in a later publication.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('men', 'Species', '9606', (155, 158))	('testicular cancer', 'Phenotype', 'HP:0010788', (32, 49))	('testicular cancer', 'Disease', 'MESH:D013736', (32, 49))	('improper', 'Var', (58, 66))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('men', 'Species', '9606', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('testicular cancer', 'Disease', (32, 49))
8686	26847433	In addition, by interfering with normal testicular development, EDCs may increase the risk of neoplastic development.	('EDCs', 'Var', (64, 68))	('neoplastic development', 'CPA', (94, 116))	('interfering', 'NegReg', (16, 27))	('men', 'Species', '9606', (112, 115))	('men', 'Species', '9606', (58, 61))
8694	26847433	Interruption of hormonal function within the developing tissues have been shown to lead to undescended testicles (cryptorchidism), improper positioning of the urethral opening (hypospadia) and sterility.	('sterility', 'Disease', (193, 202))	('hypospadia', 'Disease', 'MESH:D007021', (177, 187))	('hypospadia', 'Disease', (177, 187))	('positioning of the urethral opening', 'Phenotype', 'HP:0100627', (140, 175))	('Interruption', 'Var', (0, 12))	('urethral opening', 'Disease', 'MESH:D014526', (159, 175))	('cryptorchidism', 'Disease', 'MESH:D003456', (114, 128))	('cryptorchidism', 'Disease', (114, 128))	('undescended testicles', 'Phenotype', 'HP:0000028', (91, 112))	('hypospadia', 'Phenotype', 'HP:0000047', (177, 187))	('undescended testicles', 'CPA', (91, 112))	('lead to', 'Reg', (83, 90))	('cryptorchidism', 'Phenotype', 'HP:0000028', (114, 128))	('urethral opening', 'Disease', (159, 175))	('improper positioning', 'CPA', (131, 151))
8700	26847433	Alteration of the hormonal milieu during gestation or perinatal life by exposure to exogenous estrogens or anti-androgens resulted in the malformations described in TDS as well as Leydig cell tumors and teratomas.	('anti-androgens', 'Var', (107, 121))	('malformations', 'Disease', 'MESH:D000014', (138, 151))	('malformations', 'Disease', (138, 151))	('rat', 'Species', '10116', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (180, 198))	('teratomas', 'Phenotype', 'HP:0009792', (203, 212))	('teratomas', 'Disease', (203, 212))	('TDS', 'Disease', (165, 168))	('teratomas', 'Disease', 'MESH:D013724', (203, 212))	('Leydig cell tumors', 'Disease', (180, 198))	('resulted in', 'Reg', (122, 133))	('rat', 'Species', '10116', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (180, 198))
8701	26847433	Several male CD-1 mouse offspring exposed to DES through daily prenatal injections (100ug/kg/d) became infertile and 15 of 24 males had noticeable testicular abnormalities including intra-abdominal testes at 9-10 months of age.	('DES', 'Chemical', 'MESH:D004054', (45, 48))	('CD-1', 'Gene', '111334', (13, 17))	('mouse', 'Species', '10090', (18, 23))	('testicular abnormalities', 'Disease', 'MESH:D013733', (147, 171))	('testicular abnormalities', 'Disease', (147, 171))	('infertile', 'Disease', 'MESH:D007247', (103, 112))	('CD-1', 'Gene', (13, 17))	('infertile', 'Disease', (103, 112))	('intra-abdominal', 'Disease', (182, 197))	('testicular abnormalities', 'Phenotype', 'HP:0000035', (147, 171))	('100ug/kg/d', 'Var', (84, 94))	('intra-abdominal', 'Disease', 'MESH:D059325', (182, 197))
8713	26847433	The findings that miRs involved in testicular development show aberrant expression in TGCTs also lend support to the link between TC and abnormal development of the testes.	('TGCTs', 'Gene', (86, 91))	('abnormal development of the testes', 'Phenotype', 'HP:0008733', (137, 171))	('aberrant expression', 'Var', (63, 82))	('men', 'Species', '9606', (153, 156))	('men', 'Species', '9606', (53, 56))	('link', 'Reg', (117, 121))
8726	26847433	In contrast, a US study found an inverse correlation between PCB congeners and TC, whereas a Norwegian study found epidemiologic evidence that some PCB congeners (99 and 167) may be linked to TC risk.	('linked', 'Reg', (182, 188))	('inverse', 'NegReg', (33, 40))	('PCB', 'Gene', '5091', (61, 64))	('PCB', 'Gene', (61, 64))	('99', 'Var', (163, 165))	('PCB', 'Gene', '5091', (148, 151))	('PCB', 'Gene', (148, 151))
8727	26847433	Finally, a recent case control study (125 patients vs. 103 controls) concluded that serum concentration of PCBs and hexachlorobenzene were tied to a statistically significant increase in TC risk and lower semen quality.	('hexachlorobenzene', 'Chemical', 'MESH:D006581', (116, 133))	('PCBs', 'Gene', (107, 111))	('rat', 'Species', '10116', (97, 100))	('lower', 'NegReg', (199, 204))	('hexachlorobenzene', 'Var', (116, 133))	('PCBs', 'Chemical', 'MESH:D011078', (107, 111))	('men', 'Species', '9606', (207, 210))	('increase', 'PosReg', (175, 183))	('serum', 'MPA', (84, 89))	('semen quality', 'CPA', (205, 218))	('patients', 'Species', '9606', (42, 50))
8728	26847433	presented the first evidence that AGD was correlated with incomplete testicular descent in infants exposed prenatally to phthalates.	('phthalate', 'Chemical', 'MESH:C032279', (121, 130))	('AGD', 'Var', (34, 37))	('incomplete testicular descent', 'CPA', (58, 87))	('infants', 'Species', '9606', (91, 98))
8738	26847433	Male Long-Evans and Holtzman rats, and Syrian hamsters exposed to TCDD perinatally showed dose-dependent developmental defects that ranged from reduced epididymis weights to reduced AGD, delayed testicular descent and reduced sperm number and quality.	('reduced', 'NegReg', (144, 151))	('men', 'Species', '9606', (112, 115))	('epididymis', 'Disease', (152, 162))	('reduced sperm', 'Phenotype', 'HP:0012207', (218, 231))	('Syrian hamsters', 'Species', '10036', (39, 54))	('testicular descent', 'CPA', (195, 213))	('man', 'Species', '9606', (25, 28))	('delayed testicular', 'Phenotype', 'HP:0008734', (187, 205))	('delayed', 'NegReg', (187, 194))	('AGD', 'MPA', (182, 185))	('sperm number', 'CPA', (226, 238))	('reduced', 'NegReg', (218, 225))	('reduced', 'NegReg', (174, 181))	('TCDD', 'Var', (66, 70))	('epididymis', 'Disease', 'MESH:D004823', (152, 162))	('rats', 'Species', '10116', (29, 33))	('reduced AGD', 'Phenotype', 'HP:0410245', (174, 185))	('TCDD', 'Chemical', 'MESH:D000072317', (66, 70))
8763	26847433	BRCA1/2 germline mutations, Klinefelter and Cowden syndrome), lifestyles (obesity, excessive alcohol intake, hormone manipulation), and occupational hazards (exhaust emissions, high temperatures).	('germline mutations', 'Var', (8, 26))	('BRCA1', 'Gene', (0, 5))	('rat', 'Species', '10116', (187, 190))	('Cowden syndrome', 'Disease', 'MESH:D006223', (44, 59))	('Cowden syndrome', 'Disease', (44, 59))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('obesity', 'Disease', (74, 81))	('Klinefelter', 'Disease', (28, 39))	('excessive alcohol', 'Phenotype', 'HP:0030955', (83, 100))	('man', 'Species', '9606', (117, 120))	('BRCA1', 'Gene', '672', (0, 5))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))	('alcohol', 'Chemical', 'MESH:D000438', (93, 100))
8773	26847433	EDCs have been linked to higher incidences of gynecomastia in humans.	('EDCs', 'Var', (0, 4))	('gynecomastia', 'Disease', 'MESH:D006177', (46, 58))	('gynecomastia', 'Disease', (46, 58))	('gynecomastia', 'Phenotype', 'HP:0000771', (46, 58))	('humans', 'Species', '9606', (62, 68))
8789	26847433	In adult male Sprague-Dawley rats, exposure to methoxychlor or a combination of genistein and methoxychlor resulted in increased longitudinal growth, density and size of the MGs, increased number of ductal branches and alveolar mass, and exhibited ductal hyperplasia.	('longitudinal growth', 'CPA', (129, 148))	('MGs', 'Chemical', 'MESH:D008274', (174, 177))	('Sprague-Dawley rats', 'Species', '10116', (14, 33))	('methoxychlor', 'Var', (94, 106))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (248, 266))	('ductal hyperplasia', 'Disease', (248, 266))	('methoxychlor', 'Chemical', 'MESH:D008731', (94, 106))	('genistein', 'Chemical', 'MESH:D019833', (80, 89))	('methoxychlor', 'Chemical', 'MESH:D008731', (47, 59))	('alveolar mass', 'Disease', (219, 232))	('alveolar mass', 'Disease', 'MESH:C536030', (219, 232))	('increased', 'PosReg', (179, 188))	('increased', 'PosReg', (119, 128))
8791	26847433	However, as the Endocrine Society has recently asserted, more research is required to establish the link between defects of the male reproductive system, including cancers, and EDCs, such as the ones discussed above.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('defects', 'Var', (113, 120))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('EDCs', 'Disease', (177, 181))
8820	26847433	We have discussed how manipulation of systemic hormone synthesis, residential reduction or aromatization of circulating hormones, and receptor function or expression in rodents results in distinct changes in organ structure, function, and development.	('changes', 'Reg', (197, 204))	('aromatization', 'Var', (91, 104))	('development', 'CPA', (239, 250))	('men', 'Species', '9606', (246, 249))	('reduction', 'NegReg', (78, 87))	('manipulation', 'Var', (22, 34))	('function', 'MPA', (225, 233))	('man', 'Species', '9606', (22, 25))	('organ structure', 'MPA', (208, 223))
8830	24731683	In XY gonadal dysgenesis, the presence of a Y chromosome or Y-chromosome material renders the patient at increased risk for developing gonadal malignancy.	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (6, 24))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (6, 24))	('gonadal malignancy', 'Phenotype', 'HP:0010785', (135, 153))	('Y-chromosome material', 'Var', (60, 81))	('gonadal malignancy', 'Disease', 'MESH:D009369', (135, 153))	('presence', 'Var', (30, 38))	('gonadal malignancy', 'Disease', (135, 153))	('Y chromosome', 'Var', (44, 56))	('patient', 'Species', '9606', (94, 101))	('gonadal dysgenesis', 'Disease', (6, 24))
8836	24731683	Gonadal dysgenesis is a term used for a unique subset of disorders of sexual development (DSD) characterized by incomplete or defective formation of the gonads (ovary or testis) due to either structural or numerical anomalies of the sex chromosomes or mutations in the genes involved in the development of the gonad.	('Gonadal dysgenesis', 'Disease', 'MESH:D006059', (0, 18))	('DSD', 'Disease', (90, 93))	('defective', 'NegReg', (126, 135))	('mutations', 'Var', (252, 261))	('ovary or testis', 'Disease', (161, 176))	('ovary or testis', 'Disease', 'MESH:D013736', (161, 176))	('Gonadal dysgenesis', 'Disease', (0, 18))	('anomalies of the sex', 'Disease', 'MESH:D012729', (216, 236))	('anomalies of the sex', 'Disease', (216, 236))	('Gonadal dysgenesis', 'Phenotype', 'HP:0000133', (0, 18))	('DSD', 'Disease', 'MESH:D058533', (90, 93))
8841	24731683	Patients with gonadal dysgenesis who have a Y chromosome or Y-chromosome material are at increased risk for developing germ cell tumors such as gonadoblastoma or carcinoma in situ (CIS), with the potential for malignant transformation to dysgerminoma or seminoma, respectively.	('dysgerminoma', 'Disease', 'MESH:D004407', (238, 250))	('carcinoma in situ', 'Disease', (162, 179))	('seminoma', 'Disease', 'MESH:D018239', (254, 262))	('germ cell tumors', 'Phenotype', 'HP:0100728', (119, 135))	('germ cell tumors', 'Disease', 'MESH:D009373', (119, 135))	('gonadal dysgenesis', 'Disease', (14, 32))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (162, 179))	('dysgerminoma', 'Phenotype', 'HP:0100621', (238, 250))	('Patients', 'Species', '9606', (0, 8))	('Y chromosome', 'Var', (44, 56))	('germ cell tumors', 'Disease', (119, 135))	('carcinoma in situ', 'Disease', 'MESH:D002278', (162, 179))	('dysgerminoma', 'Disease', (238, 250))	('gonadoblastoma', 'Phenotype', 'HP:0000150', (144, 158))	('germ cell tumor', 'Phenotype', 'HP:0100728', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gonadoblastoma', 'Disease', 'MESH:D018238', (144, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (14, 32))	('Y-chromosome material', 'Var', (60, 81))	('gonadoblastoma', 'Disease', (144, 158))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (14, 32))	('seminoma', 'Disease', (254, 262))	('CIS', 'Phenotype', 'HP:0030075', (181, 184))
8870	24731683	Mutations and deletions in the SRY (sex-determining gene on the Y chromosome) have been reported in the literature to account for 10-20% of the cases of 46,XY CGD.	('SRY', 'Gene', (31, 34))	('deletions', 'Var', (14, 23))	('SRY', 'Gene', '6736', (31, 34))	('Mutations', 'Var', (0, 9))
8871	24731683	Other mutations identified have included NR5A1 (9q33), DHH (12q13.1), NROB1 (DAX 1), WNT4 , DMRT1 (9p24.3) deletion, CBX2 (17q25) deletion, and a heterozygous mutation in MAP3K1 (5q11.2).	('CBX2', 'Gene', '84733', (117, 121))	('MAP3K1', 'Gene', (171, 177))	('DMRT1', 'Gene', '1761', (92, 97))	('DAX 1', 'Gene', (77, 82))	('NR5A1', 'Gene', '2516', (41, 46))	('DHH', 'Gene', (55, 58))	('MAP3K1', 'Gene', '4214', (171, 177))	('DAX 1', 'Gene', '190', (77, 82))	('DMRT1', 'Gene', (92, 97))	('WNT4', 'Gene', (85, 89))	('NROB1', 'Gene', '190', (70, 75))	('NROB1', 'Gene', (70, 75))	('WNT4', 'Gene', '54361', (85, 89))	('NR5A1', 'Gene', (41, 46))	('deletion', 'Var', (107, 115))	('DHH', 'Gene', '50846', (55, 58))	('CBX2', 'Gene', (117, 121))
8900	24731683	Mutations have been described in SRY , NR5A1(9q33), DHH (12q13.1), NROB1 (DAX 1), and WNT4 .	('DAX 1', 'Gene', (74, 79))	('NROB1', 'Gene', '190', (67, 72))	('NROB1', 'Gene', (67, 72))	('WNT4', 'Gene', (86, 90))	('DHH', 'Gene', '50846', (52, 55))	('WNT4', 'Gene', '54361', (86, 90))	('NR5A1', 'Gene', (39, 44))	('DAX 1', 'Gene', '190', (74, 79))	('NR5A1', 'Gene', '2516', (39, 44))	('Mutations', 'Var', (0, 9))	('DHH', 'Gene', (52, 55))	('SRY', 'Gene', '6736', (33, 36))	('SRY', 'Gene', (33, 36))
8902	24731683	Campomelic dysplasia is a skeletal malformation syndrome caused by mutations in SOX9 .	('caused by', 'Reg', (57, 66))	('mutations', 'Var', (67, 76))	('SOX9', 'Gene', (80, 84))	('Campomelic dysplasia', 'Disease', (0, 20))	('Campomelic dysplasia', 'Disease', 'MESH:D055036', (0, 20))	('SOX9', 'Gene', '6662', (80, 84))	('skeletal malformation', 'Phenotype', 'HP:0000924', (26, 47))	('skeletal malformation syndrome', 'Disease', (26, 56))	('skeletal malformation syndrome', 'Disease', 'MESH:D000014', (26, 56))
8939	24731683	The risk of developing gonadal malignancy in patients with PGD who have 45,X/46,XY and variants is reported by Cools, et al., as 15-40%.	('PGD', 'Chemical', '-', (59, 62))	('gonadal malignancy', 'Disease', 'MESH:D009369', (23, 41))	('variants', 'Var', (87, 95))	('patients', 'Species', '9606', (45, 53))	('gonadal malignancy', 'Phenotype', 'HP:0010785', (23, 41))	('gonadal malignancy', 'Disease', (23, 41))
8940	24731683	In patients with mixed gonadal dysgenesis or asymmetrical gonadal differentiation, the estimated tumor prevalence is reported to be approximately 15%, although this figure may be an underestimation.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('asymmetrical', 'Var', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('gonadal dysgenesis', 'Disease', (23, 41))	('patients', 'Species', '9606', (3, 11))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (23, 41))	('mixed gonadal dysgenesis', 'Phenotype', 'HP:0000133', (17, 41))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (23, 41))
9044	23660945	Of particular interest for GCT patients is that androgen deficiency has been found to be a risk factor for the development of the MetS, and cured survivors are often found to have some degree of CT-induced hypogonadism, which may persist for up to 10 years after treatment.	('GCT', 'Phenotype', 'HP:0100728', (27, 30))	('deficiency', 'Var', (57, 67))	('men', 'Species', '9606', (268, 271))	('men', 'Species', '9606', (118, 121))	('hypogonadism', 'Phenotype', 'HP:0000135', (206, 218))	('patients', 'Species', '9606', (31, 39))	('hypogonadism', 'Disease', (206, 218))	('MetS', 'Disease', (130, 134))	('androgen', 'Protein', (48, 56))	('androgen deficiency', 'Phenotype', 'HP:0008226', (48, 67))	('hypogonadism', 'Disease', 'MESH:D007006', (206, 218))
9074	23660945	Combination-CT patients had significantly higher fasting serum concentrations of cholesterol, LDL-cholesterol, and triglyceride than that in controls, and higher serum cholesterol and triglyceride concentrations compared with that in surgery patients (Table 3).	('patients', 'Species', '9606', (15, 23))	('triglyceride', 'Chemical', 'MESH:D014280', (115, 127))	('Combination-CT', 'Var', (0, 14))	('cholesterol', 'Chemical', 'MESH:D002784', (98, 109))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('triglyceride', 'Chemical', 'MESH:D014280', (184, 196))	('higher', 'PosReg', (42, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (168, 179))	('higher serum cholesterol', 'Phenotype', 'HP:0003124', (155, 179))	('LDL-cholesterol', 'MPA', (94, 109))	('higher fasting serum concentrations of cholesterol', 'Phenotype', 'HP:0003124', (42, 92))	('triglyceride', 'MPA', (115, 127))	('higher', 'PosReg', (155, 161))	('patients', 'Species', '9606', (242, 250))
9086	23660945	Irrespective of the use of the IDF or NCEP-ATPIII criteria, survivors with the lowest quartile testosterone levels (<12.0 nmol l-1) had a MetS prevalence higher than the other three quartiles (OR, 2.5 and 95% CI, 1.3-4.7; and OR, 1.7 and 95% CI, 0.8-3.6, respectively).	('testosterone', 'Chemical', 'MESH:D013739', (95, 107))	('MetS', 'MPA', (138, 142))	('<12.0', 'Var', (116, 121))	('testosterone', 'MPA', (95, 107))
9110	23660945	Apart from these favourable effects on lipid metabolism, testosterone supplementation also results in increased BMD, muscle mass, and fat-free body mass.	('testosterone', 'Chemical', 'MESH:D013739', (57, 69))	('testosterone', 'Gene', (57, 69))	('lipid metabolism', 'MPA', (39, 55))	('fat-free body mass', 'CPA', (134, 152))	('BMD', 'Disease', (112, 115))	('men', 'Species', '9606', (76, 79))	('BMD', 'Disease', 'MESH:D020388', (112, 115))	('supplementation', 'Var', (70, 85))	('muscle mass', 'CPA', (117, 128))	('increased', 'PosReg', (102, 111))	('lipid', 'Chemical', 'MESH:D008055', (39, 44))
9117	23660945	In our opinion, this would allow for evidence-based counselling of GCT survivors to adhere to a lifestyle that favourably affects the modifiable risk factors for MetS and cardiovascular risk, such as regular exercise, low-carbohydrate diet, and smoking cessation.	('smoking cessation', 'Disease', (245, 262))	('MetS', 'Disease', (162, 166))	('affects', 'Reg', (122, 129))	('GCT', 'Phenotype', 'HP:0100728', (67, 70))	('carbohydrate', 'Chemical', 'MESH:D002241', (222, 234))	('low-carbohydrate', 'Var', (218, 234))
9125	9083348	This implies that 7.6% of men in the general population will be carriers of the mutant allele and that 0.1% would be homozygote and are, therefore, at high risk of developing the cancer.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutant', 'Var', (80, 86))	('men', 'Species', '9606', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
9157	31360893	Ovarian reserve varies among women and is affected by additional factors, including genetic polymorphisms associated with age of menopause and others in genes encoding drug metabolism enzymes may also affect risk of ovarian toxicity.	('genetic polymorphisms', 'Var', (84, 105))	('women', 'Species', '9606', (29, 34))	('ovarian toxicity', 'Disease', 'MESH:D010049', (216, 232))	('men', 'Species', '9606', (31, 34))	('affect', 'Reg', (201, 207))	('Ovarian reserve', 'CPA', (0, 15))	('ovarian toxicity', 'Disease', (216, 232))	('men', 'Species', '9606', (129, 132))
9161	31360893	Abnormalities of traditional laboratory markers such as follicle-stimulating hormone, estradiol, and inhibin-B levels are late markers of ovarian aging.	('Abnormalities', 'Var', (0, 13))	('follicle-stimulating', 'MPA', (56, 76))	('ovarian aging', 'Phenotype', 'HP:0008209', (138, 151))	('inhibin-B levels', 'MPA', (101, 117))	('estradiol', 'MPA', (86, 95))	('ovarian aging', 'Disease', 'MESH:D010051', (138, 151))	('ovarian aging', 'Disease', (138, 151))
9168	31360893	Most studies support the impact of alkylating chemotherapy on infertility and surrogates, including acute ovarian failure (AOF) and premature menopause, but not all have identified a detrimental effect.	('alkylating', 'Var', (35, 45))	('infertility', 'Phenotype', 'HP:0000789', (62, 73))	('men', 'Species', '9606', (142, 145))	('acute ovarian failure', 'Disease', (100, 121))	('ovarian failure', 'Phenotype', 'HP:0008209', (106, 121))	('infertility', 'Disease', (62, 73))	('premature menopause', 'Phenotype', 'HP:0008209', (132, 151))	('acute ovarian failure', 'Disease', 'MESH:D058186', (100, 121))	('men', 'Species', '9606', (188, 191))	('infertility', 'Disease', 'MESH:D007247', (62, 73))	('premature menopause', 'Disease', (132, 151))
9180	31360893	In a randomized trial comparing the efficacy of a doxorubicin/docetaxel to regimens combining cyclophosphamide, doxorubicin, and a taxane, either sequentially (AC-T) or concurrently (TAC), in which 70% of participants were older than 40 years old, rates of TRA were lower with doxorubicin/docetaxel (38%) relative to AC-T (70%) and TAC (58%) (P < .001).	('men', 'Species', '9606', (79, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('taxane', 'Chemical', 'MESH:C080625', (131, 137))	('docetaxel', 'Chemical', 'MESH:D000077143', (62, 71))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (94, 110))	('AC', 'Chemical', 'MESH:D000186', (333, 335))	('doxorubicin', 'Chemical', 'MESH:D004317', (112, 123))	('TRA', 'Disease', (257, 260))	('doxorubicin', 'Chemical', 'MESH:D004317', (277, 288))	('docetaxel', 'Chemical', 'MESH:D000077143', (289, 298))	('doxorubicin/docetaxel', 'Var', (277, 298))	('AC', 'Chemical', 'MESH:D000186', (184, 186))	('AC', 'Chemical', 'MESH:D000186', (317, 319))	('AC', 'Chemical', 'MESH:D000186', (160, 162))	('participants', 'Species', '9606', (205, 217))	('lower', 'NegReg', (266, 271))
9185	31360893	AC-T has been associated with numerically higher rates of TRA than AC alone (29% vs 19% in a high-quality prospective study and an odds ratio [OR] of 1.59 [95% CI = 0.8 to 3.2] in a large retrospective study), though neither difference was statistically significant.	('TRA', 'Disease', (58, 61))	('AC', 'Chemical', 'MESH:D000186', (0, 2))	('higher', 'PosReg', (42, 48))	('AC-T', 'Var', (0, 4))	('AC', 'Chemical', 'MESH:D000186', (67, 69))
9194	31360893	Cisplatin was associated with reduced pregnancy rates in males, but not females, in the CCSS.	('reduced pregnancy rates', 'Phenotype', 'HP:0001622', (30, 53))	('pregnancy rates', 'CPA', (38, 53))	('reduced pregnancy rates in males', 'Phenotype', 'HP:0012041', (30, 62))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('reduced', 'NegReg', (30, 37))	('Cisplatin', 'Var', (0, 9))
9225	31360893	The average age of menopause is slightly lower following 131I (49.5 vs 51.0 years), but there is no difference in birth rate and 131I does not appear to have long-term effects on fertility.	('131I', 'Var', (57, 61))	('lower', 'NegReg', (41, 46))	('131I', 'Chemical', 'MESH:C000614965', (57, 61))	('131I', 'Chemical', 'MESH:C000614965', (129, 133))	('men', 'Species', '9606', (19, 22))	('average age of menopause', 'Phenotype', 'HP:0008209', (4, 28))
9285	31360893	Among males unexposed to radiation, exposure to individual alkylators, including cyclophosphamide (3.6-7.4 gm/m2, HR = 0.89, 95% CI = 0.77 to 1.03; >7.4 gm/m2, HR = 0.60, 95% CI = 0.51 to 0.71), ifosfamide (26-53 gm/m2, HR = 0.61, 95% CI = 0.36 to 1.01; >53 gm/m2, HR = 0.42, 95% CI = 0.23 to 0.79), and procarbazine (<3.3 gm/m2, HR = 0.63, 95% CI = 0.44 to 0.91; 3.3-5 gm/m2, HR = 0.38, 95% CI = 0.24 to 0.60; >5 gm/m2, HR = 0.30, 95% CI = 0.20 to 0.46), was associated with statistically significant decreases in male fecundity.	('ifosfamide', 'Chemical', 'MESH:D007069', (195, 205))	('male fecundity', 'CPA', (515, 529))	('<3.3 gm/m2', 'Var', (318, 328))	('decreases', 'NegReg', (502, 511))	('26-53 gm/m2', 'Var', (207, 218))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (81, 97))
9290	31360893	Importantly, the CCSS confirmed that cisplatin, a DNA crosslinking agent, is associated with decreased male fertility (<355 mg/m2, HR = 0.85, 95% CI = 0.56 to 1.27; 355-487 mg/m2, HR = 0.74, 95% CI = 0.52 to 1.07; > 488 mg/m2; HR = 0.56, 95% CI = 0.39 to 0.82).	('cisplatin', 'Var', (37, 46))	('male fertility', 'CPA', (103, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('decreased', 'NegReg', (93, 102))
9295	31360893	A prospective study of men treated with unilateral orchiectomy followed by surveillance or adjuvant therapy found that paternity rates without cryopreserved sperm were lower among men who received radiotherapy (65%) or cisplatin (<850 mg [62%]; >850 mg [38%]) than men who underwent surveillance (81%), but no difference was seen between retroperitoneal lymph node dissection (77%) and surveillance.	('unilateral orchiectomy', 'Phenotype', 'HP:0012741', (40, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('radiotherapy', 'Var', (197, 209))	('men', 'Species', '9606', (265, 268))	('lower', 'NegReg', (168, 173))	('<850 mg', 'Var', (230, 237))	('men', 'Species', '9606', (180, 183))	('paternity', 'CPA', (119, 128))	('men', 'Species', '9606', (23, 26))
9299	31360893	Return to normospermia appears to be statistically significantly more likely with carboplatin than cisplatin (HR = 4.5, 95% CI = 2.6 to 7.8).	('to 7', 'Species', '1214577', (133, 137))	('carboplatin', 'Chemical', 'MESH:D016190', (82, 93))	('carboplatin', 'Var', (82, 93))	('normospermia', 'Disease', (10, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
9332	31360893	Similarly, among men treated for rectal cancer, exposures under 1.3 Gy lead to transient azoospermia in greater than 70%, but almost all patients recover spermatogenesis.	('exposures', 'Var', (48, 57))	('rectal cancer', 'Disease', (33, 46))	('recover', 'PosReg', (146, 153))	('rectal cancer', 'Phenotype', 'HP:0100743', (33, 46))	('azoospermia', 'Disease', (89, 100))	('patients', 'Species', '9606', (137, 145))	('azoospermia', 'Phenotype', 'HP:0000027', (89, 100))	('azoospermia', 'Disease', 'MESH:D053713', (89, 100))	('rectal cancer', 'Disease', 'MESH:D012004', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('spermatogenesis', 'MPA', (154, 169))	('men', 'Species', '9606', (17, 20))
9437	19224508	Microarray analysis revealed that EGCs and first- and second-generation cancer stem cells were highly similar; however, approximately 1,000 differentially expressed transcripts could be identified corresponding to alterations in oncogenes and genes associated with motility and development.	('oncogenes', 'Gene', (229, 238))	('rat', 'Species', '10116', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('differentially expressed transcripts', 'MPA', (140, 176))	('alterations', 'Var', (214, 225))	('rat', 'Species', '10116', (218, 221))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
9438	19224508	Combined, the data suggest that the activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the cancer stem cell population of tumors derived from pluripotent cells.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('metastatic behavior', 'CPA', (200, 219))	('tumors', 'Disease', (258, 264))	('oncogenic pathways', 'Pathway', (50, 68))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('activation', 'PosReg', (36, 46))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('genetic', 'Var', (97, 104))
9459	19224508	In murine models of testicular teratoma, such as deletion of the tumor suppressor Pten, the initial transformation event is described as the conversion of PGCs to pluripotent EGCs.	('conversion', 'MPA', (141, 151))	('PGC', 'Gene', '109820', (155, 158))	('PGC', 'Gene', (155, 158))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('testicular teratoma', 'Disease', 'MESH:C562472', (20, 39))	('Pten', 'Gene', (82, 86))	('Pten', 'Gene', '19211', (82, 86))	('testicular teratoma', 'Phenotype', 'HP:0100616', (20, 39))	('murine', 'Species', '10090', (3, 9))	('teratoma', 'Phenotype', 'HP:0009792', (31, 39))	('deletion', 'Var', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('testicular teratoma', 'Disease', (20, 39))
9501	19224508	Cultured PGCs (EGCs) were derived from E12.5 C57BL/6 mice.	('E12.5', 'Var', (39, 44))	('PGC', 'Gene', '109820', (9, 12))	('mice', 'Species', '10090', (53, 57))	('PGC', 'Gene', (9, 12))
9511	19224508	However, in contrast to the murine EGC line, transplantations of murine ESCs into the testis of SCID mice resulted in metastasis in two-thirds of tumors, suggesting that pluripotent ESCs are more tumorigenic than EGCs in vivo.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (196, 201))	('metastasis', 'CPA', (118, 128))	('resulted in', 'Reg', (106, 117))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('mice', 'Species', '10090', (101, 105))	('SCID', 'Disease', 'MESH:D053632', (96, 100))	('murine', 'Species', '10090', (28, 34))	('SCID', 'Disease', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumors', 'Disease', (146, 152))	('pluripotent', 'Var', (170, 181))	('murine', 'Species', '10090', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
9534	19224508	The EGC line was 40,XY; however, G-banding identified two stable structural changes in 100% of cells involving a duplication of B2-C7 on chromosome 4 and a deletion of C3-F1 on chromosome 6.	('B2-C7', 'Disease', 'MESH:C566443', (128, 133))	('B2-C7', 'Disease', (128, 133))	('deletion', 'Var', (156, 164))	('duplication', 'Var', (113, 124))
9536	19224508	The gross genomic changes included isochromosomes iso(8) and iso(15), translocations (t) t(6;8) and t(11;14), as well as loss of the Y chromosome del(Y) and in one case a hypotriploid karyotype (supporting information Fig.	('loss', 'NegReg', (121, 125))	('isochromosomes iso', 'Var', (35, 53))	('hypotriploid', 'Disease', 'None', (171, 183))	('translocations', 'CPA', (70, 84))	('hypotriploid', 'Disease', (171, 183))
9542	19224508	Furthermore, RA-treated EGCs displayed increased expression of genes associated with differentiation, as well as increased numbers of apoptotic cells and a decreased proliferation rate (supporting information Fig.	('rat', 'Species', '10116', (173, 176))	('RA', 'Chemical', 'MESH:D014212', (13, 15))	('rat', 'Species', '10116', (180, 183))	('proliferation rate', 'CPA', (166, 184))	('expression of genes', 'MPA', (49, 68))	('decreased', 'NegReg', (156, 165))	('RA-treated', 'Var', (13, 23))	('increased', 'PosReg', (39, 48))	('increased', 'PosReg', (113, 122))
9585	19224508	Furthermore, using this model, our results demonstrate that genetic instability is associated with cancer stem cell formation in vivo, and this is particularly evident with the transplantation of human pluripotent cells.	('rat', 'Species', '10116', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('genetic instability', 'Var', (60, 79))	('human', 'Species', '9606', (196, 201))	('cancer', 'Disease', (99, 105))	('associated', 'Reg', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
9586	19224508	Genetic instability is a hallmark of testicular germ cell tumor (reviewed in).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Genetic instability', 'Var', (0, 19))	('germ cell tumor', 'Phenotype', 'HP:0100728', (48, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
9592	19224508	Progression from CIS to the invasive disease is associated with additional chromosomal rearrangements and duplications at 12p.	('invasive disease', 'Disease', (28, 44))	('duplications', 'Var', (106, 118))	('CIS', 'Phenotype', 'HP:0030075', (17, 20))	('invasive disease', 'Disease', 'MESH:D009362', (28, 44))	('chromosomal rearrangements', 'Var', (75, 101))
9600	19224508	Therefore, severe genetic instability in testicular cancer may abrogate the positive effects of RA resulting in treatment resistance.	('testicular cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('RA', 'Chemical', 'MESH:D014212', (96, 98))	('testicular cancer', 'Phenotype', 'HP:0010788', (41, 58))	('treatment resistance', 'CPA', (112, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (41, 58))	('severe genetic instability', 'Var', (11, 37))	('abrogate', 'NegReg', (63, 71))
9610	19224508	A tantalizing hypothesis is that increased expression of Igf2 due to abnormal epigenetic reprogramming in the germ line may be a functional contributor to germ cell tumor formation.	('Igf2', 'Gene', (57, 61))	('germ cell tumor', 'Phenotype', 'HP:0100728', (155, 170))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('epigenetic', 'Var', (78, 88))	('expression', 'MPA', (43, 53))	('tumor', 'Disease', (165, 170))
9616	19224508	Mutations in NDS1 result in Sotos syndrome, which is associated with neurological disorders, overgrowth, and cancer.	('neurological disorders', 'Disease', (69, 91))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('NDS1', 'Gene', (13, 17))	('cancer', 'Disease', (109, 115))	('Mutations', 'Var', (0, 9))	('Sotos syndrome', 'Disease', 'MESH:D058495', (28, 42))	('neurological disorders', 'Disease', 'MESH:D009422', (69, 91))	('result in', 'Reg', (18, 27))	('Sotos syndrome', 'Disease', (28, 42))	('overgrowth', 'Phenotype', 'HP:0001548', (93, 103))
9679	16966068	multiple lung metastases, HCG > 10000) and in patients with suspected metastatic disease on clinical grounds.	('lung metastases', 'Disease', (9, 24))	('patients', 'Species', '9606', (46, 54))	('HCG > 10000', 'Var', (26, 37))	('lung metastases', 'Disease', 'MESH:D009362', (9, 24))
9792	32102532	PET-CT positivity was defined as a site of abnormal FDG uptake in tissue histologically proven or clinically or radiographically suspected to represent tumor involvement.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('FDG', 'Gene', (52, 55))	('positivity', 'Var', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('PET-CT', 'Gene', (0, 6))	('FDG', 'Gene', '23583', (52, 55))
9906	29560096	Our analysis provides independent replication of the associations for risk SNPs at 2q14.2 (rs2713206 at P = 3.03 x 10-2; P-meta = 3.92 x 10-8; nearest gene, TFCP2L1) and rs12912292 at 15q21.3 (P = 7.96 x 10-11; P-meta = 1.55 x 10-19; nearest gene PRTG).	('rs12912292', 'Var', (170, 180))	('rs2713206', 'Var', (91, 100))	('PRTG', 'Gene', (247, 251))	('PRTG', 'Gene', '283659', (247, 251))	('rs12912292', 'Mutation', 'rs12912292', (170, 180))	('TFCP2L1', 'Gene', '29842', (157, 164))	('TFCP2L1', 'Gene', (157, 164))	('rs2713206', 'Mutation', 'rs2713206', (91, 100))
9914	29560096	We recently described enrichment in familial TGCT using exome sequencing of rare disruptive mutations in genes relating to ciliary and microtubule functions; however, these variants account for only a minor fraction of disease heritability.	('men', 'Species', '9606', (28, 31))	('familial TGCT', 'Disease', (36, 49))	('disruptive', 'NegReg', (81, 91))	('mutations', 'Var', (92, 101))
9916	29560096	The reported index SNP from the TECAC meta-analysis, rs12912292, showed a highly significant association in the UK OncoArray dataset (P = 7.96 x 10-11), as did its most strongly linked directly genotyped tagging SNP (rs12899976, r2 > 1.0, D' > 1.0, P = 2.34 x 10-11).	('rs12912292', 'Var', (53, 63))	('rs12899976', 'Mutation', 'rs12899976', (217, 227))	('rs12899976', 'Var', (217, 227))	('rs12912292', 'Mutation', 'rs12912292', (53, 63))
9917	29560096	Notably, SNPs in this region did show evidence of association in the meta-analysis undertaken in Litchfield et al., including rs12912292.	('rs12912292', 'Var', (126, 136))	('association', 'Reg', (50, 61))	('rs12912292', 'Mutation', 'rs12912292', (126, 136))
9918	29560096	However, due to poor phet and I2 values associated with rs12912292, an alternative SNP (rs7175728) had been chosen for replication genotyping in 1,801 cases and 4027 controls, which failed to replicate (P = 0.97, OR = 0.9986).	('rs12912292', 'Var', (56, 66))	('rs7175728', 'Mutation', 'rs7175728', (88, 97))	('I2 values', 'MPA', (30, 39))	('rs7175728', 'Var', (88, 97))	('rs12912292', 'Mutation', 'rs12912292', (56, 66))
9921	29560096	Finally, we investigated whether the two SNPs showing evidence of association in the current study (rs12912292 and rs2713206) showed differences in risk allele frequency in phenotypically-defined subgroups of TGCT cases (Table 3).	('rs12912292', 'Mutation', 'rs12912292', (100, 110))	('TGCT', 'Disease', (209, 213))	('rs2713206', 'Mutation', 'rs2713206', (115, 124))	('rs12912292', 'Var', (100, 110))	('rs2713206', 'Var', (115, 124))
9923	29560096	rs2713206 at 2q14.2 localizes to the intron of TFCP2L1 in an LD block of ~50 kb.	('rs2713206', 'Mutation', 'rs2713206', (0, 9))	('rs2713206', 'Var', (0, 9))	('TFCP2L1', 'Gene', '29842', (47, 54))	('TFCP2L1', 'Gene', (47, 54))
9927	29560096	rs12912292 at 15q21.3 resides in a 130 kb region of LD that only contains PRTG (protogenin), which encodes an immunoglobulin superfamily transmembrane protein expressed in the developing nervous system.	('PRTG', 'Gene', (74, 78))	('PRTG', 'Gene', '283659', (74, 78))	('rs12912292', 'Var', (0, 10))	('protogenin', 'Gene', (80, 90))	('protogenin', 'Gene', '283659', (80, 90))	('rs12912292', 'Mutation', 'rs12912292', (0, 10))
9928	29560096	rs12912292 displays strong eQTL effects for PRTG in muscle-skeletal (GTEx data, P = 1.9e-13) and thyroid (P = 5.1e-12) tissues; there is, however, no evidence for association of rs12912292 with expression of PRTG in either normal testes or TGCT.	('PRTG', 'Gene', '283659', (208, 212))	('PRTG', 'Gene', '283659', (44, 48))	('rs12912292', 'Var', (178, 188))	('PRTG', 'Gene', (44, 48))	('association', 'Interaction', (163, 174))	('rs12912292', 'Mutation', 'rs12912292', (178, 188))	('rs12912292', 'Mutation', 'rs12912292', (0, 10))	('PRTG', 'Gene', (208, 212))
9929	29560096	Our data did not provide evidence supporting association with TGCT risk for SNPs at three of the loci analyzed (rs3755605 at 3q26.2, rs11769858 at 7q36.3 and rs61408740 at 10q26.13).	('rs61408740', 'Var', (158, 168))	('SNPs', 'Disease', (76, 80))	('rs11769858', 'Mutation', 'rs11769858', (133, 143))	('rs3755605', 'Var', (112, 121))	('rs3755605', 'Mutation', 'rs3755605', (112, 121))	('rs11769858', 'Var', (133, 143))	('rs61408740', 'Mutation', 'rs61408740', (158, 168))
9966	29062883	Tumor marker evaluation showed CA-125447.8, Beta hCG < 2, CEA < 0.5, CA19-9 7.43.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CEA', 'Gene', '5670', (58, 61))	('hCG < 2', 'Gene', (49, 56))	('hCG < 2', 'Gene', '23731', (49, 56))	('CEA', 'Gene', (58, 61))	('CA-125447.8', 'Var', (31, 42))
10025	27144435	Androgen suppresses testicular cancer cell growth in vitro and in vivo Silencing of androgen receptor (AR)-meditated androgen signaling is thought to be associated with the development of testicular germ cell tumors (TGCTs).	('testicular germ cell tumors', 'Disease', (188, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('germ cell tumors', 'Phenotype', 'HP:0100728', (199, 215))	('androgen receptor', 'Gene', (84, 101))	('men', 'Species', '9606', (180, 183))	('testicular cancer', 'Phenotype', 'HP:0010788', (20, 37))	('testicular', 'Disease', (20, 30))	('associated', 'Reg', (153, 163))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('Silencing', 'Var', (71, 80))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (188, 215))	('cancer', 'Disease', (31, 37))	('androgen receptor', 'Gene', '367', (84, 101))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('suppresses', 'NegReg', (9, 19))
10029	27144435	Tryptophan hydroxylase 1 (TPH1), the rate limit enzyme in serotonin synthesis, was one of the genes which expression was reduced in DHT-treated SE cells.	('Tryptophan hydroxylase 1', 'Gene', '7166', (0, 24))	('TPH1', 'Gene', '7166', (26, 30))	('Tryptophan hydroxylase 1', 'Gene', (0, 24))	('expression', 'MPA', (106, 116))	('reduced', 'NegReg', (121, 128))	('DHT', 'Chemical', '-', (132, 135))	('DHT-treated', 'Var', (132, 143))	('TPH1', 'Gene', (26, 30))	('serotonin', 'Chemical', 'MESH:D012701', (58, 67))
10032	27144435	These results suggested that silencing of androgen/AR signaling may cause initiation and progression of SE through increase in TPH1 gene expression level.	('TPH1', 'Gene', '7166', (127, 131))	('silencing', 'Var', (29, 38))	('cause', 'Reg', (68, 73))	('increase', 'PosReg', (115, 123))	('expression level', 'MPA', (137, 153))	('TPH1', 'Gene', (127, 131))
10043	27144435	Furthermore, the risk of SE is high in patients with androgen-insensitivity syndrome (AIS), a condition associated with aberrant repression of the AR signal due to loss-of-function mutations in the AR gene.	('patients', 'Species', '9606', (39, 47))	('AIS', 'Disease', 'OMIM:181800', (86, 89))	('AIS', 'Disease', (86, 89))	('loss-of-function', 'NegReg', (164, 180))	('androgen-insensitivity syndrome', 'Phenotype', 'HP:0008226', (53, 84))	('androgen-insensitivity syndrome', 'Disease', (53, 84))	('mutations', 'Var', (181, 190))	('AIS', 'Phenotype', 'HP:0008226', (86, 89))
10050	27144435	AR protein levels were also significantly higher in TCam-2 cells than in NSE cells (Figure 1B).	('higher', 'PosReg', (42, 48))	('TCam-2', 'CellLine', 'CVCL:T012', (52, 58))	('AR protein levels', 'MPA', (0, 17))	('TCam-2', 'Var', (52, 58))
10062	27144435	Among these 19 genes, we focused on TPH1, which is associated with the metabolism of serotonin, because dysregulation of serotonin metabolism is known to be associated with cancer progression.	('serotonin', 'Chemical', 'MESH:D012701', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('associated', 'Reg', (157, 167))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('TPH1', 'Gene', (36, 40))	('serotonin', 'Chemical', 'MESH:D012701', (85, 94))	('dysregulation', 'Var', (104, 117))	('TPH1', 'Gene', '7166', (36, 40))
10063	27144435	Quantitative RT-PCR revealed that the expression of TPH1 was reduced by DHT treatment and this reduction was not observed in AR knockdown cells (Figure 4B).	('expression', 'MPA', (38, 48))	('DHT treatment', 'Var', (72, 85))	('TPH1', 'Gene', (52, 56))	('TPH1', 'Gene', '7166', (52, 56))	('DHT', 'Chemical', '-', (72, 75))	('men', 'Species', '9606', (81, 84))	('reduced', 'NegReg', (61, 68))
10068	27144435	The mRNA expression of TPH1 in TCam-2 cells exhibited 0.3-fold decrease by the knockdown of TPH1 (Figure 5A).	('TPH1', 'Gene', '7166', (23, 27))	('TCam-2', 'CellLine', 'CVCL:T012', (31, 37))	('decrease', 'NegReg', (63, 71))	('mRNA expression', 'MPA', (4, 19))	('knockdown', 'Var', (79, 88))	('TPH1', 'Gene', (92, 96))	('TPH1', 'Gene', (23, 27))	('TPH1', 'Gene', '7166', (92, 96))
10071	27144435	Furthermore, cell growth of TCam-2 cells was also suppressed by knockdown of TPH1 (Figure 5C).	('cell growth of', 'CPA', (13, 27))	('suppressed', 'NegReg', (50, 60))	('TPH1', 'Gene', '7166', (77, 81))	('TCam-2', 'CellLine', 'CVCL:T012', (28, 34))	('knockdown', 'Var', (64, 73))	('TPH1', 'Gene', (77, 81))
10077	27144435	As the results, four of 5-HTs (5-HT7, 5-HT1A, 5-HT2A and 5-HT3) were highly expressed in TCam-2 cells.	('TCam-2', 'CellLine', 'CVCL:T012', (89, 95))	('5-HT2A', 'Gene', (46, 52))	('5-HT', 'Chemical', 'MESH:D012701', (57, 61))	('5-HT2A', 'Gene', '3356', (46, 52))	('5-HT1A', 'Gene', '3350', (38, 44))	('5-HT7', 'Var', (31, 36))	('5-HT', 'Chemical', 'MESH:D012701', (38, 42))	('5-HT', 'Chemical', 'MESH:D012701', (24, 28))	('5-HT', 'Chemical', 'MESH:D012701', (31, 35))	('5-HT1A', 'Gene', (38, 44))	('5-HT', 'Chemical', 'MESH:D012701', (46, 50))
10083	27144435	Transcripts of TH or c-fos were decreased by DHT (Figure 6B).	('Transcripts', 'MPA', (0, 11))	('DHT', 'Chemical', '-', (45, 48))	('TH', 'Gene', '21823', (15, 17))	('c-fos', 'Protein', (21, 26))	('DHT', 'Var', (45, 48))	('decreased', 'NegReg', (32, 41))
10086	27144435	The mRNA expression of 5-HT7 in TCam-2 cells exhibited 0.2-fold decrease by the knockdown of 5-HT7 (Figure 6C).	('knockdown', 'Var', (80, 89))	('5-HT', 'Chemical', 'MESH:D012701', (23, 27))	('decrease', 'NegReg', (64, 72))	('5-HT7', 'Var', (93, 98))	('mRNA expression', 'MPA', (4, 19))	('5-HT', 'Chemical', 'MESH:D012701', (93, 97))	('TCam-2', 'CellLine', 'CVCL:T012', (32, 38))
10087	27144435	TCam-2 cell growth was suppressed by 5-HT7 knockdown in TCam-2 cells (Figure 6D).	('5-HT', 'Chemical', 'MESH:D012701', (37, 41))	('suppressed', 'NegReg', (23, 33))	('TCam-2', 'CellLine', 'CVCL:T012', (0, 6))	('knockdown', 'Var', (43, 52))	('TCam-2', 'CellLine', 'CVCL:T012', (56, 62))	('TCam-2 cell growth', 'CPA', (0, 18))
10089	27144435	Considering together that DHT had inhibitory effects to the serotonin synthesis pathway in SE cells (Figure 5B), DHT may suppress SE cell growth by inhibition of TPH1-mediated serotonin synthesis pathway.	('suppress', 'NegReg', (121, 129))	('inhibition', 'NegReg', (148, 158))	('DHT', 'Var', (113, 116))	('TPH1', 'Gene', (162, 166))	('TPH1', 'Gene', '7166', (162, 166))	('serotonin synthesis pathway', 'Pathway', (60, 87))	('serotonin', 'Chemical', 'MESH:D012701', (60, 69))	('SE cell growth', 'CPA', (130, 144))	('DHT', 'Chemical', '-', (26, 29))	('DHT', 'Chemical', '-', (113, 116))	('serotonin', 'Chemical', 'MESH:D012701', (176, 185))
10093	27144435	Dysregulation in normal organogenesis is associated with initiation and progression of cancer.	('cancer', 'Disease', (87, 93))	('associated', 'Reg', (41, 51))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
10102	27144435	Immunohistochemistry analysis of breast cancer tissue using anti-TPH1 antibodies indicated that aberrant expression of TPH1 is associated with the progression of breast cancer.	('TPH1', 'Gene', (119, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('TPH1', 'Gene', '7166', (119, 123))	('associated with', 'Reg', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('TPH1', 'Gene', (65, 69))	('aberrant', 'Var', (96, 104))	('TPH1', 'Gene', '7166', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (162, 175))	('expression', 'MPA', (105, 115))	('breast cancer', 'Disease', (33, 46))
10103	27144435	Additionally, in the current report, we showed that knockdown of TPH1 expression suppresses SE cell growth.	('TPH1', 'Gene', (65, 69))	('suppresses', 'NegReg', (81, 91))	('TPH1', 'Gene', '7166', (65, 69))	('SE cell growth', 'CPA', (92, 106))	('knockdown', 'Var', (52, 61))
10104	27144435	Immunohistochemistry of human SE tissue using anti-TPH1 antibody may provide further evidence of the association between aberrant expression of TPH1 and SE progression.	('human', 'Species', '9606', (24, 29))	('TPH1', 'Gene', (144, 148))	('TPH1', 'Gene', '7166', (144, 148))	('TPH1', 'Gene', (51, 55))	('TPH1', 'Gene', '7166', (51, 55))	('aberrant', 'Var', (121, 129))	('SE progression', 'Disease', (153, 167))	('association', 'Interaction', (101, 112))
10109	27144435	Our results revealed that knockdown of AR expression abolished this effect, supporting the hypothesis that the AR is involved in the regulation of TPH1.	('TPH1', 'Gene', '7166', (147, 151))	('knockdown', 'Var', (26, 35))	('TPH1', 'Gene', (147, 151))
10113	27144435	siRNAs specific for TPH1 (TPH1HSS110923) and 5-HT7 (HTR7HSS105140) were purchased from Invitrogen.	('TPH1', 'Gene', '7166', (26, 30))	('TPH1', 'Gene', (20, 24))	('TPH1HSS110923', 'Gene', '7166', (26, 39))	('TPH1', 'Gene', '7166', (20, 24))	('HTR7HSS105140', 'Var', (52, 65))	('5-HT', 'Chemical', 'MESH:D012701', (45, 49))	('HTR7', 'CellLine', 'CVCL:D728', (52, 56))	('TPH1HSS110923', 'Gene', (26, 39))	('TPH1', 'Gene', (26, 30))
10210	23321215	Failure to switch off OCT4 in GC perinatally can lead to development of carcinoma in situ (CIS), the precursor of testicular germ cell cancer (TGCC), for which there is no animal model.	('cancer', 'Disease', (135, 141))	('Failure', 'Var', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinoma in situ', 'Disease', (72, 89))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (72, 89))	('CIS', 'Phenotype', 'HP:0030075', (91, 94))	('germ cell cancer', 'Phenotype', 'HP:0100728', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lead to', 'Reg', (49, 56))	('men', 'Species', '9606', (64, 67))	('carcinoma in situ', 'Disease', 'MESH:D002278', (72, 89))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
10218	23321215	The percentage of OCT4+ GC fell from 54% in late fetal life to <0.5% at 2.5 weeks of age and none were detected after 5-7 weeks in marmosets.	('marmosets', 'Species', '38020', (131, 140))	('OCT4+ GC', 'Var', (18, 26))	('fell', 'NegReg', (27, 31))
10231	23321215	Also, GC differentiation in rodents is synchronous; for example, all GC in the rat coordinately lose expression of the pluripotency marker OCT4, so that by e19 OCT4-positive GC are absent.	('expression of the pluripotency marker OCT4', 'MPA', (101, 143))	('lose', 'NegReg', (96, 100))	('e19', 'Var', (156, 159))	('rat', 'Species', '10116', (79, 82))
10235	23321215	In contrast, reported that the GC population expressing OCT4 and AP2gamma is stable, with numbers remaining constant until at least 8 weeks of age.	('AP2gamma', 'Gene', (65, 73))	('AP2gamma', 'Gene', '7022', (65, 73))	('OCT4', 'Var', (56, 60))
10236	23321215	This question is of particular importance because OCT4, AP2gamma and NANOG are also markers of carcinoma in situ (CIS), the precursor of testicular germ cell cancer (TGCC) in humans.	('germ cell cancer', 'Phenotype', 'HP:0100728', (148, 164))	('AP2gamma', 'Gene', '7022', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('carcinoma in situ', 'Disease', 'MESH:D002278', (95, 112))	('AP2gamma', 'Gene', (56, 64))	('NANOG', 'Gene', '79923', (69, 74))	('cancer', 'Disease', (158, 164))	('NANOG', 'Gene', (69, 74))	('OCT4', 'Var', (50, 54))	('humans', 'Species', '9606', (175, 181))	('carcinoma in situ', 'Disease', (95, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('CIS', 'Phenotype', 'HP:0030075', (114, 117))
10335	23321215	It is possible either that OCT4+ GC lose expression of this marker during the proliferation cycle and instead become VASA+, or that continuing OCT4+ GC proliferation is counterbalanced by increased apoptosis in this subpopulation.	('lose', 'NegReg', (36, 40))	('expression', 'MPA', (41, 51))	('rat', 'Species', '10116', (85, 88))	('rat', 'Species', '10116', (159, 162))	('OCT4+ GC', 'Var', (143, 151))
10401	21236595	Rates of acute toxicities were lower among patients receiving 20Gy, with no difference in relapse-free survival or overall survival.	('toxicities', 'Disease', (15, 25))	('patients', 'Species', '9606', (43, 51))	('lower', 'NegReg', (31, 36))	('toxicities', 'Disease', 'MESH:D064420', (15, 25))	('acute', 'MPA', (9, 14))	('20Gy', 'Var', (62, 66))	('relapse-free survival', 'CPA', (90, 111))
10402	21236595	With the recognition that PMI increases cardiac mortality, treatment to the mediastinum was largely abandoned by the mid-1980's.	('men', 'Species', '9606', (64, 67))	('PMI', 'Var', (26, 29))	('cardiac mortality', 'MPA', (40, 57))	('increases', 'PosReg', (30, 39))
10424	21236595	The organ-specific cancer incidence rate was calculated according to  , where I0org is the organ-specific cancer incidence rate for a low dose (EAR per 10,000 patients/yr/Gy), D is the total dose administered, and alphaorg is an organ-specific cell sterilization parameter.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('patients', 'Species', '9606', (159, 167))	('I0org', 'Var', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
10429	21236595	Protons also achieved significant reductions in mean doses to the pancreas (1697cGy vs. 1991cGy, p=0.0002), large bowel (352cGy vs. 651cGy, p=0.0015), and liver (33cGy vs. 313cGy, p=0.0006).	('1697cGy', 'Var', (76, 83))	('large bowel', 'Phenotype', 'HP:0002037', (108, 119))	('352cGy', 'Var', (121, 127))	('reductions', 'NegReg', (34, 44))	('bowel', 'Disease', 'MESH:D015212', (114, 119))	('doses', 'MPA', (53, 58))	('bowel', 'Disease', (114, 119))
10430	21236595	The average maximum point dose to the large bowel was also lower with protons (2618cGy vs. 2732cGy, p=0.0096).	('bowel', 'Disease', (44, 49))	('lower', 'NegReg', (59, 64))	('maximum point dose', 'MPA', (12, 30))	('2732cGy', 'Var', (91, 98))	('2618cGy', 'Var', (79, 86))	('large bowel', 'Phenotype', 'HP:0002037', (38, 49))	('bowel', 'Disease', 'MESH:D015212', (44, 49))
10464	21236595	Longer follow-up from prospective trials is needed to determine the risk of secondary cancers from single-agent carboplatin.	('carboplatin', 'Chemical', 'MESH:D016190', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('single-agent', 'Var', (99, 111))	('secondary cancers', 'Disease', 'MESH:D009369', (76, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('secondary cancers', 'Disease', (76, 93))
10474	21236595	In that dosimetric study, AP-PA treatment plans with 6MV photons were predicted to result in a 20.8-23.3% risk of secondary cancers for a 75-year-old patient treated with radiotherapy to the para-aortic region at age 35, compared with a 19.8% risk for the general population.	('secondary cancers', 'Disease', (114, 131))	('patient', 'Species', '9606', (150, 157))	('AP-PA', 'Var', (26, 31))	('AP-PA', 'Chemical', 'MESH:C012276', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('men', 'Species', '9606', (37, 40))	('secondary cancers', 'Disease', 'MESH:D009369', (114, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('result in', 'Reg', (83, 92))
10519	19278865	When the INSL3 gene is mutated in mice, initial testis descent does not occur.	('INSL3', 'Gene', (9, 14))	('mutated', 'Var', (23, 30))	('mice', 'Species', '10090', (34, 38))
10560	19278865	Phthalates have been demonstrated to inhibit expression of crucial genes in the steroidogenic pathway, thus leading to lower T production, lower Insl3 mRNA and INSL3 protein expression and reduced FLC numbers.	('Insl3', 'Gene', '114215', (145, 150))	('Phthalates', 'Var', (0, 10))	('lower', 'NegReg', (119, 124))	('FLC numbers', 'MPA', (197, 208))	('reduced', 'NegReg', (189, 196))	('INSL3', 'Protein', (160, 165))	('Phthalates', 'Chemical', 'MESH:C032279', (0, 10))	('T production', 'MPA', (125, 137))	('inhibit', 'NegReg', (37, 44))	('steroidogenic pathway', 'Pathway', (80, 101))	('Insl3', 'Gene', (145, 150))	('expression', 'MPA', (45, 55))	('lower', 'NegReg', (139, 144))	('rat', 'Species', '10116', (28, 31))
10562	19278865	One of the persistent effects of disrupted FLC might be the tumor-like FLC aggregation.	('disrupted', 'Var', (33, 42))	('FLC aggregation', 'Disease', 'MESH:D020914', (71, 86))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FLC aggregation', 'Disease', (71, 86))	('FLC', 'Gene', (43, 46))	('tumor', 'Disease', (60, 65))
10567	19278865	Reduced T does not cause FLC aggregation; therefore, other factors are responsible.	('Reduced', 'Var', (0, 7))	('FLC aggregation', 'Disease', (25, 40))	('FLC aggregation', 'Disease', 'MESH:D020914', (25, 40))
10593	19278865	Although multiple changes occur in fetal testicular cells including FLCs, Sertoli cells and germ cells, the changes in FLCs are apparently the direct causes of TDS-like syndromes such as hypospadias and cryptorchidism.	('Sertoli cell', 'Phenotype', 'HP:0100619', (74, 86))	('causes', 'Reg', (150, 156))	('FLCs', 'Gene', (119, 123))	('TDS-like syndrome', 'Disease', (160, 177))	('hypospadias', 'Disease', 'MESH:D007021', (187, 198))	('TDS-like syndrome', 'Disease', 'MESH:C537419', (160, 177))	('cryptorchidism', 'Phenotype', 'HP:0000028', (203, 217))	('hypospadias', 'Disease', (187, 198))	('cryptorchidism', 'Disease', (203, 217))	('changes', 'Var', (108, 115))	('Sertoli cells', 'Phenotype', 'HP:0100619', (74, 87))	('hypospadias', 'Phenotype', 'HP:0000047', (187, 198))
10599	19278865	Therefore, it is likely that phthalates could also be associated with epigenetic modifications of testicular genes.	('epigenetic modifications', 'Var', (70, 94))	('phthalates', 'Chemical', 'MESH:C032279', (29, 39))	('associated', 'Reg', (54, 64))	('testicular genes', 'Gene', (98, 114))
10609	18071360	Testicular cancer in twins: a meta-analysis In a meta-analysis of testicular cancer in twins, twins had a 30% increased risk (estimate 1.31, 95% CI 1.1-1.6), providing indirect support for the hypothesis that in utero hormone variations influence risk of testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (255, 272))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('variations', 'Var', (226, 236))	('Testicular cancer', 'Disease', (0, 17))	('testicular cancer', 'Disease', (66, 83))	('testicular cancer', 'Disease', (255, 272))	('influence', 'Reg', (237, 246))	('Testicular cancer', 'Disease', 'MESH:D013736', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('testicular cancer', 'Phenotype', 'HP:0010788', (66, 83))	('Testicular cancer', 'Phenotype', 'HP:0010788', (0, 17))	('testicular cancer', 'Disease', 'MESH:D013736', (255, 272))	('testicular cancer', 'Disease', 'MESH:D013736', (66, 83))
10622	18071360	Only two studies have previously found a significant positive association between twinning and the development of testicular cancer, with four others generating suggestive but non-significant results and one finding a non-significant protective effect.	('testicular cancer', 'Disease', 'MESH:D013736', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('testicular cancer', 'Disease', (114, 131))	('twinning', 'Var', (82, 90))	('testicular cancer', 'Phenotype', 'HP:0010788', (114, 131))	('men', 'Species', '9606', (106, 109))
10634	23599692	Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence.	('Seminoma', 'Disease', 'MESH:D018239', (65, 73))	('cancer', 'Disease', (162, 168))	('Zebrafish', 'Species', '7955', (31, 40))	('Seminoma', 'Disease', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Predispose', 'Reg', (20, 30))	('Seminoma', 'Disease', 'MESH:D018239', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Seminomas', 'Disease', 'MESH:D018239', (55, 64))	('Mutations', 'Var', (0, 9))	('Seminoma', 'Disease', (55, 63))	('Seminomas', 'Disease', (55, 64))	('cell tumors', 'Disease', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cell tumors', 'Disease', 'MESH:D005935', (113, 124))	('germ cell tumors', 'Phenotype', 'HP:0100728', (108, 124))	('LRRC50', 'Gene', '386722', (13, 19))	('Humans', 'Species', '9606', (45, 51))	('germ cell tumor', 'Phenotype', 'HP:0100728', (108, 123))	('LRRC50', 'Gene', (13, 19))	('men', 'Species', '9606', (178, 181))	('human', 'Species', '9606', (91, 96))
10636	23599692	Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas.	('Leucine-Rich Repeat Containing protein 50', 'Gene', '386722', (55, 96))	('Leucine-Rich Repeat Containing protein 50', 'Gene', (55, 96))	('susceptible', 'Reg', (194, 205))	('lrrc50', 'Gene', (98, 104))	('dnaaf1', 'Gene', '386722', (117, 123))	('nonsense mutation', 'Var', (34, 51))	('dnaaf1', 'Gene', (117, 123))	('seminomas', 'Disease', 'MESH:D018239', (226, 235))	('seminomas', 'Disease', (226, 235))	('Zebrafish', 'Species', '7955', (0, 9))
10638	23599692	In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas.	('LRRC50', 'Gene', (46, 52))	('seminomas', 'Disease', 'MESH:D018239', (255, 264))	('seminomas', 'Disease', (255, 264))	('expression', 'MPA', (217, 227))	('seminomas', 'Disease', (115, 124))	('seminomas', 'Disease', 'MESH:D018239', (115, 124))	('Arg488* change', 'Var', (150, 164))	('mutations', 'Var', (53, 62))	('Arg488', 'Chemical', '-', (150, 156))	('Thr590Met', 'SUBSTITUTION', 'None', (180, 189))	('humans', 'Species', '9606', (3, 9))	('Thr590Met', 'Var', (180, 189))
10639	23599692	Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation.	('men', 'Species', '9606', (24, 27))	('loss-of-function', 'NegReg', (73, 89))	('Thr590Met', 'SUBSTITUTION', 'None', (55, 64))	('Thr590Met', 'Var', (55, 64))	('Zebrafish', 'Species', '7955', (0, 9))
10640	23599692	Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort).	('seminoma tumors', 'Disease', (99, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('seminoma tumors', 'Disease', 'MESH:D018239', (99, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pathogenic', 'Reg', (25, 35))	('Gln307Glu', 'Var', (36, 45))	('Gln307Glu', 'SUBSTITUTION', 'None', (36, 45))
10647	23599692	We therefore analyzed this gene in a subset of human seminoma samples and recovered mutations that were subsequently demonstrated to prohibit protein function.	('seminoma', 'Disease', (53, 61))	('prohibit', 'NegReg', (133, 141))	('protein', 'Protein', (142, 149))	('mutations', 'Var', (84, 93))	('seminoma', 'Disease', 'MESH:D018239', (53, 61))	('human', 'Species', '9606', (47, 52))
10659	23599692	We previously described a loss-of-function mutation in zebrafish lrrc50Hu255h, of which homozygous mutants display the ciliopathy phenotypes of primary ciliary dyskinesia (PCD) (CILD1; MIM 244400) in humans.	('PCD', 'Disease', 'MESH:D007619', (172, 175))	('dyskinesia', 'Disease', (160, 170))	('mutation', 'Var', (43, 51))	('dyskinesia', 'Phenotype', 'HP:0100660', (160, 170))	('lrrc50Hu255h', 'Gene', (65, 77))	('zebrafish', 'Species', '7955', (55, 64))	('dyskinesia', 'Disease', 'MESH:D004409', (160, 170))	('PCD', 'Disease', (172, 175))	('mutants', 'Var', (99, 106))	('loss-of-function', 'NegReg', (26, 42))	('humans', 'Species', '9606', (200, 206))	('ciliary dyskinesia', 'Phenotype', 'HP:0012265', (152, 170))
10661	23599692	Here, we describe the susceptibility to tumor formation of heterozygous lrrc50Hu255h zebrafish and suggest a tumor suppressor role for LRRC50 (alias DNAAF1; dynein assembly factor 1) in the specific development of the TGCT subtype seminoma in both zebrafish and man.	('DNAAF1', 'Gene', (149, 155))	('subtype seminoma', 'Disease', 'MESH:D018239', (223, 239))	('subtype seminoma', 'Disease', (223, 239))	('alias', 'Disease', (143, 148))	('zebrafish', 'Species', '7955', (248, 257))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('lrrc50Hu255h', 'Var', (72, 84))	('alias', 'Disease', 'None', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('LRRC50', 'Var', (135, 141))	('man', 'Species', '9606', (262, 265))	('men', 'Species', '9606', (206, 209))	('DNAAF1', 'Gene', '386722', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('zebrafish', 'Species', '7955', (85, 94))	('tumor', 'Disease', (109, 114))
10662	23599692	Whereas homozygous lrrc50 (-/-) mutants develop lethal defects during larval development due to severe ciliopathy phenotypes, heterozygous lrrc50hu255h (+/-) zebrafish develop into adulthood without apparent defects.	('lrrc50', 'Gene', (19, 25))	('zebrafish', 'Species', '7955', (158, 167))	('mutants', 'Var', (32, 39))	('lrrc50hu255h', 'Var', (139, 151))	('men', 'Species', '9606', (84, 87))	('ciliopathy', 'MPA', (103, 113))
10668	23599692	Analysis of 104 randomly selected age-matched male zebrafish (24-44 months old) that had similarly been generated through N-ethyl-N-nitrosourea (ENU) mutagenesis showed a common background level (16.3%) of TGCT formation (Figure 1A).	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (122, 143))	('TGCT formation', 'MPA', (206, 220))	('mutagenesis', 'Var', (150, 161))	('zebrafish', 'Species', '7955', (51, 60))
10671	23599692	Three testes from fish without externally evident tumors (Figure 1A) morphologically contained increased numbers of both pre- and post-meiotic cells that most likely represents hyperplasia, but might additionally suggest that population expansion precedes tumorigenesis (Figure S3B).	('population expansion', 'Var', (226, 246))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('hyperplasia', 'Disease', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('hyperplasia', 'Disease', 'MESH:D006965', (177, 188))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (256, 261))
10676	23599692	Ziwi IHC on lrrc50Hu255h tumors shows strong staining in the majority of cells with the exception of somatic tissue.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('lrrc50Hu255h', 'Var', (12, 24))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Ziwi', 'Gene', '368200', (0, 4))	('staining', 'MPA', (45, 53))	('Ziwi', 'Gene', (0, 4))
10680	23599692	We next interrogated the somatic loss of the wild-type lrrc50 allele in zebrafish tumorigenesis by genotyping the Hu255h (c.263T>A/p.Lys88*) nonsense mutation and LOH was found in 44.4% of tumors (n = 4/9) (Figure 2F); direct sequencing of the coding regions of the lrrc50 locus revealed no additional mutations.	('lrrc50', 'Gene', (266, 272))	('tumor', 'Disease', (189, 194))	('zebrafish', 'Species', '7955', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('c.263T>A/p.Lys88*', 'Var', (122, 139))	('c.263T>A', 'Mutation', 'c.263T>A', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('p.Lys88*', 'Mutation', 'p.K88*', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lrrc50', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
10683	23599692	promotor/intronic sequences, large chromosomal deletions), epigenetic alterations, or unrelated background tumors could obscure genotypic analysis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('epigenetic alterations', 'Var', (59, 81))	('large chromosomal deletions', 'Var', (29, 56))
10684	23599692	Although we cannot exclude an underlying haploinsufficient mechanism, we suggest that zebrafish lrrc50hu255h seminoma progression is consistent with biallelic inactivation.	('seminoma', 'Disease', (109, 117))	('lrrc50hu255h', 'Var', (96, 108))	('haploinsufficient', 'Disease', 'MESH:D058495', (41, 58))	('zebrafish', 'Species', '7955', (86, 95))	('seminoma', 'Disease', 'MESH:D018239', (109, 117))	('haploinsufficient', 'Disease', (41, 58))
10685	23599692	We next conducted LRRC50 mutational analysis in a collection of 30 human seminomas and five spermatocytic seminomas (the latter as controls) (Table 1).	('mutational', 'Var', (25, 35))	('seminomas', 'Disease', 'MESH:D018239', (73, 82))	('seminomas', 'Disease', (73, 82))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (92, 115))	('seminomas', 'Disease', 'MESH:D018239', (106, 115))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (92, 115))	('spermatocytic seminomas', 'Disease', (92, 115))	('human', 'Species', '9606', (67, 72))	('seminomas', 'Disease', (106, 115))	('LRRC50', 'Gene', (18, 24))
10686	23599692	We identified one individual (SE14) diagnosed with a stage-II seminoma and a contra-lateral stage I seminoma within a six-year interval; both tumors have a nonsense c.1462C>T/p.Arg488* mutation in exon 8 (Figure 3A, 3B, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('I seminoma', 'Disease', (98, 108))	('I seminoma', 'Disease', 'MESH:D018239', (98, 108))	('I seminoma', 'Disease', (60, 70))	('I seminoma', 'Disease', 'MESH:D018239', (60, 70))	('c.1462C>T', 'Mutation', 'rs375641621', (165, 174))	('c.1462C>T/p.Arg488*', 'Var', (165, 184))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('p.Arg488*', 'Mutation', 'p.R488*', (175, 184))
10687	23599692	Corresponding peripheral blood (PBL) revealed a heterozygous germline c.1462C>T/p.Arg488* (TMP_ESP_16_84203896) LRRC50 mutation, which is extremely rare and identified in 0.008% (1/12,999) of chromosomes in the NHLBI Exome Variant Server (NHLBI ESP, http://evs.gs.washington.edu/EVS/).	('ESP', 'Gene', (245, 248))	('LRRC50', 'Gene', (112, 118))	('ESP', 'Gene', (95, 98))	('p.Arg488*', 'Mutation', 'p.R488*', (80, 89))	('ESP', 'Gene', '148713', (245, 248))	('ESP', 'Gene', '148713', (95, 98))	('c.1462C>T', 'Mutation', 'rs375641621', (70, 79))	('c.1462C>T/p.Arg488*', 'Var', (70, 89))
10688	23599692	Both tumor DNA chromatograms show a consistently stronger mutant peak compared to PBL, indicating biallelic loss in at least a subset of tumor cells, or presence of non-tumorous cells (somatic tissue, lymphocytes).	('mutant', 'Var', (58, 64))	('loss', 'NegReg', (108, 112))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('non-tumorous', 'Disease', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('non-tumorous', 'Disease', 'MESH:D009369', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('stronger', 'PosReg', (49, 57))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
10689	23599692	Analysis of SNPs in closest proximity to the mutation, rs17856705 and rs2288020, showed perfect heterozygosity in both seminomas and PBL, supportive of a localized LOH event.	('seminomas', 'Disease', 'MESH:D018239', (119, 128))	('seminomas', 'Disease', (119, 128))	('rs2288020', 'Var', (70, 79))	('rs17856705', 'Mutation', 'rs17856705', (55, 65))	('rs2288020', 'Mutation', 'rs2288020', (70, 79))	('PBL', 'Disease', (133, 136))	('rs17856705', 'Var', (55, 65))
10690	23599692	Accordingly, IHC staining of SE14-tumor sections with alpha-LRRC50 indicates no detectable protein expression, whereas IHC on rete testis (non-tumorous normal control tissue) from SE14 confirms presence of LRRC50 in ciliated somatic tissue and antibody specificity (Figure 3C).	('SE14-tumor', 'Disease', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('LRRC50', 'Var', (206, 212))	('SE14-tumor', 'Disease', 'MESH:D009369', (29, 39))	('non-tumorous', 'Disease', (139, 151))	('protein expression', 'MPA', (91, 109))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('non-tumorous', 'Disease', 'MESH:D009369', (139, 151))
10696	23599692	Additionally, genotype data in dbSNP137 showed that Thr590Met is not present in homozygosity in the NHLBI ESP cohort suggesting that it is a deleterious change likely under purifying selection.	('ESP', 'Gene', '148713', (106, 109))	('Thr590Met', 'SUBSTITUTION', 'None', (52, 61))	('dbSNP137', 'Chemical', '-', (31, 39))	('Thr590Met', 'Var', (52, 61))	('ESP', 'Gene', (106, 109))
10698	23599692	Again, the mutant chromatogram is stronger in the tumor than in PBL, suggesting LOH.	('mutant', 'Var', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('stronger', 'MPA', (34, 42))	('tumor', 'Disease', (50, 55))
10699	23599692	In the total seminoma population (n = 38) we identified a significantly enriched, heterozygous, conserved mutation, c.919C>G/p.Gln307Glu (n = 5, 5/76 alleles, P = 0.0013, Fisher's exact test), potentially associated with seminoma as it is absent in a healthy male control group (n = 100, 0/200 alleles) (Table 1, Table 2 and Figure 3A, 3F).	('c.919C>G/p.Gln307Glu', 'Var', (116, 136))	('total seminoma', 'Phenotype', 'HP:0100617', (7, 21))	('p.Gln307Glu', 'Mutation', 'rs111472069', (125, 136))	('seminoma', 'Disease', (13, 21))	('seminoma', 'Disease', 'MESH:D018239', (221, 229))	('c.919C>G', 'Mutation', 'rs111472069', (116, 124))	('associated with', 'Reg', (205, 220))	('seminoma', 'Disease', 'MESH:D018239', (13, 21))	('seminoma', 'Disease', (221, 229))
10700	23599692	The Gln307Glu allele is present 2.9% (375/12625) in the ESP cohort, however we cannot exclude the possibility that some ESP males may have been affected with seminomas.	('seminomas', 'Disease', (158, 167))	('ESP', 'Gene', (56, 59))	('Gln307Glu', 'Var', (4, 13))	('Gln307Glu', 'SUBSTITUTION', 'None', (4, 13))	('ESP', 'Gene', '148713', (56, 59))	('affected', 'Reg', (144, 152))	('ESP', 'Gene', (120, 123))	('ESP', 'Gene', '148713', (120, 123))	('seminomas', 'Disease', 'MESH:D018239', (158, 167))
10701	23599692	To test the functional consequences of Thr590Met and Gln307Glu on protein function, an in vivo complementation approach was employed in zebrafish.	('Thr590Met', 'SUBSTITUTION', 'None', (39, 48))	('Thr590Met', 'Var', (39, 48))	('test', 'Reg', (3, 7))	('men', 'Species', '9606', (101, 104))	('Gln307Glu', 'Var', (53, 62))	('zebrafish', 'Species', '7955', (136, 145))	('Gln307Glu', 'SUBSTITUTION', 'None', (53, 62))
10702	23599692	Since maternally-derived WT lrrc50 mRNA can still be detected in lrrc50hu255h mutants early in development, we opted to use transient morpholino (MO)-induced suppression designed to block maternal and embryo-derived lrrc50 translation.	('lrrc50hu255h', 'Gene', (65, 77))	('men', 'Species', '9606', (102, 105))	('morpholino', 'Chemical', 'MESH:D060172', (134, 144))	('mutants', 'Var', (78, 85))
10703	23599692	We have previously shown that in addition to the PCD and renal cystic phenotypes of lrrc50 mutants, transient MO-induced suppression of lrrc50 gives rise to gastrulation phenotypes in mid-somitic embryos, which can be rescued by wild-type (WT) capped human LRRC50 mRNA (Figure 4A, 4B, scoring shown in Table S1).	('suppression', 'NegReg', (121, 132))	('gastrulation phenotypes', 'CPA', (157, 180))	('lrrc50', 'Gene', (84, 90))	('PCD', 'Disease', 'MESH:D007619', (49, 52))	('mid-somitic', 'Disease', 'MESH:C565122', (184, 195))	('lrrc50', 'Gene', (136, 142))	('human', 'Species', '9606', (251, 256))	('renal cystic', 'Disease', (57, 69))	('mid-somitic', 'Disease', (184, 195))	('mutants', 'Var', (91, 98))	('PCD', 'Disease', (49, 52))	('renal cystic', 'Disease', 'MESH:D052177', (57, 69))
10704	23599692	Here, we test LRRC50 mRNA harboring either Thr590Met or Gln307Glu missense mutations to rescue MO-induced gastrulation defects.	('Thr590Met', 'Var', (43, 52))	('gastrulation defects', 'Disease', 'MESH:D005128', (106, 126))	('Gln307Glu', 'SUBSTITUTION', 'None', (56, 65))	('Gln307Glu', 'Var', (56, 65))	('gastrulation defects', 'Disease', (106, 126))	('Thr590Met', 'SUBSTITUTION', 'None', (43, 52))
10713	23599692	In this manuscript we characterize a novel vertebrate model for human seminoma associated with biallelic inactivation of lrrc50 in at least 44.4% of tumors tested.	('human', 'Species', '9606', (64, 69))	('seminoma', 'Disease', 'MESH:D018239', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('biallelic', 'Var', (95, 104))	('man', 'Species', '9606', (66, 69))	('tumors', 'Disease', (149, 155))	('lrrc50', 'Gene', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('man', 'Species', '9606', (8, 11))	('seminoma', 'Disease', (70, 78))
10714	23599692	We translated this finding to humans and identified pathogenic germline LRRC50 mutations in two human seminoma pedigrees that had at least partially lost expression of the wild-type allele in their tumors.	('human', 'Species', '9606', (30, 35))	('human', 'Species', '9606', (96, 101))	('seminoma', 'Disease', (102, 110))	('mutations', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('humans', 'Species', '9606', (30, 36))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('lost', 'NegReg', (149, 153))	('LRRC50', 'Gene', (72, 78))	('seminoma', 'Disease', 'MESH:D018239', (102, 110))	('pathogenic', 'Reg', (52, 62))	('expression', 'MPA', (154, 164))
10715	23599692	In addition, a significant enrichment of a pathogenic Gln307Glu change in sporadic seminomas (13% of cases) was identified, which is absent from a healthy control population, and low in the general population.	('pathogenic', 'Reg', (43, 53))	('sporadic seminomas', 'Disease', 'MESH:D018239', (74, 92))	('sporadic seminomas', 'Disease', (74, 92))	('men', 'Species', '9606', (33, 36))	('Gln307Glu', 'Var', (54, 63))	('Gln307Glu', 'SUBSTITUTION', 'None', (54, 63))
10716	23599692	Although functional evidence indicates that Gln307Glu is detrimental to protein function, population frequency data suggests that in homozygosity, it is likely not sufficient to cause PCD when inherited in the germline (0.001% of the ESP cohort is homozygous for this change).	('men', 'Species', '9606', (62, 65))	('detrimental', 'NegReg', (57, 68))	('Gln307Glu', 'Var', (44, 53))	('Gln307Glu', 'SUBSTITUTION', 'None', (44, 53))	('PCD', 'Disease', (184, 187))	('cause', 'Reg', (178, 183))	('PCD', 'Disease', 'MESH:D007619', (184, 187))	('ESP', 'Gene', (234, 237))	('protein function', 'MPA', (72, 88))	('ESP', 'Gene', '148713', (234, 237))
10720	23599692	One other study of genetic instability (gin) zebrafish mutants between 30-34 months old identified a 28% tumor incidence compared to 5% in wild-type animals, and seminomas are observed in ~20% of the gin mutants.	('mutants', 'Var', (55, 62))	('seminomas', 'Disease', 'MESH:D018239', (162, 171))	('seminomas', 'Disease', (162, 171))	('zebrafish', 'Species', '7955', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mutants', 'Var', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
10722	23599692	Of interest, genetic mutant zebrafish lines are typically more susceptible to develop a different tumor spectrum, most notable malignant peripheral nerve sheath tumors (zMPNST) (Figure S2A), as has been described for p53, ribosomal protein mutants and genomic instability mutants.	('tumor', 'Disease', (161, 166))	('mutants', 'Var', (240, 247))	('mutant', 'Var', (21, 27))	('zebrafish', 'Species', '7955', (28, 37))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (127, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('nerve sheath tumors', 'Disease', 'MESH:D010524', (148, 167))	('nerve sheath tumors', 'Disease', (148, 167))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ribosomal', 'Protein', (222, 231))	('tumor', 'Disease', (98, 103))	('susceptible', 'Reg', (63, 74))	('develop', 'PosReg', (78, 85))	('genetic mutant', 'Var', (13, 27))
10723	23599692	The recently described mutant Alk6b zebrafish are similarly predisposed to GCT formation; of interest, tumor formation occurs earlier in life in this genetic model.	('GCT formation', 'Disease', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('Alk6b', 'Gene', (30, 35))	('zebrafish', 'Species', '7955', (36, 45))	('Alk6b', 'Gene', '100149664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('mutant', 'Var', (23, 29))
10724	23599692	The introduced loss-of-function Alk6b mutation fails to activate BMP target genes through downstream nuclear p-SMAD1/5/8.	('Alk6b', 'Gene', (32, 37))	('BMP', 'Gene', (65, 68))	('SMAD1/5', 'Gene', '4086;4090', (111, 118))	('mutation', 'Var', (38, 46))	('Alk6b', 'Gene', '100149664', (32, 37))	('BMP', 'Gene', '649', (65, 68))	('loss-of-function', 'NegReg', (15, 31))	('SMAD1/5', 'Gene', (111, 118))
10732	23599692	Since LRRC50 mutations have been reported in PCD, a multifaceted disease that includes infertility, we cannot exclude a correlation with impaired sperm motility, however, thus far no systematic association between PCD and seminoma has been described.	('impaired sperm motility', 'Disease', (137, 160))	('PCD', 'Disease', 'MESH:D007619', (45, 48))	('seminoma', 'Disease', (222, 230))	('infertility', 'Phenotype', 'HP:0000789', (87, 98))	('infertility', 'Disease', 'MESH:D007247', (87, 98))	('PCD', 'Disease', (214, 217))	('infertility', 'Disease', (87, 98))	('PCD', 'Disease', 'MESH:D007619', (214, 217))	('LRRC50', 'Gene', (6, 12))	('reported', 'Reg', (33, 41))	('impaired sperm motility', 'Phenotype', 'HP:0012207', (137, 160))	('mutations', 'Var', (13, 22))	('PCD', 'Disease', (45, 48))	('seminoma', 'Disease', 'MESH:D018239', (222, 230))	('impaired sperm motility', 'Disease', 'MESH:D015835', (137, 160))
10733	23599692	Of interest though, motile cilia protein DNAH9 (MIM 603330) is frequently mutated in breast cancer (MIM 114480) and in line with this notion, ciliary frequencies are reduced on cells derived from breast tumors.	('DNAH9', 'Gene', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ciliary frequencies', 'CPA', (142, 161))	('breast cancer', 'Disease', (85, 98))	('DNAH9', 'Gene', '1770', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('breast tumors', 'Phenotype', 'HP:0100013', (196, 209))	('reduced', 'NegReg', (166, 173))	('breast tumors', 'Disease', 'MESH:D001943', (196, 209))	('MIM 114480', 'Var', (100, 110))	('motile cilia protein', 'Disease', 'MESH:C536287', (20, 40))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MIM 603330', 'Var', (48, 58))	('motile cilia protein', 'Disease', (20, 40))	('breast tumors', 'Disease', (196, 209))
10738	23599692	Furthermore, we have described that primary cilia formation is inhibited upon shRNA-mediated knockdown in mammalian cells, and show increased LRRC50 mRNA expression upon primary cilia formation (Figure S6B).	('knockdown', 'Var', (93, 102))	('LRRC50', 'Gene', (142, 148))	('primary cilia formation', 'CPA', (36, 59))	('increased', 'PosReg', (132, 141))	('inhibited', 'NegReg', (63, 72))	('mammalian', 'Species', '9606', (106, 115))	('mRNA expression', 'MPA', (149, 164))	('shRNA-mediated', 'Gene', (78, 92))
10741	23599692	In what way the dysfunction or loss of LRRC50 affects autonomous early germ cell development, and whether it induces a block in maturation, deregulates differentiation or proliferation and systematically leads to seminoma development, remains elusive.	('block', 'NegReg', (119, 124))	('maturation', 'CPA', (128, 138))	('seminoma', 'Disease', 'MESH:D018239', (213, 221))	('affects', 'Reg', (46, 53))	('LRRC50', 'Gene', (39, 45))	('dysfunction', 'Disease', 'MESH:D006331', (16, 27))	('loss', 'Var', (31, 35))	('autonomous early germ cell development', 'CPA', (54, 92))	('dysfunction', 'Disease', (16, 27))	('deregulates', 'NegReg', (140, 151))	('seminoma', 'Disease', (213, 221))	('differentiation', 'CPA', (152, 167))	('men', 'Species', '9606', (229, 232))	('men', 'Species', '9606', (88, 91))	('leads to', 'Reg', (204, 212))	('proliferation', 'CPA', (171, 184))
10743	23599692	Although common characteristics have been extensively described to include aneuploidy and non-random gain and loss of chromosomes, of which gain of 12p appears important in metastatic tumors, little information on early initiating events is available.	('loss', 'NegReg', (110, 114))	('aneuploidy', 'Disease', 'MESH:D000782', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gain', 'PosReg', (101, 105))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('aneuploidy', 'Disease', (75, 85))	('gain', 'Var', (140, 144))
10747	23599692	Mutations in both pathway components are identified in seminomas and non-seminomas, hence differentiating factors amongst these tumors remain unknown.	('identified', 'Reg', (41, 51))	('seminomas and non-seminomas', 'Disease', 'MESH:D018239', (55, 82))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
10748	23599692	Furthermore, N- and KRAS activation mutations and LOH of well-accepted tumor suppressors APC, p53 and CDH-1 have been identified in both seminomas and non-seminomas.	('KRAS', 'Gene', '3845', (20, 24))	('LOH', 'NegReg', (50, 53))	('p53', 'Gene', (94, 97))	('seminomas and non-seminomas', 'Disease', 'MESH:D018239', (137, 164))	('APC', 'Disease', 'MESH:D011125', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('APC', 'Disease', (89, 92))	('mutations', 'Var', (36, 45))	('identified', 'Reg', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CDH-1', 'Gene', '999', (102, 107))	('tumor', 'Disease', (71, 76))	('KRAS', 'Gene', (20, 24))	('CDH-1', 'Gene', (102, 107))
10755	23599692	Prior to tissue isolation, zebrafish were euthanized by overdose of MS222.	('MS222', 'Var', (68, 73))	('zebrafish', 'Species', '7955', (27, 36))	('overdose', 'Disease', 'MESH:D062787', (56, 64))	('overdose', 'Disease', (56, 64))
10765	23599692	mRNA probes; LRRC50 Hs00698399_m1 and RPL19 Hs01577060_gH, were purchased from Applied Biosystems.	('RPL19', 'Gene', (38, 43))	('RPL19', 'Gene', '6143', (38, 43))	('Hs01577060_gH', 'Var', (44, 57))
10772	23599692	Primary antibodies used were alpha-phosphorylated-histone H3 (1:1000, Upstate; 06-570), alpha-Ziwi (1:100,) and alpha-gamma-H2Ax (1:200, Cell Signaling).	('alpha-gamma-H2Ax', 'Var', (112, 128))	('Ziwi', 'Gene', (94, 98))	('Ziwi', 'Gene', '368200', (94, 98))
10780	23599692	We used site-directed mutagenesis to introduce missense changes Thr590Met and Gln307Glu into the WT pCS2+ LRRC50 construct (Quick-Change Site Directed Mutagenesis kit, Agilent) and used linearized plasmid to transcribe mRNA (SP6 mMessage mMachine kit, Ambion).	('Thr590Met', 'SUBSTITUTION', 'None', (64, 73))	('Thr590Met', 'Var', (64, 73))	('Gln307Glu', 'Var', (78, 87))	('Gln307Glu', 'SUBSTITUTION', 'None', (78, 87))
10790	23599692	Between 24 months and 44 months of age, male lrrc50Hu255h zebrafish (TGCT tumors n = 24, normal n = 0) compared controls (TGCT tumors n = 17, normal n = 87).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('lrrc50Hu255h', 'Var', (45, 57))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('zebrafish', 'Species', '7955', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
10794	23599692	To calculate the putative overrepresentation of c.919C>G/p.Gln307Glu in the seminoma cohort (Figure 3F), a two-tailed Fisher's exact test in a 2x2 contingency table was used as the data is categorical and sample sizes are large.	('p.Gln307Glu', 'Mutation', 'rs111472069', (57, 68))	('c.919C>G/p.Gln307Glu', 'Var', (48, 68))	('seminoma cohort', 'Disease', 'MESH:D018239', (76, 91))	('seminoma cohort', 'Disease', (76, 91))	('c.919C>G', 'Mutation', 'rs111472069', (48, 56))
10804	19755987	Chemotherapy with cyclophosphamide and cisplatin, and also radiotherapy, seem to increase the risk of subsequent neoplasms in the bladder.	('cisplatin', 'Var', (39, 48))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (18, 34))	('neoplasms in the bladder', 'Phenotype', 'HP:0009725', (113, 137))	('neoplasms', 'Phenotype', 'HP:0002664', (113, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (113, 121))	('neoplasms', 'Disease', 'MESH:D009369', (113, 122))	('neoplasms', 'Disease', (113, 122))
10809	19755987	Variants in genes coding for xenobiotic-transforming enzymes and polymorphisms in DNA repair genes may also modify cancer susceptibility (Easton et al, 2007; Kellen et al, 2007; Murta-Nascimento et al, 2007b; Sanderson et al, 2007; Andrew et al, 2008).	('cancer', 'Disease', (115, 121))	('Variants', 'Var', (0, 8))	('men', 'Species', '9606', (189, 192))	('xenobiotic-', 'Phenotype', 'HP:0031838', (29, 40))	('polymorphisms', 'Var', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('modify', 'Reg', (108, 114))	('DNA repair', 'Gene', (82, 92))
10915	19755987	However, it has been hypothesised that cisplatin may act as radiation enhancer and contribute to a shortened latency periods for radiogenic bladder cancer.	('shortened', 'NegReg', (99, 108))	('cisplatin', 'Var', (39, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('enhancer', 'PosReg', (70, 78))	('radiogenic bladder', 'Phenotype', 'HP:0000011', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('latency', 'MPA', (109, 116))
10923	19755987	Mutations in DNA repair genes (XRCC3) and variants in genes coding for xenobiotic-transforming enzymes (NAT2, GSTM1, GSTP1 and NQO1) have been shown to modify the susceptibility to bladder cancer (Chao et al, 2006; Chaturvedi et al, 2007; Easton et al, 2007; Figueroa et al, 2007; Kellen et al, 2007; Sanderson et al, 2007; Murta-Nascimento et al, 2007b).	('GSTM1', 'Gene', (110, 115))	('modify', 'Reg', (152, 158))	('susceptibility', 'Reg', (163, 177))	('men', 'Species', '9606', (335, 338))	('xenobiotic-', 'Phenotype', 'HP:0031838', (71, 82))	('NAT2', 'Gene', '10', (104, 108))	('variants', 'Var', (42, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (181, 195))	('Mutations', 'Var', (0, 9))	('NAT2', 'Gene', (104, 108))	('bladder cancer', 'Disease', (181, 195))	('XRCC3', 'Gene', (31, 36))	('GSTM1', 'Gene', '2944', (110, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (181, 195))	('NQO1', 'Gene', '1728', (127, 131))	('GSTP1', 'Gene', '2950', (117, 122))	('GSTP1', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('NQO1', 'Gene', (127, 131))	('XRCC3', 'Gene', '7517', (31, 36))
10924	19755987	These variants may be associated with an increased risk of cancer at additional sites.	('variants', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('associated', 'Reg', (22, 32))
10925	19755987	For example, two meta-analyses that explored the relevance of GSTM1 null status on stomach cancer found a modest risk increase (La Torre et al, 2005; Saadat, 2006).	('GSTM1', 'Gene', (62, 67))	('null status', 'Var', (68, 79))	('stomach cancer', 'Disease', (83, 97))	('stomach cancer', 'Phenotype', 'HP:0012126', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GSTM1', 'Gene', '2944', (62, 67))	('stomach cancer', 'Disease', 'MESH:D013274', (83, 97))
10927	19755987	These polymorphisms are relatively common in Swedes, but the low penetrances conferred by the risk alleles (genotype relative risks between 1.2 and 1.5) result in a limited contribution of the variants to the increased risk of bladder neoplasms among cancer patients.	('bladder neoplasms', 'Disease', 'MESH:D001749', (227, 244))	('bladder neoplasms', 'Disease', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('neoplasms', 'Phenotype', 'HP:0002664', (235, 244))	('variants', 'Var', (193, 201))	('neoplasm', 'Phenotype', 'HP:0002664', (235, 243))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('patients', 'Species', '9606', (258, 266))	('bladder neoplasms', 'Phenotype', 'HP:0009725', (227, 244))	('cancer', 'Disease', (251, 257))
10949	29197138	Overall, these findings first elucidate that TR4 is a novel prognostic marker and plays a critical role in the metastatic capacity of Tcam-2 cells by EMT regulation and, consequently, targeting TR4-AKT3 pathway may serve as a potential therapeutic approach for seminoma.	('EMT regulation', 'CPA', (150, 164))	('seminoma', 'Disease', 'MESH:D018239', (261, 269))	('TR4', 'Gene', (45, 48))	('seminoma', 'Disease', (261, 269))	('AKT3', 'Gene', (198, 202))	('metastatic capacity', 'CPA', (111, 130))	('AKT3', 'Gene', '10000', (198, 202))	('targeting', 'Var', (184, 193))
10979	29197138	After rinsing twice with PBS, cells were incubated for 1-2 hours with N-cadherin (1:200), anti-E-cadherin (1:200) or anti-AKT3 (1:200).	('E-cadherin', 'Gene', (95, 105))	('1:200', 'Var', (82, 87))	('N-cadherin', 'Gene', (70, 80))	('PBS', 'Chemical', 'MESH:D007854', (25, 28))	('E-cadherin', 'Gene', '999', (95, 105))	('1:200', 'Var', (107, 112))	('AKT3', 'Gene', (122, 126))	('N-cadherin', 'Gene', '1000', (70, 80))	('AKT3', 'Gene', '10000', (122, 126))
11011	29197138	As indicated in Figure 4B,C, overexpressing TR4 decreased mRNA and protein levels of E-cadherin, but raised the mRNA and protein levels of snail and mesenchymal markers, such as N-cadherin and Vimentin.	('N-cadherin', 'Gene', (178, 188))	('overexpressing', 'Var', (29, 43))	('Vimentin', 'Gene', (193, 201))	('snail', 'Gene', (139, 144))	('raised', 'PosReg', (101, 107))	('decreased', 'NegReg', (48, 57))	('E-cadherin', 'Gene', (85, 95))	('N-cadherin', 'Gene', '1000', (178, 188))	('E-cadherin', 'Gene', '999', (85, 95))	('Vimentin', 'Gene', '7431', (193, 201))	('TR4', 'Gene', (44, 47))	('snail', 'Gene', '6615', (139, 144))
11012	29197138	However, after silencing TR4 in Tcam-2 cells, upregulation of E-cadherin and reduced N-cadherin, vimentin and snail were observed in mRNA (Figure 4D) as well as increased protein levels (Figure 4E).	('TR4', 'Gene', (25, 28))	('N-cadherin', 'Gene', (85, 95))	('snail', 'Gene', (110, 115))	('upregulation', 'PosReg', (46, 58))	('vimentin', 'Gene', '7431', (97, 105))	('N-cadherin', 'Gene', '1000', (85, 95))	('vimentin', 'Gene', (97, 105))	('protein levels', 'MPA', (171, 185))	('silencing', 'Var', (15, 24))	('reduced', 'NegReg', (77, 84))	('snail', 'Gene', '6615', (110, 115))	('E-cadherin', 'Gene', (62, 72))	('increased', 'PosReg', (161, 170))	('E-cadherin', 'Gene', '999', (62, 72))
11013	29197138	Immunofluorescence analysis for EMT markers E-cadherin and N-cadherin in Tcam-2-TR4, Tcam-2-shTR4 and their control cells confirmed the effects of TR4 on the EMT phenotype (Figure 4G,F).	('N-cadherin', 'Gene', (59, 69))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('effects', 'Reg', (136, 143))	('Tcam-2-TR4', 'Var', (73, 83))	('N-cadherin', 'Gene', '1000', (59, 69))	('EMT phenotype', 'CPA', (158, 171))
11014	29197138	Together, the results from Figure 4A-F suggested that TR4 had a positive effect on the EMT phenotype in seminoma cells, indicating that TR4 might modulate seminoma progression through induction of EMT.	('modulate', 'Reg', (146, 154))	('seminoma', 'Disease', 'MESH:D018239', (104, 112))	('TR4', 'Var', (136, 139))	('seminoma', 'Disease', 'MESH:D018239', (155, 163))	('EMT phenotype', 'CPA', (87, 100))	('EMT', 'CPA', (197, 200))	('seminoma', 'Disease', (104, 112))	('seminoma', 'Disease', (155, 163))
11023	29197138	Moreover, the results from western blot analysis (Figure 6E) and immunofluorescence (Figure 6F) of the EMT-related factors demonstrated downregulation of N-cadherin and upregulation of E-cadherin when AKT3 siRNA were transfected into Tcam-2-TR4 cells, indicating that interrupting AKT3 could reverse TR4-induced EMT.	('N-cadherin', 'Gene', (154, 164))	('AKT3', 'Gene', (201, 205))	('N-cadherin', 'Gene', '1000', (154, 164))	('upregulation', 'PosReg', (169, 181))	('downregulation', 'NegReg', (136, 150))	('AKT3', 'Gene', '10000', (201, 205))	('interrupting', 'Var', (268, 280))	('E-cadherin', 'Gene', (185, 195))	('E-cadherin', 'Gene', '999', (185, 195))	('AKT3', 'Gene', (281, 285))	('AKT3', 'Gene', '10000', (281, 285))
11024	29197138	Taken together, the results from Figure 6A-F showed significant suppression of the TR4 function by knocking down AKT3 in Tcam-2 cells.	('knocking', 'Var', (99, 107))	('AKT3', 'Gene', (113, 117))	('function', 'MPA', (87, 95))	('AKT3', 'Gene', '10000', (113, 117))	('TR4', 'Protein', (83, 86))	('suppression', 'NegReg', (64, 75))
11028	29197138	The results indicated that overexpression of TR4 significantly increased the luciferase activity in Tcam-2 cells and Cos-7 cells (these cells rarely contain endogenous TR4 to exclude the influence of the endogenous TR4), but no difference was observed in cells co-transfected with luciferase plasmid containing mutated TR4RE (Figure 7C,D).	('increased', 'PosReg', (63, 72))	('TR4', 'Gene', (45, 48))	('luciferase', 'Enzyme', (77, 87))	('activity', 'MPA', (88, 96))	('mutated', 'Var', (311, 318))	('Cos-7', 'CellLine', 'CVCL:0224', (117, 122))
11040	29197138	Here, in mechanism dissection studies, we screened several genes that were associated with seminoma progression and the results showed that AKT3 was the most significantly changed molecule after TR4 manipulation, which promoted tumor progression through induction of EMT.	('seminoma', 'Disease', (91, 99))	('TR4', 'Gene', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('EMT', 'CPA', (267, 270))	('manipulation', 'Var', (199, 211))	('promoted', 'PosReg', (219, 227))	('tumor', 'Disease', (228, 233))	('seminoma', 'Disease', 'MESH:D018239', (91, 99))	('AKT3', 'Gene', (140, 144))	('AKT3', 'Gene', '10000', (140, 144))
11153	27281266	Added to radiotherapy (RT), cisplatin increases the incidence of acute and long-term toxicities, with nephrotoxicity being the drug-specific and dose-limiting adverse effect.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('acute and', 'MPA', (65, 74))	('toxicities', 'Disease', 'MESH:D064420', (85, 95))	('nephrotoxicity', 'Disease', (102, 116))	('cisplatin', 'Var', (28, 37))	('nephrotoxicity', 'Disease', 'MESH:D007674', (102, 116))	('toxicities', 'Disease', (85, 95))
11164	27281266	CRT of the head and neck causes mucositis, dysphagia and nausea, which significantly limit oral hydration, increasing risk of nephrotoxicity.	('nausea', 'Disease', 'MESH:D009325', (57, 63))	('dysphagia', 'Phenotype', 'HP:0002015', (43, 52))	('limit', 'NegReg', (85, 90))	('dysphagia', 'Disease', 'MESH:D003680', (43, 52))	('causes', 'Reg', (25, 31))	('mucositis', 'Disease', (32, 41))	('dysphagia', 'Disease', (43, 52))	('oral hydration', 'MPA', (91, 105))	('nephrotoxicity', 'Disease', (126, 140))	('nephrotoxicity', 'Disease', 'MESH:D007674', (126, 140))	('mucositis', 'Disease', 'MESH:D052016', (32, 41))	('nausea', 'Phenotype', 'HP:0002018', (57, 63))	('nausea', 'Disease', (57, 63))	('CRT', 'Var', (0, 3))
11213	27281266	Patients with baseline low SCr and high eGFR had significantly lower weight (p<0.0001 and p=0.02) and BMI (p=0.0001 and p=0.006).	('lower weight', 'Phenotype', 'HP:0004325', (63, 75))	('low SCr', 'Var', (23, 30))	('lower', 'NegReg', (63, 68))	('BMI', 'CPA', (102, 105))	('eGFR', 'Gene', '1956', (40, 44))	('eGFR', 'Gene', (40, 44))	('weight', 'CPA', (69, 75))	('Patients', 'Species', '9606', (0, 8))	('Cr', 'Chemical', 'MESH:D003404', (28, 30))
11294	27281266	Patients with BMI>30 had fewer AKI events despite cisplatin dose being calculated based on actual body weight.	('fewer', 'NegReg', (25, 30))	('AKI events', 'Disease', (31, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('BMI>30', 'Var', (14, 20))	('Patients', 'Species', '9606', (0, 8))
11413	25677133	Finally, the deficiency of the pro-apoptotic factor BAX in mice led to decreased germ cell apoptosis at PND5 and PND15 and disrupted spermatogenesis, further stressing the importance of apoptosis in this process.	('disrupted spermatogenesis', 'Phenotype', 'HP:0008669', (123, 148))	('germ cell apoptosis', 'CPA', (81, 100))	('mice', 'Species', '10090', (59, 63))	('deficiency', 'Var', (13, 23))	('disrupted', 'NegReg', (123, 132))	('BAX', 'Gene', (52, 55))	('PND15', 'Gene', (113, 118))	('decreased', 'NegReg', (71, 80))	('spermatogenesis', 'CPA', (133, 148))
11446	25677133	A small proportion of germ cells strongly positive for cleaved Casp9 were observed in PND8 spermatogonial preparations, as well as a few germ cells weakly positive for cleaved Casp3 (Figure 1b, top panel).	('cleaved', 'Var', (55, 62))	('Casp9', 'Protein', (63, 68))	('rat', 'Species', '10116', (111, 114))	('positive', 'Reg', (42, 50))
11451	25677133	Interestingly, the majority of the 84 genes analyzed were more highly expressed in RA-treated gonocytes than in untreated cells, as seen by the heat map (Figure 2b) and scatter plot (Figure 2c).	('RA-treated', 'Var', (83, 93))	('RA', 'Chemical', 'MESH:D014212', (83, 85))	('more highly expressed', 'PosReg', (58, 79))
11488	25677133	Similar to its common interacting partner p53, Gadd45a-/- mice have shown genomic instability, including aneuploidy and gene amplification, associated with the tendency to develop tumors following genotoxic stress.	('aneuploidy', 'Disease', 'MESH:D000782', (105, 115))	('develop', 'PosReg', (172, 179))	('associated', 'Reg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mice', 'Species', '10090', (58, 62))	('aneuploidy', 'Disease', (105, 115))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('genomic instability', 'CPA', (74, 93))	('gene amplification', 'Var', (120, 138))
11489	25677133	With regards to testicular development, although Gadd45g-/- mice have problems with sexual development, including male infertility and an intersex phenotype, Gadd45a and b-/- mice did not have problems with testis development or sex determination.	('Gadd45g', 'Gene', (49, 56))	('intersex', 'Disease', (138, 146))	('mice', 'Species', '10090', (175, 179))	('mice', 'Species', '10090', (60, 64))	('problems with sexual', 'Phenotype', 'HP:0030214', (70, 90))	('male infertility', 'Phenotype', 'HP:0003251', (114, 130))	('infertility', 'Phenotype', 'HP:0000789', (119, 130))	('Gadd45g', 'Gene', '23882', (49, 56))	('problems', 'Reg', (70, 78))	('testis development', 'CPA', (207, 225))	('sexual development', 'CPA', (84, 102))	('Gadd45a', 'Var', (158, 165))	('infertility', 'Disease', 'MESH:D007247', (119, 130))	('infertility', 'Disease', (119, 130))
11495	25677133	Studies have shown that inactivation of Casp9 is embryonic lethal, whereas Casp3 knockout mice died in the weeks following birth, preventing the study of their potential role in spermatogenesis.	('Casp3', 'Gene', (75, 80))	('Casp9', 'Gene', (40, 45))	('inactivation', 'Var', (24, 36))	('preventing', 'NegReg', (130, 140))	('mice', 'Species', '10090', (90, 94))
11498	25677133	Interestingly, Sall4 is a marker for undifferentiated spermatogonia, while Sall4a is upregulated at PND7, a period at which germ cells should have relocated to the basement membrane and when postnatal germ cell apoptosis rises.	('Sall4', 'Gene', '686412', (15, 20))	('Sall4', 'Gene', '686412', (75, 80))	('upregulated', 'PosReg', (85, 96))	('Sall4', 'Gene', (15, 20))	('Sall4', 'Gene', (75, 80))	('PND7', 'Var', (100, 104))
11509	25677133	In this model, the presence of IAP antagonist would promote IAP proteasomal degradation, leading to an aberrant NF-kappaB activation and increased tumor cell survival and proliferation.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('IAP', 'Gene', (31, 34))	('IAP proteasomal degradation', 'MPA', (60, 87))	('presence', 'Var', (19, 27))	('NF-kappaB', 'Protein', (112, 121))	('activation', 'PosReg', (122, 132))	('increased', 'PosReg', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('rat', 'Species', '10116', (178, 181))	('proliferation', 'CPA', (171, 184))	('promote', 'PosReg', (52, 59))
11642	32326899	However, cisplatin-sensitivity was not affected following pharmacological inhibition of Nodal/Activin signalling or siRNA-mediated knockdown of the obligate co-receptor CRIPTO in NTera2 cells in vitro or in a xenograft model.	('knockdown', 'Var', (131, 140))	('cisplatin-sensitivity', 'MPA', (9, 30))	('Activin', 'Gene', (94, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('NTera2', 'CellLine', 'CVCL:0034', (179, 185))	('Activin', 'Gene', '83729', (94, 101))
11665	32326899	Therefore, we hypothesised that dysregulation of the Nodal signalling pathway is involved in the regulation of pluripotency factor expression and proliferation in malignant germ cells, and thus is associated with the characteristically high cisplatin-sensitivity of these cells.	('Nodal signalling pathway', 'Pathway', (53, 77))	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('dysregulation', 'Var', (32, 45))	('involved', 'Reg', (81, 89))	('cisplatin-sensitivity', 'MPA', (241, 262))	('pluripotency factor expression', 'MPA', (111, 141))	('associated', 'Reg', (197, 207))
11686	32326899	In brief, cells were cultured in DMEM supplemented with 10% fetal bovine serum, glutamine (58.5 mg/ml), penicillin (100 U/ml) and streptomycin (100 mg/ml) at 37  C in a 5% CO2 atmosphere.	('glutamine', 'Chemical', 'MESH:D005973', (80, 89))	('100 mg/ml', 'Var', (144, 153))	('CO2', 'Chemical', 'MESH:D002245', (172, 175))	('100 U/ml', 'Var', (116, 124))	('58.5 mg/ml', 'Var', (91, 101))	('DMEM', 'Chemical', '-', (33, 37))	('streptomycin', 'Chemical', 'MESH:D013307', (130, 142))	('penicillin', 'Chemical', 'MESH:D010406', (104, 114))
11691	32326899	Proliferation of NTera2 cells was determined after 24 h and 48 h treatment with SB431542, and after co-treatments with SB431542 or recombinant Lefty and cisplatin.	('SB431542', 'Chemical', 'MESH:C459179', (80, 88))	('SB431542', 'Var', (80, 88))	('Lefty', 'Gene', (143, 148))	('NTera2', 'CellLine', 'CVCL:0034', (17, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('SB431542', 'Chemical', 'MESH:C459179', (119, 127))	('Proliferation', 'CPA', (0, 13))	('Lefty', 'Gene', '7044', (143, 148))
11696	32326899	Medium composition was: DMEM:F12, penicillin (100 U/ml), streptomycin (100 mg/ml), insulin, transferrin, selenium (x 1) and 10% fetal bovine serum.	('selenium', 'Chemical', 'MESH:D012643', (105, 113))	('DMEM', 'Chemical', '-', (24, 28))	('100', 'Var', (71, 74))	('F12', 'Chemical', 'MESH:C007782', (29, 32))	('penicillin', 'Chemical', 'MESH:D010406', (34, 44))	('streptomycin', 'Chemical', 'MESH:D013307', (57, 69))	('transferrin', 'Gene', '7018', (92, 103))	('insulin', 'Gene', (83, 90))	('transferrin', 'Gene', (92, 103))	('insulin', 'Gene', '3630', (83, 90))
11728	32326899	In contrast, treatment with SB431542 (40 muM, 20 muM and 4 muM) for 48 h resulted in significantly lower expression of pluripotency factors OCT4 (40 muM and 20 muM, P < 0.01, 4 muM, P < 0.05) and NANOG (P < 0.001) as well as NODAL, CRIPTO and LEFTY1 (all P < 0.001) in NTera2 cells (Fig.	('muM', 'Gene', '56925', (59, 62))	('pluripotency factors OCT4', 'MPA', (119, 144))	('NANOG', 'Gene', '79923', (196, 201))	('LEFTY1', 'Gene', '10637', (243, 249))	('muM', 'Gene', '56925', (177, 180))	('muM', 'Gene', (59, 62))	('NANOG', 'Gene', (196, 201))	('SB431542', 'Var', (28, 36))	('muM', 'Gene', (177, 180))	('expression', 'MPA', (105, 115))	('LEFTY1', 'Gene', (243, 249))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', '56925', (41, 44))	('lower', 'NegReg', (99, 104))	('muM', 'Gene', (41, 44))	('muM', 'Gene', (49, 52))	('muM', 'Gene', '56925', (160, 163))	('muM', 'Gene', (160, 163))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', (149, 152))	('NTera2', 'CellLine', 'CVCL:0034', (269, 275))	('SB431542', 'Chemical', 'MESH:C459179', (28, 36))
11739	32326899	None of the treatments significantly affected (P > 0.05) proliferation (BrdU+/mm2), apoptosis (cPARP+/mm2) or number of GCNIS cells (OCT4+/mm2) compared to the vehicle controls after 48 h (Fig.	('GCNIS', 'Chemical', '-', (120, 125))	('cPARP+/mm2', 'Var', (95, 105))	('apoptosis', 'CPA', (84, 93))	('BrdU', 'Chemical', 'MESH:D001973', (72, 76))
11742	32326899	However, co-treatment with 20 muM SB431542 and 1 muM cisplatin significantly increased (P < 0.05) proliferation compared to cells treated with 1 muM cisplatin only, indicating that the cells were less sensitive to the cisplatin treatment (Fig.	('muM', 'Gene', (30, 33))	('muM', 'Gene', '56925', (49, 52))	('muM', 'Gene', '56925', (145, 148))	('muM', 'Gene', (49, 52))	('SB431542', 'Chemical', 'MESH:C459179', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('muM', 'Gene', (145, 148))	('SB431542', 'Var', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (218, 227))	('increased', 'PosReg', (77, 86))	('muM', 'Gene', '56925', (30, 33))	('proliferation', 'CPA', (98, 111))
11743	32326899	Generally, there was a tendency towards reduced cisplatin-sensitivity when cells were co-treated with SB431542 and cisplatin regardless of the doses used, although for most combinations of doses this was not statistically significant (P > 0.05).	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('SB431542', 'Chemical', 'MESH:C459179', (102, 110))	('SB431542', 'Var', (102, 110))	('reduced', 'NegReg', (40, 47))	('cisplatin-sensitivity', 'MPA', (48, 69))
11747	32326899	The expression of CRIPTO was significantly reduced (P < 0.05) upon transfection with siCRIPTO compared to the siCTRL (Fig.	('transfection', 'Var', (67, 79))	('CRIPTO', 'Gene', (18, 24))	('siCRIPTO', 'Disease', 'None', (85, 93))	('expression', 'MPA', (4, 14))	('siCRIPTO', 'Disease', (85, 93))	('reduced', 'NegReg', (43, 50))
11753	32326899	7), while in mice treated with cisplatin alone and cisplatin + SB431542, the tumour size was significantly reduced (P < 0.01 and P < 0.001) compared to the vehicle controls already 3 days after the treatments were initiated.	('mice', 'Species', '10090', (13, 17))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('SB431542', 'Chemical', 'MESH:C459179', (63, 71))	('tumour', 'Disease', (77, 83))	('reduced', 'NegReg', (107, 114))	('cisplatin + SB431542', 'Var', (51, 71))	('cisplatin', 'Var', (31, 40))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
11754	32326899	However, no significant difference (P > 0.05) in tumour size was found between mice treated with cisplatin alone and cisplatin + SB431542 at any of the evaluated time-point (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('SB431542', 'Chemical', 'MESH:C459179', (129, 137))	('mice', 'Species', '10090', (79, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('cisplatin', 'Var', (117, 126))	('tumour', 'Disease', (49, 55))
11769	32326899	Aberrant re-activation of Nodal signalling has been reported in various types of cancers, including cancer stem cells which also express pluripotency factors, and several studies have shown that inhibition of Nodal/(Activin) signalling reduces the tumorigenic potential both in vitro and in cancer mouse models.	('re-activation', 'PosReg', (9, 22))	('Activin', 'Gene', (216, 223))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (291, 297))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('Activin', 'Gene', '83729', (216, 223))	('reduces', 'NegReg', (236, 243))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('mouse', 'Species', '10090', (298, 303))	('tumorigenic potential', 'CPA', (248, 269))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('inhibition', 'Var', (195, 205))
11772	32326899	Overall, we did not observe pronounced effects on cisplatin-sensitivity following inhibition of Nodal signalling in vitro or in the xenograft model, except tendencies toward reduced cisplatin-sensitivity after in vitro pharmaceutical inhibition of Nodal/Activin signalling and siRNA-mediated knockdown of the obligate co-receptor CRIPTO.	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('Activin', 'Gene', (254, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('Activin', 'Gene', '83729', (254, 261))	('cisplatin-sensitivity', 'MPA', (182, 203))	('reduced', 'NegReg', (174, 181))	('knockdown', 'Var', (292, 301))
11775	32326899	We speculate that inhibition of Nodal signalling promotes downregulation of pluripotency factor expression in the malignant germ cells driving them towards a more differentiated phenotype, which is associated with reduced cisplatin-sensitivity.	('cisplatin-sensitivity', 'MPA', (222, 243))	('pluripotency', 'Protein', (76, 88))	('downregulation', 'NegReg', (58, 72))	('more', 'PosReg', (158, 162))	('reduced', 'NegReg', (214, 221))	('inhibition', 'Var', (18, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (222, 231))
11779	32326899	In contrast to several other types of cancers in which the Nodal pathway is also re-activated, inhibition of Nodal (and Activin) signalling did not affect tumour cell proliferation or augment cisplatin-sensitivity in TGCTs in vitro or in the xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Activin', 'Gene', (120, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (192, 201))	('affect', 'Reg', (148, 154))	('inhibition', 'Var', (95, 105))	('cisplatin-sensitivity', 'MPA', (192, 213))	('Activin', 'Gene', '83729', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))	('augment', 'Reg', (184, 191))	('tumour', 'Disease', (155, 161))
11809	30112437	It is also associated with the loss of expression of MSH2 due to deletions in the epithelial cell adhesion molecule (EpCAM) gene.	('epithelial cell adhesion molecule', 'Gene', '4072', (82, 115))	('EpCAM', 'Gene', (117, 122))	('MSH2', 'Gene', (53, 57))	('MSH2', 'Gene', '4436', (53, 57))	('loss', 'NegReg', (31, 35))	('EpCAM', 'Gene', '4072', (117, 122))	('deletions', 'Var', (65, 74))	('expression', 'MPA', (39, 49))	('epithelial cell adhesion molecule', 'Gene', (82, 115))
11810	30112437	Urological tumors in Lynch syndrome are particularly associated with MSH2 mutation and MSH6.	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('MSH6', 'Gene', (87, 91))	('Lynch syndrome', 'Disease', 'MESH:D003123', (21, 35))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('MSH2', 'Gene', (69, 73))	('MSH6', 'Gene', '2956', (87, 91))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('associated', 'Reg', (53, 63))	('MSH2', 'Gene', '4436', (69, 73))	('Lynch syndrome', 'Disease', (21, 35))
11812	30112437	The first allele inactivation in patients with Lynch syndrome originates from the inherited germline mutation; the second allele is inactivated by another mechanism (somatic mutation, loss of heterozygosity or epigenetic silencing).	('epigenetic silencing', 'Var', (210, 230))	('germline', 'Var', (92, 100))	('patients', 'Species', '9606', (33, 41))	('Lynch syndrome', 'Disease', (47, 61))	('loss of heterozygosity', 'Var', (184, 206))	('Lynch syndrome', 'Disease', 'MESH:D003123', (47, 61))	('inactivation', 'NegReg', (17, 29))
11824	30112437	Excised tumors may initially be tested for microsatellite instability and immunohistochemistry as described above.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('microsatellite instability', 'Var', (43, 69))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
11829	30112437	However, it is well recognised as a Lynch-associated malignancy, especially in individuals with MSH2 and MSH6 gene mutation.	('MSH2', 'Gene', (96, 100))	('MSH6', 'Gene', (105, 109))	('MSH2', 'Gene', '4436', (96, 100))	('malignancy', 'Disease', 'MESH:D009369', (53, 63))	('malignancy', 'Disease', (53, 63))	('mutation', 'Var', (115, 123))	('MSH6', 'Gene', '2956', (105, 109))
11857	30112437	In particular, Skeldon et al examined the risk of bladder cancer in Canadian cohort of 321 patients with MMR gene mutations.	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (114, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('bladder cancer', 'Disease', (50, 64))	('MMR gene', 'Gene', (105, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))
11858	30112437	Of those with MSH2 mutations (n = 177), 6.21% of patients had bladder cancer (n = 11).	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (62, 76))	('mutations', 'Var', (19, 28))	('MSH2', 'Gene', (14, 18))	('MSH2', 'Gene', '4436', (14, 18))	('patients', 'Species', '9606', (49, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (62, 76))	('bladder cancer', 'Disease', (62, 76))
11859	30112437	When this was compared with the general Canadian population, the relative risk of bladder cancer in MSH2 carriers was significantly higher (p < 0.001) with earlier age of onset (59.6 years vs >70 years).	('higher', 'PosReg', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carriers', 'Var', (105, 113))	('MSH2', 'Gene', (100, 104))	('MSH2', 'Gene', '4436', (100, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))
11861	30112437	54 patients with bladder cancer were identified, with 86% having a MSH2 mutation.	('MSH2', 'Gene', (67, 71))	('MSH2', 'Gene', '4436', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('patients', 'Species', '9606', (3, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('bladder cancer', 'Disease', (17, 31))	('mutation', 'Var', (72, 80))
11876	30112437	It identified 23 studies (six molecular studies, 18 risk studies) that analysed data on prostate cancer in MMR gene mutation carriers.	('MMR', 'Gene', (107, 110))	('prostate cancer', 'Disease', (88, 103))	('mutation', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))
11877	30112437	It found that 74 percent (95% CI, range 57-85%) of prostate cancers in mutation carriers were MMR-deficient (especially MSH2 mutations).	('MMR-deficient', 'Disease', (94, 107))	('mutations', 'Var', (125, 134))	('MSH2', 'Gene', (120, 124))	('MMR-deficient', 'Disease', 'MESH:C536143', (94, 107))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('prostate cancers', 'Disease', 'MESH:D011471', (51, 67))	('mutation', 'Var', (71, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('MSH2', 'Gene', '4436', (120, 124))	('prostate cancers', 'Phenotype', 'HP:0012125', (51, 67))	('prostate cancers', 'Disease', (51, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
11885	30112437	The known susceptibility of BRCA mutation carriers to prostate cancer provides another interesting twist to this narrative, since the protein products of BRCA1 and BRCA2 are involved with DNA repair and other associated functions to stabilize DNA, similar to MMR proteins.	('BRCA', 'Gene', '672', (154, 158))	('mutation', 'Var', (33, 41))	('involved', 'Reg', (174, 182))	('BRCA', 'Gene', (164, 168))	('prostate cancer', 'Disease', (54, 69))	('BRCA1', 'Gene', (154, 159))	('DNA repair', 'MPA', (188, 198))	('BRCA', 'Gene', (154, 158))	('stabilize DNA', 'MPA', (233, 246))	('BRCA1', 'Gene', '672', (154, 159))	('BRCA', 'Gene', (28, 32))	('BRCA', 'Gene', '672', (28, 32))	('BRCA2', 'Gene', '675', (164, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('BRCA2', 'Gene', (164, 169))	('BRCA', 'Gene', '672', (164, 168))
11887	30112437	Barrow et al recommended a trial of PSA testing in MSH2 mutation carriers from 40-50 years.	('PSA', 'Disease', (36, 39))	('men', 'Species', '9606', (18, 21))	('MSH2', 'Gene', (51, 55))	('MSH2', 'Gene', '4436', (51, 55))	('mutation', 'Var', (56, 64))
11897	30112437	Conversely, Carcano et al found no microsatellite instability and normal MLH1 and MSH2 expression in all 133 specimens primary testicular germ cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('microsatellite', 'Var', (35, 49))	('MSH2', 'Gene', (82, 86))	('MSH2', 'Gene', '4436', (82, 86))	('men', 'Species', '9606', (114, 117))	('germ cell tumors', 'Phenotype', 'HP:0100728', (138, 154))	('expression', 'MPA', (87, 97))	('MLH1', 'Gene', '4292', (73, 77))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('MLH1', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
11899	30112437	The lack of microsatellite instability is more often observed in studies pertaining to primary testicular cancers, whereas, its presence may play a role in refractory or recurrent tumors.	('testicular cancers', 'Disease', (95, 113))	('role', 'Reg', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('testicular cancer', 'Phenotype', 'HP:0010788', (95, 112))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('microsatellite instability', 'Var', (12, 38))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('testicular cancers', 'Phenotype', 'HP:0010788', (95, 113))	('testicular cancers', 'Disease', 'MESH:D013736', (95, 113))	('play', 'Reg', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
11956	23840520	A colon tumor develops when a cell accumulates a sufficient set of mutations.	('colon tumor', 'Disease', 'MESH:D015179', (2, 13))	('colon tumor', 'Phenotype', 'HP:0100273', (2, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutations', 'Var', (67, 76))	('colon tumor', 'Disease', (2, 13))
11961	23840520	A tumor develops, and is diagnosed, when one of these cells accumulates a sufficient set of mutations.	('A tumor', 'Disease', 'MESH:D009369', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('A tumor', 'Disease', (0, 7))	('mutations', 'Var', (92, 101))
11970	23840520	Tumors are diagnosed when the first of many similar cells accumulate a sufficient set of mutations.	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (89, 98))
11973	23840520	A tumor is diagnosed when the first of these many similar cells has accumulated a sufficient set of mutations.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('A tumor', 'Disease', (0, 7))	('A tumor', 'Disease', 'MESH:D009369', (0, 7))
12007	23840520	Certain mutations in BRCA1 significantly increase the risk that a woman will develop breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('BRCA1', 'Gene', '672', (21, 26))	('breast cancer', 'Disease', (85, 98))	('increase', 'Reg', (41, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('BRCA1', 'Gene', (21, 26))	('mutations', 'Var', (8, 17))	('woman', 'Species', '9606', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
12008	23840520	However, these mutations are rare and less than 10% of breast cancers in the US population occur in women with these mutations.	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (55, 69))	('breast cancers', 'Disease', 'MESH:D001943', (55, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('breast cancers', 'Disease', (55, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('women', 'Species', '9606', (100, 105))
12017	23840520	Epigenetic alterations play a key role in the carcinogenesis process.	('Epigenetic alterations', 'Var', (0, 22))	('carcinogenesis', 'Disease', (46, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))
12059	20028501	With regard to late cardiovascular problems, cisplatin is thought to initiate degenerative processes of vessel walls, thus causing occlusive vascular disease in the long run.	('occlusive vascular disease', 'Phenotype', 'HP:0004950', (131, 157))	('degenerative processes', 'CPA', (78, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cardiovascular problems', 'Phenotype', 'HP:0001626', (20, 43))	('occlusive vascular disease', 'Disease', (131, 157))	('occlusive vascular disease', 'Disease', 'MESH:D008641', (131, 157))	('cisplatin', 'Var', (45, 54))	('causing', 'Reg', (123, 130))
12093	20028501	increased levels of von Willebrand factor and other thrombosis-associated factors in patients receiving cisplatinum as well as with cisplatin-induced hypomagnesemia and with clinical observations of arterial thromboses and even myocardial infarctions in TGCT patients undergoing chemotherapy.	('levels', 'MPA', (10, 16))	('hypomagnesemia', 'Disease', (150, 164))	('patients', 'Species', '9606', (259, 267))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('arterial thromboses', 'Phenotype', 'HP:0004420', (199, 218))	('von Willebrand factor', 'Gene', (20, 41))	('patients', 'Species', '9606', (85, 93))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (150, 164))	('TGCT', 'Phenotype', 'HP:0010788', (254, 258))	('cisplatinum', 'Var', (104, 115))	('hypomagnesemia', 'Disease', 'MESH:C537153', (150, 164))	('cisplatinum', 'Chemical', 'MESH:D002945', (104, 115))	('von Willebrand factor', 'Gene', '7450', (20, 41))	('myocardial infarctions', 'Disease', 'MESH:D009203', (228, 250))	('myocardial infarctions', 'Phenotype', 'HP:0001658', (228, 250))	('thrombosis', 'Disease', 'MESH:D013927', (52, 62))	('arterial thromboses', 'CPA', (199, 218))	('increased', 'PosReg', (0, 9))	('thrombosis', 'Disease', (52, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))	('myocardial infarctions', 'Disease', (228, 250))
12117	12459049	Ectopic hTERT expression in combination with two oncogenes (SV40 large-T and H-ras) has been shown to cause tumorigenic conversion of normal human epithelial and fibroblast cells in experimental settings.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cause', 'Reg', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('hTERT', 'Gene', '7015', (8, 13))	('human', 'Species', '9606', (141, 146))	('Ectopic', 'Var', (0, 7))	('hTERT', 'Gene', (8, 13))	('men', 'Species', '9606', (188, 191))
12124	12459049	immortalization by reactivation of telomerase, already exists and thus accelerates carcinogenesis.	('reactivation', 'Var', (19, 31))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('telomerase', 'Protein', (35, 45))	('carcinogenesis', 'Disease', (83, 97))	('accelerates', 'PosReg', (71, 82))
12258	30419889	For both, the QLQ-C30 and the QLQ-TC26, high impairment is indicated by low scores for the functioning scales and high scores for the symptom scales.	('functioning scales', 'MPA', (91, 109))	('QLQ-C30', 'Var', (14, 21))	('men', 'Species', '9606', (51, 54))	('QLQ-TC26', 'Chemical', '-', (30, 38))	('QLQ-TC26', 'Var', (30, 38))	('low', 'NegReg', (72, 75))
12358	28447668	Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity.	('pancreatic', 'Disease', (49, 59))	('regulatory activity', 'MPA', (173, 192))	('decreased lung cancer', 'Disease', 'MESH:D008175', (79, 100))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('melanoma', 'Disease', (105, 113))	('enhanced', 'PosReg', (164, 172))	('decreased lung', 'Phenotype', 'HP:0002089', (79, 93))	('decreased lung cancer', 'Disease', (79, 100))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('increased', 'PosReg', (39, 48))	('preferred protein-binding', 'Interaction', (134, 159))	('rs36115365-C', 'Var', (10, 22))	('pancreatic', 'Disease', 'MESH:D010195', (49, 59))	('rs36115365', 'Mutation', 'rs36115365', (10, 20))
12360	28447668	Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148.	('Zinc finger protein 148', 'Gene', (58, 81))	('rs36115365', 'Mutation', 'rs36115365', (94, 104))	('Zinc finger protein 148', 'Gene', '7707', (58, 81))	('binding', 'Interaction', (129, 136))	('ZNF148', 'Gene', (83, 89))	('rs36115365-C', 'Var', (94, 106))	('binding', 'Interaction', (47, 54))
12362	28447668	Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.	('rs36115365', 'Mutation', 'rs36115365', (87, 97))	('rs36115365', 'Var', (87, 97))	('TERT', 'Gene', (185, 189))	('TERT', 'Gene', '7015', (185, 189))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('influencing', 'Reg', (109, 120))
12363	28447668	Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers.	('susceptibility', 'Reg', (74, 88))	('numerous cancers', 'Disease', 'MESH:D009369', (92, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('associated', 'Reg', (58, 68))	('chr5p15.33', 'Gene', (37, 47))	('numerous cancers', 'Disease', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Genetic variants', 'Var', (0, 16))
12364	28447668	Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.	('telomerase reverse transcriptase', 'Gene', '7015', (119, 151))	('rs36115365', 'Var', (95, 105))	('TERT', 'Gene', '7015', (153, 157))	('influencing', 'Reg', (107, 118))	('rs36115365', 'Mutation', 'rs36115365', (95, 105))	('telomerase reverse transcriptase', 'Gene', (119, 151))	('TERT', 'Gene', (153, 157))
12365	28447668	Risk variants across a small genomic region on chromosome 5p15.33 have been reported in genome wide association studies (GWAS) for at least eleven cancer types including bladder, breast, glioma, lung, melanoma, non-melanoma skin cancer, ovarian, pancreas, prostate, testicular germ cell cancer and chronic lymphocytic leukaemia.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('cancer', 'Disease', (287, 293))	('melanoma', 'Disease', (215, 223))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('glioma', 'Disease', (187, 193))	('ovarian, pancreas', 'Disease', 'MESH:D010190', (237, 254))	('prostate', 'Disease', (256, 264))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (211, 235))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('chronic lymphocytic leukaemia', 'Disease', 'MESH:D015451', (298, 327))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (298, 327))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('non-melanoma skin cancer', 'Disease', (211, 235))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('skin cancer', 'Phenotype', 'HP:0008069', (224, 235))	('bladder', 'Disease', (170, 177))	('breast', 'Disease', (179, 185))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('germ cell cancer', 'Phenotype', 'HP:0100728', (277, 293))	('chronic lymphocytic leukaemia', 'Disease', (298, 327))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('lung', 'Disease', (195, 199))	('variants', 'Var', (5, 13))	('cancer', 'Disease', (147, 153))
12372	28447668	), originally reported to be associated with risk of pancreatic, lung, bladder cancer, and melanoma, marked by either rs401681 or rs402710 (refs).	('lung', 'Disease', (65, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('pancreatic', 'Disease', 'MESH:D010195', (53, 63))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('pancreatic', 'Disease', (53, 63))	('melanoma', 'Disease', (91, 99))	('rs401681', 'Mutation', 'rs401681', (118, 126))	('rs401681', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('bladder cancer', 'Disease', (71, 85))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('rs402710', 'Mutation', 'rs402710', (130, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('rs402710', 'Var', (130, 138))
12373	28447668	By conducting fine-mapping across multiple cancers and subsequently investigating the functional consequences of the subset of genetic variants most strongly associated with cancer risk, we find that risk of pancreatic, testicular and lung cancer conferred by this locus may predominantly be explained by a single-SNP.	('testicular', 'Disease', (220, 230))	('multiple cancers', 'Disease', 'MESH:D009369', (34, 50))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancer', 'Disease', (240, 246))	('pancreatic', 'Disease', 'MESH:D010195', (208, 218))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('associated', 'Reg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (174, 180))	('multiple cancers', 'Disease', (34, 50))	('lung cancer', 'Disease', (235, 246))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('pancreatic', 'Disease', (208, 218))	('variants', 'Var', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
12374	28447668	This variant, rs36115365, exhibited preferred protein-binding and enhanced regulatory activity for the C-allele, associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk.	('pancreatic', 'Disease', 'MESH:D010195', (139, 149))	('rs36115365', 'Mutation', 'rs36115365', (14, 24))	('regulatory activity', 'MPA', (75, 94))	('pancreatic', 'Disease', (139, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('decreased lung', 'Phenotype', 'HP:0002089', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('decreased lung cancer', 'Disease', 'MESH:D008175', (169, 190))	('increased', 'PosReg', (129, 138))	('enhanced', 'PosReg', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('decreased lung cancer', 'Disease', (169, 190))	('rs36115365', 'Var', (14, 24))	('protein-binding', 'Interaction', (46, 61))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))
12375	28447668	Transcriptional gene silencing of the regulatory region encompassing this variant resulted in repression of TERT but not CLPTM1L expression in an allele-specific manner.	('repression', 'NegReg', (94, 104))	('expression', 'MPA', (129, 139))	('variant', 'Var', (74, 81))	('CLPTM1L', 'Gene', '81037', (121, 128))	('TERT', 'Gene', (108, 112))	('TERT', 'Gene', '7015', (108, 112))	('CLPTM1L', 'Gene', (121, 128))
12376	28447668	Proteomic analysis identified allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, a finding supported by binding of purified recombinant ZNF148 specifically to the C-allele, as well as by ChIP analysis showing allele-preferential binding of endogenous ZNF148 to rs36115365-C. Knockdown of ZNF148 resulted in reduced TERT expression, telomerase activity and telomere length.	('telomerase', 'CPA', (359, 369))	('Zinc finger protein 148', 'Gene', (58, 81))	('TERT', 'Gene', (342, 346))	('reduced', 'NegReg', (334, 341))	('rs36115365-C', 'Var', (94, 106))	('ZNF148', 'Gene', (315, 321))	('TERT', 'Gene', '7015', (342, 346))	('rs36115365', 'Mutation', 'rs36115365', (94, 104))	('Zinc finger protein 148', 'Gene', '7707', (58, 81))	('rs36115365', 'Mutation', 'rs36115365', (288, 298))	('telomere length', 'CPA', (383, 398))	('Knockdown', 'Var', (302, 311))	('rs36115365-C. Knockdown', 'Var', (288, 311))	('activity', 'MPA', (370, 378))	('binding', 'Interaction', (47, 54))
12377	28447668	Taken together, these results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT via ZNF148 in a manner consistent with elevated TERT expression in carriers of the C allele.	('rs36115365', 'Var', (105, 115))	('TERT', 'Gene', '7015', (139, 143))	('TERT', 'Gene', (192, 196))	('TERT', 'Gene', '7015', (192, 196))	('rs36115365', 'Mutation', 'rs36115365', (105, 115))	('association', 'Interaction', (48, 59))	('TERT', 'Gene', (139, 143))	('influencing', 'Reg', (127, 138))	('elevated', 'PosReg', (183, 191))
12378	28447668	We performed imputation and fine-mapping of the multi-cancer risk locus in the CLPTM1L gene (Region 2, originally marked by rs401681 and rs402710) using GWAS data for four cancers previously shown to have associations with this locus, namely pancreatic, testicular and lung cancer, and melanoma.	('pancreatic', 'Disease', 'MESH:D010195', (242, 252))	('rs401681', 'Mutation', 'rs401681', (124, 132))	('lung cancer', 'Disease', (269, 280))	('CLPTM1L', 'Gene', '81037', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('rs402710', 'Var', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('melanoma', 'Disease', (286, 294))	('pancreatic', 'Disease', (242, 252))	('multi-cancer', 'Disease', (48, 60))	('multi-cancer', 'Disease', 'MESH:D009369', (48, 60))	('CLPTM1L', 'Gene', (79, 86))	('rs402710', 'Mutation', 'rs402710', (137, 145))	('testicular', 'Disease', (254, 264))	('lung cancer', 'Disease', 'MESH:D008175', (269, 280))	('rs401681', 'Var', (124, 132))	('associations', 'Interaction', (205, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('melanoma', 'Disease', 'MESH:D008545', (286, 294))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
12379	28447668	For pancreatic cancer, fine-mapping identified SNPs with P values significantly lower than the previously published association signal marked by rs401681, with rs451360 being the smallest (P=2.0 x 10-10 for rs451360; P=3.7 x 10-7 for rs401681; Supplementary Table 1).	('pancreatic cancer', 'Disease', (4, 21))	('rs401681', 'Mutation', 'rs401681', (234, 242))	('rs451360', 'Mutation', 'rs451360', (160, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (4, 21))	('rs401681', 'Mutation', 'rs401681', (145, 153))	('rs451360', 'Var', (207, 215))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('lower', 'NegReg', (80, 85))	('rs451360', 'Mutation', 'rs451360', (207, 215))	('rs451360', 'Var', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('rs401681', 'Var', (234, 242))
12381	28447668	Fine-mapping of Region 2 for testicular germ cell tumours (TGCT) and lung cancer revealed that the strongest SNP for each was among this group of nine SNPs (rs35953391 for TGCT, P=1.08 x 10-9; and rs37004 for lung cancer, P=1.18 x 10-13; Supplementary Table 1).	('germ cell tumour', 'Phenotype', 'HP:0100728', (40, 56))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (29, 57))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Disease', (209, 220))	('rs37004', 'Var', (197, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('rs35953391', 'Mutation', 'rs35953391', (157, 167))	('testicular germ cell tumours', 'Disease', (29, 57))	('TGCT', 'Disease', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung cancer', 'Disease', (69, 80))	('rs35953391', 'Var', (157, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('rs37004', 'Mutation', 'rs37004', (197, 204))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
12382	28447668	Conditional analysis for the most significant SNP across each cancer resulted in a substantial loss of the signal for the other eight SNPs in pancreatic (PConditional=0.47-0.91), testicular (PConditional=0.21-0.92) and lung cancer (PConditional=0.09-0.45).	('pancreatic', 'Disease', 'MESH:D010195', (142, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('pancreatic', 'Disease', (142, 152))	('lung cancer', 'Disease', (219, 230))	('SNP', 'Var', (46, 49))	('signal', 'MPA', (107, 113))	('cancer', 'Disease', (62, 68))	('testicular', 'Disease', (179, 189))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('lung cancer', 'Disease', 'MESH:D008175', (219, 230))	('loss', 'NegReg', (95, 99))	('cancer', 'Disease', (224, 230))
12386	28447668	We also noted in the 1000G Phase 3, version 1 reference dataset an insertion/deletion variant that was highly correlated with these nine SNPs (rs3030832, r2=0.96 to rs451360 in EUR) that had not been included in the imputation reference based off an earlier version (1000G Phase 1, version 3).	('insertion/deletion', 'Var', (67, 85))	('rs451360', 'Mutation', 'rs451360', (165, 173))	('rs451360', 'Var', (165, 173))	('rs3030832', 'Mutation', 'rs3030832', (143, 152))	('rs3030832', 'Var', (143, 152))
12387	28447668	We therefore re-imputed the pancreatic cancer GWAS with the newer 1000G reference set and observed an association signal similar in strength and significance to that of the other nine variants (rs3030832, P=8.25 x 10-10, OR=1.28 95% CI 1.18-1.39; Supplementary Table 2) indicating that this indel variant should likewise be considered a candidate functional risk variant.	('rs3030832', 'Mutation', 'rs3030832', (194, 203))	('pancreatic cancer', 'Disease', (28, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('rs3030832', 'Var', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))
12388	28447668	Overall, these ten variants extend across the entire length of CLPTM1L, from the promoter to ~6 kb downstream of the gene (Fig.	('CLPTM1L', 'Gene', (63, 70))	('extend', 'Reg', (28, 34))	('variants', 'Var', (19, 27))	('CLPTM1L', 'Gene', '81037', (63, 70))
12389	28447668	Three variants, rs36115365, rs380145 and rs27071, are located within potential gene regulatory regions, annotated by the ENCODE project (Fig.	('rs27071', 'Var', (41, 48))	('rs36115365', 'Mutation', 'rs36115365', (16, 26))	('rs380145', 'Var', (28, 36))	('rs27071', 'Mutation', 'rs27071', (41, 48))	('rs380145', 'Mutation', 'rs380145', (28, 36))	('rs36115365', 'Var', (16, 26))
12390	28447668	We sought to assess whether any of the ten highly correlated sequence variants influence differential protein binding via electrophoretic mobility shift assays (EMSA) in the PANC-1 and/or MIA PaCa-2 pancreatic cancer cell lines (Fig.	('protein', 'Protein', (102, 109))	('electrophoretic mobility shift assays', 'MPA', (122, 159))	('MIA PaCa-2 pancreatic cancer', 'Disease', (188, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('variants', 'Var', (70, 78))	('influence', 'Reg', (79, 88))	('PANC-1', 'CellLine', 'CVCL:0480', (174, 180))	('MIA PaCa-2 pancreatic cancer', 'Disease', 'MESH:D010190', (188, 216))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('differential', 'MPA', (89, 101))
12391	28447668	Only rs36115365 exhibited allele-specific binding (Fig.	('rs36115365', 'Var', (5, 15))	('rs36115365', 'Mutation', 'rs36115365', (5, 15))	('binding', 'Interaction', (42, 49))
12393	28447668	EMSA assays for rs36115365 in seven additional cancer cell lines, including pancreatic cancer (MIA PaCa-2, Supplementary Fig.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('pancreatic cancer', 'Disease', (76, 93))	('rs36115365', 'Mutation', 'rs36115365', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rs36115365', 'Var', (16, 26))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))
12398	28447668	3d) showed a similar pattern of allele-preferential binding to the C allele of rs36115365.	('binding', 'Interaction', (52, 59))	('rs36115365', 'Var', (79, 89))	('rs36115365', 'Mutation', 'rs36115365', (79, 89))
12400	28447668	The region harbouring rs36115365 demonstrated an allele-specific increase in luciferase reporter activity as compared to empty vector that was consistent across all eight cancer cell lines tested (Fig.	('increase', 'PosReg', (65, 73))	('luciferase', 'Enzyme', (77, 87))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('rs36115365', 'Mutation', 'rs36115365', (22, 32))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('rs36115365', 'Var', (22, 32))
12402	28447668	Transcriptional activity of the genomic region surrounding rs36115365 (240 bp) was higher in the forward (plasmids FG and FC) as compared to the reverse (plasmids RG and RC) orientation.	('rs36115365', 'Var', (59, 69))	('rs36115365', 'Mutation', 'rs36115365', (59, 69))	('higher', 'PosReg', (83, 89))	('Transcriptional activity', 'MPA', (0, 24))
12404	28447668	Analysis of imputed GWAS data from pancreatic and testicular cancers conditioned on rs36115365 are consistent with rs36115365 accounting for the majority of the Region 2 signal (PConditional=0.03-0.99 and PConditional=0.22-0.92, respectively for the grouping of eight SNPs highly correlated with rs36115365; Supplementary Table 1), with the minor C allele being positively associated with risk.	('rs36115365', 'Mutation', 'rs36115365', (115, 125))	('testicular cancer', 'Phenotype', 'HP:0010788', (50, 67))	('rs36115365', 'Mutation', 'rs36115365', (84, 94))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('rs36115365', 'Var', (296, 306))	('testicular cancers', 'Phenotype', 'HP:0010788', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('rs36115365', 'Var', (115, 125))	('pancreatic and testicular cancers', 'Disease', 'MESH:D010190', (35, 68))	('rs36115365', 'Mutation', 'rs36115365', (296, 306))	('rs36115365', 'Var', (84, 94))
12405	28447668	In lung cancer and melanoma, however, fine-mapping data suggest that the genetic architecture underlying risk in Region 2 may be more complex, but are nonetheless consistent with a functional role for rs36115365.	('lung cancer', 'Disease', (3, 14))	('rs36115365', 'Mutation', 'rs36115365', (201, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('rs36115365', 'Var', (201, 211))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
12406	28447668	For lung, in contrast to pancreatic and testicular cancers, the C allele of rs36115365 is negatively associated with risk.	('lung', 'Disease', (4, 8))	('negatively', 'NegReg', (90, 100))	('testicular cancer', 'Phenotype', 'HP:0010788', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('rs36115365', 'Var', (76, 86))	('pancreatic and testicular cancers', 'Disease', 'MESH:D010190', (25, 58))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('testicular cancers', 'Phenotype', 'HP:0010788', (40, 58))	('rs36115365', 'Mutation', 'rs36115365', (76, 86))
12407	28447668	Conditioning on rs36115365 revealed a possible secondary signal for lung cancer risk within the eight highly correlated SNPs (PConditional=3.74 x 10-5-0.11; Supplementary Table 1).	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('rs36115365', 'Mutation', 'rs36115365', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('rs36115365', 'Var', (16, 26))
12408	28447668	For melanoma, rs36115365 was not significant in single-SNP analysis (P=0.70), but became more significant after conditioning on the best Region 2 SNP (rs2447853, PConditional=1.09 x 10-4; Supplementary Table 1), with the C allele also being negatively associated with risk (OR=0.86; 95% CI 0.80-0.93).	('negatively', 'NegReg', (241, 251))	('rs2447853', 'Var', (151, 160))	('rs36115365', 'Mutation', 'rs36115365', (14, 24))	('rs2447853', 'Mutation', 'rs2447853', (151, 160))	('rs36115365', 'Var', (14, 24))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
12409	28447668	After conditioning on rs36115365 for melanoma, rs2447853 also becomes more significant (PConditional=3.01 x 10-15 versus P=5.7 x 10-12).	('rs2447853', 'Mutation', 'rs2447853', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('rs36115365', 'Mutation', 'rs36115365', (22, 32))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('rs2447853', 'Var', (47, 56))	('rs36115365', 'Var', (22, 32))
12410	28447668	These data suggest rs36115365 may influence gene expression within the TERT-CLPTM1L region and may account for either some or the entire association signal in this region, depending on the cancer type.	('rs36115365', 'Var', (19, 29))	('gene expression', 'MPA', (44, 59))	('TERT', 'Gene', (71, 75))	('TERT', 'Gene', '7015', (71, 75))	('account', 'Reg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('influence', 'Reg', (34, 43))	('rs36115365', 'Mutation', 'rs36115365', (19, 29))	('CLPTM1L', 'Gene', '81037', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CLPTM1L', 'Gene', (76, 83))	('cancer', 'Disease', (189, 195))
12411	28447668	To interrogate whether the putative gene regulatory region harbouring rs36115365 influences expression of TERT and/or CLPTM1L, siRNA mediated transcriptional gene silencing (TGS) (refs) was used to target across this region to evaluate effects on gene expression.	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('expression', 'MPA', (92, 102))	('rs36115365', 'Var', (70, 80))	('CLPTM1L', 'Gene', '81037', (118, 125))	('rs36115365', 'Mutation', 'rs36115365', (70, 80))	('CLPTM1L', 'Gene', (118, 125))	('influences', 'Reg', (81, 91))
12413	28447668	5) showed significant inhibition of TERT mRNA expression by RT-qPCR in all four cell lines tested compared to a scrambled siRNA control, suggesting a role for the targeted region in the regulation of TERT expression.	('TERT', 'Gene', '7015', (36, 40))	('RT-qPCR', 'Var', (60, 67))	('inhibition', 'NegReg', (22, 32))	('TERT', 'Gene', (200, 204))	('TERT', 'Gene', (36, 40))	('TERT', 'Gene', '7015', (200, 204))
12420	28447668	These data suggest that the genomic region harbouring rs36115365 plays a key role in the regulation of TERT, but not CLPTM1L, expression.	('rs36115365', 'Var', (54, 64))	('expression', 'MPA', (126, 136))	('CLPTM1L', 'Gene', '81037', (117, 124))	('rs36115365', 'Mutation', 'rs36115365', (54, 64))	('CLPTM1L', 'Gene', (117, 124))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))
12422	28447668	The human TERT gene harbours a synonymous SNP in exon 2 (rs2736098), linked to rs36115365 (r2=0.14, D'=1.0 in 1000G CEU), allowing for assessment of expression of TERT from chromosomes harbouring the C and G alleles of rs36115365 in cell lines heterozygous for both SNPs.	('TERT', 'Gene', '7015', (163, 167))	('rs2736098', 'Var', (57, 66))	('rs2736098', 'Mutation', 'rs2736098', (57, 66))	('human', 'Species', '9606', (4, 9))	('rs36115365', 'Var', (219, 229))	('TERT', 'Gene', (10, 14))	('TERT', 'Gene', '7015', (10, 14))	('rs36115365', 'Mutation', 'rs36115365', (79, 89))	('TERT', 'Gene', (163, 167))	('rs36115365', 'Mutation', 'rs36115365', (219, 229))
12423	28447668	We screened genomic DNA and complementary DNA (cDNA) from 55 pancreatic cell lines, as well as the melanoma, lung and testis cancer cell lines from the NCI60 panel to identify cell lines that are both heterozygous for rs36115365 and express two different alleles of rs2736098, yielding two assayable pancreatic cancer cell lines (Panc 05.04, IMIM-PC-1) and one lung cancer cell line (A549).	('pancreatic', 'Disease', (300, 310))	('rs2736098', 'Mutation', 'rs2736098', (266, 275))	('A549', 'CellLine', 'CVCL:0023', (384, 388))	('lung cancer', 'Disease', 'MESH:D008175', (361, 372))	('rs36115365', 'Mutation', 'rs36115365', (218, 228))	('testis cancer', 'Disease', (118, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (300, 317))	('pancreatic', 'Disease', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('lung cancer', 'Phenotype', 'HP:0100526', (361, 372))	('pancreatic cancer', 'Disease', (300, 317))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('IMIM-PC-1', 'CellLine', 'CVCL:4061', (342, 351))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic', 'Disease', 'MESH:D010195', (300, 310))	('testis cancer', 'Phenotype', 'HP:0010788', (118, 131))	('testis cancer', 'Disease', 'MESH:D013736', (118, 131))	('lung cancer', 'Disease', (361, 372))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (300, 317))	('rs2736098', 'Var', (266, 275))	('pancreatic', 'Disease', 'MESH:D010195', (61, 71))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('rs36115365', 'Var', (218, 228))
12426	28447668	We evaluated allele-specific levels of inhibition of TERT expression by siRNA3 (which is both closest to rs36115365 and most consistently inhibits TERT expression across the cell lines previously tested) in these three cell lines using a TaqMan allelic-discrimination assay for rs2736098.	('rs36115365', 'Var', (105, 115))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('TERT', 'Gene', (147, 151))	('inhibits', 'NegReg', (138, 146))	('rs36115365', 'Mutation', 'rs36115365', (105, 115))	('TERT', 'Gene', '7015', (147, 151))	('rs2736098', 'Mutation', 'rs2736098', (278, 287))	('siRNA3', 'Gene', (72, 78))
12428	28447668	These results indicate that rs36115365 lies in a gene-regulatory element that influences TERT expression in an allele-specific manner.	('influences', 'Reg', (78, 88))	('rs36115365', 'Var', (28, 38))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('rs36115365', 'Mutation', 'rs36115365', (28, 38))
12429	28447668	To investigate the underlying mechanism of the differential gene regulation by genotypes at rs36115365, and to identify transcription factors potentially mediating this effect, we performed pull-down with oligonucleotides corresponding to the C or the G allele of rs36115365 incubated with nuclear extracts from PANC-1 and UACC903 cell lines, followed by quantitative mass spectrometry.	('rs36115365', 'Mutation', 'rs36115365', (92, 102))	('rs36115365', 'Var', (264, 274))	('rs36115365', 'Var', (92, 102))	('PANC-1', 'CellLine', 'CVCL:0480', (312, 318))	('rs36115365', 'Mutation', 'rs36115365', (264, 274))	('oligonucleotides', 'Chemical', 'MESH:D009841', (205, 221))
12430	28447668	Three proteins (ZNF148, VEZF1/ZNF161 and ZNF281) were identified as binding the C variant of rs36115365 preferentially in label-swapping experiments performed across both PANC-1 and UACC903 cell lines using a poly-dAdT competitor (Fig.	('VEZF1', 'Gene', '7716', (24, 29))	('binding', 'Interaction', (68, 75))	('rs36115365', 'Mutation', 'rs36115365', (93, 103))	('ZNF281', 'Gene', (41, 47))	('preferentially', 'PosReg', (104, 118))	('ZNF161', 'Gene', '7716', (30, 36))	('VEZF1', 'Gene', (24, 29))	('poly-dAdT', 'Chemical', 'MESH:D011067', (209, 218))	('PANC-1', 'CellLine', 'CVCL:0480', (171, 177))	('ZNF281', 'Gene', '23528', (41, 47))	('rs36115365', 'Var', (93, 103))	('ZNF161', 'Gene', (30, 36))
12435	28447668	Furthermore, EMSAs using recombinant purified ZNF148 protein demonstrated specific binding of ZNF148 to the C allele of rs36115365 (Fig.	('ZNF148', 'Gene', (94, 100))	('rs36115365', 'Var', (120, 130))	('binding', 'Interaction', (83, 90))	('rs36115365', 'Mutation', 'rs36115365', (120, 130))
12436	28447668	Notably, the resulting band had similar mobility characteristics to both those from EMSAs of ZNF148 bound to a known binding site in the CDKN1A/p21 promoter, as well as the C allele-specific band for rs36115365 using PANC-1 nuclear extracts (Fig.	('ZNF148', 'Gene', (93, 99))	('rs36115365', 'Mutation', 'rs36115365', (200, 210))	('p21', 'Gene', (144, 147))	('CDKN1A', 'Gene', (137, 143))	('bound', 'Reg', (100, 105))	('CDKN1A', 'Gene', '1026', (137, 143))	('rs36115365', 'Var', (200, 210))	('PANC-1', 'CellLine', 'CVCL:0480', (217, 223))	('p21', 'Gene', '1026', (144, 147))
12437	28447668	Consistent with these data, ZNF148, (also named ZBP-89) a zinc-finger transcription factor of the kruppel-like family, is predicted to bind to a consensus DNA-recognition motif created by the C-allele of rs36115365 (Fig.	('ZBP-89', 'Gene', (48, 54))	('rs36115365', 'Mutation', 'rs36115365', (204, 214))	('bind', 'Interaction', (135, 139))	('rs36115365', 'Var', (204, 214))	('ZNF148', 'Gene', (28, 34))	('ZBP-89', 'Gene', '7707', (48, 54))
12438	28447668	To further establish the binding of ZNF148 to rs36115365 and surrounding genomic region, we performed chromatin-immunoprecipitation (ChIP) for ZNF148 followed by quantitative PCR, noting an enrichment of binding at rs36115365 in pancreatic and lung cancer cell lines homozygous and heterozygous for rs36115365-C as compared to background and the surrounding area (Fig.	('rs36115365', 'Mutation', 'rs36115365', (299, 309))	('rs36115365', 'Mutation', 'rs36115365', (46, 56))	('pancreatic and lung cancer', 'Disease', 'MESH:D010190', (229, 255))	('rs36115365', 'Mutation', 'rs36115365', (215, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('binding', 'Interaction', (204, 211))	('rs36115365-C', 'Var', (299, 311))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('rs36115365', 'Var', (215, 225))
12447	28447668	This reduction was similar to that observed via siRNA-mediated depletion of TERT itself, or by transcriptional gene silencing (TGS, siRNA3) to target the gene regulatory element encompassing rs36115365.	('TERT', 'Gene', '7015', (76, 80))	('rs36115365', 'Var', (191, 201))	('reduction', 'NegReg', (5, 14))	('rs36115365', 'Mutation', 'rs36115365', (191, 201))	('silencing', 'NegReg', (116, 125))	('TERT', 'Gene', (76, 80))
12450	28447668	Consistent with these data, depletion of either ZNF148 or TERT, or alternatively targeting the rs36115365 regulatory region in both A549 and MIA PaCa-2 cells all resulted in similar reductions of telomere length (Fig.	('telomere length', 'MPA', (196, 211))	('rs36115365', 'Var', (95, 105))	('A549', 'CellLine', 'CVCL:0023', (132, 136))	('rs36115365', 'Mutation', 'rs36115365', (95, 105))	('reductions', 'NegReg', (182, 192))	('TERT', 'Gene', (58, 62))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (141, 151))	('TERT', 'Gene', '7015', (58, 62))	('ZNF148', 'Gene', (48, 54))	('depletion', 'MPA', (28, 37))
12453	28447668	One of these susceptibility loci termed Region 2, initially marked by rs401681 and rs402710 in CLPTM1L, was fine-mapped in a subset-based meta-analysis across multiple cancer types and is the focus of the current study.	('CLPTM1L', 'Gene', (95, 102))	('rs402710', 'Mutation', 'rs402710', (83, 91))	('rs402710', 'Var', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('multiple cancer', 'Disease', 'MESH:D009369', (159, 174))	('rs401681', 'Mutation', 'rs401681', (70, 78))	('rs401681', 'Var', (70, 78))	('multiple cancer', 'Disease', (159, 174))	('CLPTM1L', 'Gene', '81037', (95, 102))
12454	28447668	The ten variants that mark Region 2 span the whole length of CLPTM1L to ~17 kb upstream of the transcriptional start site of TERT.	('CLPTM1L', 'Gene', '81037', (61, 68))	('CLPTM1L', 'Gene', (61, 68))	('variants', 'Var', (8, 16))	('TERT', 'Gene', (125, 129))	('TERT', 'Gene', '7015', (125, 129))
12455	28447668	Here, we identify rs36115365 as a functional SNP in this region and provide a plausible biological explanation underlying risk, featuring altered TERT, but not CLPTM1L, expression.	('rs36115365', 'Mutation', 'rs36115365', (18, 28))	('altered', 'Reg', (138, 145))	('rs36115365', 'Var', (18, 28))	('TERT', 'Gene', (146, 150))	('CLPTM1L', 'Gene', '81037', (160, 167))	('TERT', 'Gene', '7015', (146, 150))	('CLPTM1L', 'Gene', (160, 167))
12457	28447668	Little signal remained within Region 2 after accounting for rs36115365 or alternatively the respective most significant SNP in pancreatic and testicular cancer, consistent with the notion that one or more of these variants (and/or an as-of-yet unidentified variant tightly linked with these SNPs) is responsible for mediating cancer risk attributable to this locus.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('rs36115365', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('pancreatic and testicular cancer', 'Disease', 'MESH:D010190', (127, 159))	('rs36115365', 'Mutation', 'rs36115365', (60, 70))	('cancer', 'Disease', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('variants', 'Var', (214, 222))	('testicular cancer', 'Phenotype', 'HP:0010788', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
12458	28447668	For lung cancer, residual signal was seen after conditional analysis on rs36115365 (PConditional=3.74 x 10-5 to 7.71 x 10-4), indicating that this SNP may not explain the entire Region 2 signal for lung cancer.	('lung cancer', 'Disease', (198, 209))	('rs36115365', 'Mutation', 'rs36115365', (72, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('rs36115365', 'Var', (72, 82))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('to 7', 'Species', '1214577', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
12459	28447668	For melanoma, a SNP (rs2447853) highly correlated to the original GWAS SNP reported for these cancers (rs401681, r2=0.97) represents the most significant SNP in Region 2 (ref.).	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('rs401681', 'Mutation', 'rs401681', (103, 111))	('rs2447853', 'Mutation', 'rs2447853', (21, 30))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('rs2447853', 'Var', (21, 30))	('cancers', 'Disease', (94, 101))
12460	28447668	Although rs36115365 was non-significant in single-SNP analyses, it became more significant after conditioning on rs2447853 (PConditional=1.09 x 10-4).	('rs36115365', 'Var', (9, 19))	('rs36115365', 'Mutation', 'rs36115365', (9, 19))	('rs2447853', 'Mutation', 'rs2447853', (113, 122))	('rs2447853', 'Var', (113, 122))
12461	28447668	The LD structure between these SNPs and conditional analyses suggest that in melanoma both may mark independent functional variants, with the signal at rs2447853 masking the association between rs36115365 and melanoma risk in single-SNP analysis.	('rs2447853', 'Var', (152, 161))	('rs36115365', 'Mutation', 'rs36115365', (194, 204))	('masking', 'NegReg', (162, 169))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('rs2447853', 'Mutation', 'rs2447853', (152, 161))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('rs36115365', 'Var', (194, 204))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))
12462	28447668	In contrast with the other variants, preferred protein binding was seen on the minor (C) allele of rs36115365 across multiple cell lines representing all four cancer types.	('cancer', 'Disease', (159, 165))	('protein', 'Protein', (47, 54))	('rs36115365', 'Var', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('rs36115365', 'Mutation', 'rs36115365', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
12464	28447668	These data suggested rs36115365 as a strong candidate for a functional multi-cancer risk variant but did not specifically implicate which gene(s) may be influenced by this SNP.	('multi-cancer', 'Disease', (71, 83))	('multi-cancer', 'Disease', 'MESH:D009369', (71, 83))	('rs36115365', 'Var', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs36115365', 'Mutation', 'rs36115365', (21, 31))
12466	28447668	Likewise, the utility of chromosome conformation capture (3C) methods to establish a physical association between risk variants and specific target genes is greatly limited by the relatively short distances between rs36115365 and the TERT promoter.	('rs36115365', 'Mutation', 'rs36115365', (215, 225))	('TERT', 'Gene', '7015', (234, 238))	('rs36115365', 'Var', (215, 225))	('TERT', 'Gene', (234, 238))
12467	28447668	We applied this methodology to our study of an intergenic GWAS susceptibility variant, and established a role for the regulatory element in driving TERT (but not CLPTM1L) gene expression across multiple cancer types.	('multiple cancer', 'Disease', (194, 209))	('GWAS', 'Gene', (58, 62))	('variant', 'Var', (78, 85))	('multiple cancer', 'Disease', 'MESH:D009369', (194, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('TERT', 'Gene', (148, 152))	('susceptibility', 'Reg', (63, 77))	('TERT', 'Gene', '7015', (148, 152))	('CLPTM1L', 'Gene', (162, 169))	('CLPTM1L', 'Gene', '81037', (162, 169))
12468	28447668	Our results suggest that the binding of one or more proteins to the C-allele of rs36115365 is likely to play a key role in regulating TERT expression.	('rs36115365', 'Mutation', 'rs36115365', (80, 90))	('regulating', 'Reg', (123, 133))	('TERT', 'Gene', (134, 138))	('TERT', 'Gene', '7015', (134, 138))	('rs36115365', 'Var', (80, 90))	('binding', 'Interaction', (29, 36))
12469	28447668	Through quantitative mass spectrometry, we identified preferential binding of zinc finger protein 148 (ZNF148, also named ZBP-89) to the C-allele of rs36115365 in multiple cancer cell lines, and ChIP data confirmed binding of ZNF148 over rs36115365.	('rs36115365', 'Var', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rs36115365', 'Mutation', 'rs36115365', (149, 159))	('zinc finger protein 148', 'Gene', '7707', (78, 101))	('multiple cancer', 'Disease', 'MESH:D009369', (163, 178))	('rs36115365', 'Mutation', 'rs36115365', (238, 248))	('rs36115365', 'Var', (149, 159))	('preferential', 'PosReg', (54, 66))	('multiple cancer', 'Disease', (163, 178))	('ZBP-89', 'Gene', '7707', (122, 128))	('ZNF148', 'Gene', (103, 109))	('ZBP-89', 'Gene', (122, 128))	('zinc finger protein 148', 'Gene', (78, 101))	('binding', 'Interaction', (215, 222))	('binding', 'Interaction', (67, 74))
12472	28447668	Consistent with a central role for ZNF148 in regulating expression of TERT, siRNA-mediated gene knockdown of ZNF148 consistently resulted in reduced expression of TERT.	('knockdown', 'Var', (96, 105))	('TERT', 'Gene', '7015', (163, 167))	('reduced', 'NegReg', (141, 148))	('ZNF148', 'Gene', (109, 115))	('expression', 'MPA', (149, 159))	('TERT', 'Gene', (70, 74))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (70, 74))
12473	28447668	Furthermore, both knockdown of ZNF148 as well as TGS of the gene regulatory element in which rs36115365 resides reduced telomerase activity and telomere length, to a degree similar to knockdown of TERT itself.	('TERT', 'Gene', (197, 201))	('rs36115365 resides', 'Var', (93, 111))	('rs36115365', 'Mutation', 'rs36115365', (93, 103))	('TERT', 'Gene', '7015', (197, 201))	('telomerase', 'CPA', (120, 130))	('reduced', 'NegReg', (112, 119))	('ZNF148', 'Gene', (31, 37))	('telomere length', 'CPA', (144, 159))
12477	28447668	Our results indicate that ZNF148 may regulate TERT expression in pancreatic, testicular, lung, and melanoma tumour cell lines via a regulatory element that is disrupted by the G allele at rs36115365.	('TERT', 'Gene', '7015', (46, 50))	('pancreatic', 'Disease', (65, 75))	('rs36115365', 'Var', (188, 198))	('regulate', 'Reg', (37, 45))	('melanoma tumour', 'Disease', 'MESH:D008545', (99, 114))	('ZNF148', 'Gene', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('melanoma tumour', 'Disease', (99, 114))	('rs36115365', 'Mutation', 'rs36115365', (188, 198))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('TERT', 'Gene', (46, 50))	('pancreatic', 'Disease', 'MESH:D010195', (65, 75))
12478	28447668	As some of these cell lines have TERT promoter mutations (UACC903, UACC1103) whereas others do not (PANC-1, MIA PaCa-2, unpublished data), our results indicate that regulation by ZNF148 is important even in the presence of these presumably activating mutations.	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('UACC1103', 'Var', (67, 75))	('UACC903', 'Var', (58, 65))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (108, 118))	('ZNF148', 'Gene', (179, 185))	('PANC-1', 'CellLine', 'CVCL:0480', (100, 106))
12479	28447668	In summary, our work has uncovered a likely causal variant in the TERT-CLPTM1L Region 2 susceptibility locus and identified ZNF148 as a potential effector of a gene-regulatory element that mediates increased TERT expression in an allele-specific manner.	('TERT', 'Gene', (208, 212))	('causal', 'Reg', (44, 50))	('ZNF148', 'Gene', (124, 130))	('TERT', 'Gene', '7015', (208, 212))	('increased', 'PosReg', (198, 207))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('variant', 'Var', (51, 58))	('CLPTM1L', 'Gene', '81037', (71, 78))	('CLPTM1L', 'Gene', (71, 78))
12481	28447668	Our results are remarkably consistent in eight cell lines across four different cancer types and explain, at least in part, the biological underpinnings of risk for rs36115365.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rs36115365', 'Var', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('rs36115365', 'Mutation', 'rs36115365', (165, 175))	('cancer', 'Disease', (80, 86))
12482	28447668	Notably, our data suggest that the mechanism by which ZNF148 influences TERT is similar for cancer types in which the C-allele of rs36115365 contributes to increased risk, or alternatively to disease protection.	('rs36115365', 'Var', (130, 140))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ZNF148', 'Gene', (54, 60))	('rs36115365', 'Mutation', 'rs36115365', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TERT', 'Gene', '7015', (72, 76))	('TERT', 'Gene', (72, 76))	('influences', 'Reg', (61, 71))
12483	28447668	Although TERT expression and ensuing effects on telomere length may be the crucial underlying mechanism in mediating inverse risk for different cancers, studies of surrogate tissue telomere length and cancer risk have been contradictory and shown associations with short or long telomeres, or no effect.	('associations', 'Interaction', (247, 259))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('short', 'Var', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
12485	28447668	Other factors may contribute to the pleiotropic effects observed for rs36115365, including differential environmental exposures, regulatory effects through genes beyond TERT, interaction with additional risk variants and/or somatic mutations both within Region 2 and the larger TERT/CLPTM1L locus, or tissue-specific regulation of ZNF148 and other transcription factors mediating TERT expression.	('interaction', 'Interaction', (175, 186))	('rs36115365', 'Mutation', 'rs36115365', (69, 79))	('TERT', 'Gene', '7015', (169, 173))	('ZNF148', 'Gene', (331, 337))	('TERT', 'Gene', (380, 384))	('TERT', 'Gene', '7015', (380, 384))	('regulation', 'Reg', (317, 327))	('TERT', 'Gene', (278, 282))	('rs36115365', 'Var', (69, 79))	('TERT', 'Gene', '7015', (278, 282))	('TERT', 'Gene', (169, 173))	('CLPTM1L', 'Gene', '81037', (283, 290))	('CLPTM1L', 'Gene', (283, 290))
12486	28447668	Our findings represent the first steps in unravelling the complex functional consequences of carrying risk variants in Region 2 of chr5p15.33 and strongly indicate a major role for expression of TERT in influencing risk of multiple cancer types.	('chr5p15.33', 'Gene', (131, 141))	('TERT', 'Gene', (195, 199))	('variants', 'Var', (107, 115))	('multiple cancer', 'Disease', (223, 238))	('TERT', 'Gene', '7015', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('multiple cancer', 'Disease', 'MESH:D009369', (223, 238))
12492	28447668	Meta-analysis of data conducted for the Transdisciplinary Research in Cancer of the Lung has been approved as protocol numbers STUDY00023900 and STUDY00023602 which were approved by the Committee for the Protection of Human Subjects under the auspices of the Trustees of Dartmouth College Dartmouth-Hitchcock Medical Center.	('STUDY00023602', 'Var', (145, 158))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Human', 'Species', '9606', (218, 223))
12496	28447668	Imputation and association analysis for melanoma was performed using 1000G (Phase 1 integrated release 3, March 2012) as previously described.	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('1000G', 'Var', (69, 74))
12498	28447668	Within the pancreatic cancer GWAS data, all common 1000G variants (n=195, MAF>=0.01) in Region 2 (defined as the genomic region between the two recombination hotspots at 1,306,281-1,367,281 in NCBI build Hg19) had imputation accuracy (INFO) scores above 0.3 (the lowest quality score was 0.48).	('MAF', 'Gene', (74, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (11, 28))	('pancreatic cancer', 'Disease', (11, 28))	('NCBI build', 'Gene', (193, 203))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('variants', 'Var', (57, 65))	('MAF', 'Gene', '4094', (74, 77))
12499	28447668	The imputation quality for the set of nine Region 2 variants most significantly associated with pancreatic cancer risk was high in the PanScan GWAS studies, with quality scores (INFO) ranging from 0.82 to 0.96 (average 0.92).	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('variants', 'Var', (52, 60))	('associated', 'Reg', (80, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
12504	28447668	For completeness we assessed the newer 1000G (Phase 3, October 2014) reference dataset and noted an insertion/deletion variant (rs3030832) that was highly correlated to rs36115365 (r2=0.87 in EUR).	('rs3030832', 'Mutation', 'rs3030832', (128, 137))	('rs36115365', 'Var', (169, 179))	('rs36115365', 'Mutation', 'rs36115365', (169, 179))	('rs3030832', 'Var', (128, 137))
12506	28447668	rs36115365 became non-significant when analysis was conditioned on rs3030832, as was rs3030832, when analysis was conditioned on rs36115365 (Supplementary Table 2), indicating that this variant is among the highly correlated variants representing Region 2 and thus represents an additional strong functional candidate.	('rs3030832', 'Mutation', 'rs3030832', (67, 76))	('rs36115365', 'Var', (129, 139))	('rs3030832', 'Var', (67, 76))	('rs3030832', 'Mutation', 'rs3030832', (85, 94))	('rs36115365', 'Var', (0, 10))	('rs3030832', 'Var', (85, 94))	('rs36115365', 'Mutation', 'rs36115365', (129, 139))	('rs36115365', 'Mutation', 'rs36115365', (0, 10))
12508	28447668	After the analysis was conditioned on rs36115365 we noted a large drop in significance for these seven variants while conditional analysis for each of the seven variants did not dramatically influence the significance or rs36115365 (Supplementary Table 2).	('drop', 'NegReg', (66, 70))	('rs36115365', 'Mutation', 'rs36115365', (221, 231))	('significance', 'MPA', (74, 86))	('rs36115365', 'Var', (38, 48))	('rs36115365', 'Mutation', 'rs36115365', (38, 48))
12520	28447668	Supershift experiments were carried out by mixing 1 and 2 mug anti-ZNF148/ZBP-89 (sc-48811X, 200 mug per 0.1 ml, Santa Cruz), anti-VEZF1/ZNF161 (sc-98278X, 200 mug per 0.1 ml, Santa Cruz), anti-ZNF281 (sc-166933X, 200 mug per 0.1 ml, Santa Cruz), anti-ZNF740 (sc-324747, 200 mug ml-1, Santa Cruz) or anti-IgG (sc-52001, 100 mug ml-1, Santa Cruz) antibodies with nuclear extracts for 20 min at room temperature before adding labelled probe.	('ZNF281', 'Gene', '23528', (194, 200))	('sc-52001', 'Var', (310, 318))	('ZNF740', 'Gene', '283337', (252, 258))	('ZNF281', 'Gene', (194, 200))	('VEZF1', 'Gene', '7716', (131, 136))	('VEZF1', 'Gene', (131, 136))	('ZNF161', 'Gene', '7716', (137, 143))	('anti-IgG', 'Var', (300, 308))	('sc-98278X', 'Var', (145, 154))	('ZBP-89', 'Gene', '7707', (74, 80))	('ZBP-89', 'Gene', (74, 80))	('sc-166933X', 'Var', (202, 212))	('ZNF740', 'Gene', (252, 258))	('sc-324747', 'Var', (260, 269))	('ZNF161', 'Gene', (137, 143))
12532	28447668	The genomic region containing and surrounding rs36115365 (240 bps) was PCR-amplified (primers listed in Supplementary Table 5) from HapMap CEU DNA samples with the appropriate genotypes to obtain clones with each genotype, and cloned into the NheI and BglII sites of the pGL4.23[luc2/minP] (Promega) luciferase vector in the 5'-to-3' or 3'-to-5' orientation.	('rs36115365', 'Var', (46, 56))	('pGL4', 'Gene', (271, 275))	('rs36115365', 'Mutation', 'rs36115365', (46, 56))	('pGL4', 'Gene', '6390', (271, 275))	('minP', 'Gene', '89927', (284, 288))	('minP', 'Gene', (284, 288))
12538	28447668	ON-TARGETplus Human SMARTpool siRNAs to ZNF148 (cat# L-012658-00-0005), VEZF1 (ZNF161; cat# L-019623-00-0005), ZNF281 (cat# L-006958-00-0005), ZNF740 (cat# L-030075-02-0005), and TERT (cat# L-003547-00-0005) were purchased from Dharmacon RNAi and Gene Expression in GE Healthcare.	('cat# L-019623-00-0005', 'Var', (87, 108))	('VEZF1', 'Gene', '7716', (72, 77))	('Human', 'Species', '9606', (14, 19))	('TERT', 'Gene', (179, 183))	('cat# L-012658-00-0005', 'Var', (48, 69))	('ZNF161', 'Gene', (79, 85))	('ZNF740', 'Gene', (143, 149))	('TERT', 'Gene', '7015', (179, 183))	('ZNF161', 'Gene', '7716', (79, 85))	('ZNF740', 'Gene', '283337', (143, 149))	('cat# L-006958-00-0005', 'Var', (119, 140))	('VEZF1', 'Gene', (72, 77))	('ZNF281', 'Gene', '23528', (111, 117))	('cat# L-030075-02-0005', 'Var', (151, 172))	('ZNF281', 'Gene', (111, 117))
12541	28447668	Gene expression levels were quantified by quantitative real-time PCR using TaqMan assays for TERT (Hs00972656_m1), CLPTM1L (Hs00363947_m1), ACTB (cat# 4333762), ZNF148 (Hs01070570_m1), and GAPDH (cat# 4333764) from Life Technologies.	('GAPDH', 'Gene', (189, 194))	('CLPTM1L', 'Gene', (115, 122))	('Hs01070570_m1', 'Var', (169, 182))	('cat# 4333764', 'Var', (196, 208))	('Hs00363947_m1', 'Var', (124, 137))	('cat# 4333762', 'Var', (146, 158))	('CLPTM1L', 'Gene', '81037', (115, 122))	('ACTB', 'Gene', '60', (140, 144))	('ACTB', 'Gene', (140, 144))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))	('GAPDH', 'Gene', '2597', (189, 194))	('Hs00972656_m1', 'Var', (99, 112))
12543	28447668	Allele-specific TERT expression was determined using an allelic discrimination TaqMan assay for rs2736098 (assay C_26414916_20, Life Technologies), and the gene expression of each allele of TERT was also normalized to the gene expression of GAPDH.	('TERT', 'Gene', (16, 20))	('GAPDH', 'Gene', '2597', (241, 246))	('GAPDH', 'Gene', (241, 246))	('TERT', 'Gene', '7015', (16, 20))	('rs2736098', 'Var', (96, 105))	('rs2736098', 'Mutation', 'rs2736098', (96, 105))	('TERT', 'Gene', (190, 194))	('TERT', 'Gene', '7015', (190, 194))
12552	28447668	To assay effects on telomere length, siRNA3, ZNF148 siRNA (cat# L-012658-00-0005), TERT siRNA (cat# L-003547-00-0005) and a scrambled siRNA (Supplementary Table 6) were administered to MIA PaCa-2 and A549 cells at a final concentration of 15 nM.	('cat# L-012658-00-0005', 'Var', (59, 80))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (185, 195))	('cat# L-003547-00-0005', 'Var', (95, 116))	('effects', 'Reg', (9, 16))	('A549', 'CellLine', 'CVCL:0023', (200, 204))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('ZNF148', 'Gene', (45, 51))
12624	22945574	Male reprotoxicity and endocrine disruption Mammalian reproductive tract development is a tightly regulated process that can be disrupted following exposure to drugs, toxicants, endocrine disrupting chemicals or other compounds via alterations to gene and protein expression or epigenetic regulation.	('Mammalian', 'Species', '9606', (44, 53))	('epigenetic regulation', 'Var', (278, 299))	('rat', 'Species', '10116', (236, 239))	('alterations', 'Reg', (232, 243))	('men', 'Species', '9606', (80, 83))
12669	22945574	First, null mutations in both WT1 and Sf1 can alter the development of the gonad and may be involved in initiating signals that control expansion of the genital ridge.	('WT1', 'Gene', (30, 33))	('involved', 'Reg', (92, 100))	('men', 'Species', '9606', (63, 66))	('Sf1', 'Gene', '83826', (38, 41))	('null mutations', 'Var', (7, 21))	('expansion of the genital ridge', 'Phenotype', 'HP:0003247', (136, 166))	('development of the gonad', 'CPA', (56, 80))	('Sf1', 'Gene', (38, 41))	('alter', 'Reg', (46, 51))	('WT1', 'Gene', '24883', (30, 33))
12694	22945574	Several genetic causes and polymorphisms associated with cryptorchidism have been identified in human patients, including mutations in Insl3 and its receptor, RXFP2, as well as in the AR gene (which is associated with Androgen Insensitivity Syndrome).	('associated', 'Reg', (41, 51))	('patients', 'Species', '9606', (102, 110))	('associated', 'Reg', (202, 212))	('RXFP2', 'Gene', '122042', (159, 164))	('human', 'Species', '9606', (96, 101))	('Androgen Insensitivity Syndrome', 'Phenotype', 'HP:0008226', (218, 249))	('cryptorchidism', 'Disease', (57, 71))	('mutations', 'Var', (122, 131))	('Insl3', 'Gene', (135, 140))	('RXFP2', 'Gene', (159, 164))	('cryptorchidism', 'Phenotype', 'HP:0000028', (57, 71))	('AR', 'Gene', '24208', (184, 186))
12696	22945574	Hypospadias results from abnormal penile and urethral development, commonly arising from a defect in the midline fusion of the male urethra, leading to a misplaced urethral meatus.	('abnormal penile', 'Disease', (25, 40))	('abnormal penile', 'Disease', 'MESH:D004414', (25, 40))	('Hypospadias', 'Phenotype', 'HP:0000047', (0, 11))	('defect', 'Var', (91, 97))	('men', 'Species', '9606', (61, 64))	('Hypospadias', 'Disease', (0, 11))	('results from', 'Reg', (12, 24))	('arising from', 'Reg', (76, 88))	('Hypospadias', 'Disease', 'MESH:D007021', (0, 11))
12708	22945574	In the extreme case of complete AIS, a lack of activity at the androgen receptor prevents testicular descent and further development of the external male genitalia; however, normal production of MIS during fetal development inhibits uterus and fallopian tube development, resulting in an XY male genotype with a female phenotype.	('inhibits', 'NegReg', (224, 232))	('men', 'Species', '9606', (219, 222))	('lack', 'Var', (39, 43))	('MIS', 'Gene', '25378', (195, 198))	('androgen receptor', 'Gene', '24208', (63, 80))	('AIS', 'Phenotype', 'HP:0008226', (32, 35))	('MIS', 'Gene', (195, 198))	('prevents', 'NegReg', (81, 89))	('resulting in', 'Reg', (272, 284))	('men', 'Species', '9606', (128, 131))	('further development of the external male genitalia', 'Phenotype', 'HP:0003247', (113, 163))	('XY male genotype', 'CPA', (288, 304))	('men', 'Species', '9606', (266, 269))	('testicular descent', 'CPA', (90, 108))	('androgen receptor', 'Gene', (63, 80))
12710	22945574	Because GnRH stimulates FSH and LH hormone production in the pituitary, which stimulates the gonads, a GnRH deficiency leads to decreased or absent function of the testes.	('LH', 'Chemical', 'MESH:D007986', (32, 34))	('absent', 'NegReg', (141, 147))	('GnRH', 'Gene', '25194', (103, 107))	('GnRH', 'Gene', (103, 107))	('function', 'MPA', (148, 156))	('decreased', 'NegReg', (128, 137))	('GnRH', 'Gene', '25194', (8, 12))	('deficiency', 'Var', (108, 118))	('decreased or absent function of the testes', 'Phenotype', 'HP:0010468', (128, 170))	('absent function of the testes', 'Phenotype', 'HP:0010469', (141, 170))	('GnRH', 'Gene', (8, 12))
12718	22945574	In the 1950s, in utero thalidomide exposure led to drug-induced phocomelia (limb-shortening); by 1961 this sedative drug was withdrawn from the market.	('thalidomide', 'Chemical', 'MESH:D013792', (23, 34))	('phocomelia', 'Phenotype', 'HP:0009829', (64, 74))	('limb-shortening', 'Phenotype', 'HP:0009826', (76, 91))	('phocomelia', 'Disease', 'MESH:D004480', (64, 74))	('thalidomide', 'Var', (23, 34))	('phocomelia', 'Disease', (64, 74))
12719	22945574	Similarly, consumption of methylmercury-contaminated shellfish by pregnant mothers has led to neurological dysfunction in their children, most prominently in Minimata Bay, Japan, where a population was exposed from 1932 to 1968.	('neurological dysfunction', 'Disease', 'MESH:D009422', (94, 118))	('children', 'Species', '9606', (128, 136))	('led to', 'Reg', (87, 93))	('neurological dysfunction', 'Disease', (94, 118))	('methylmercury-contaminated', 'Var', (26, 52))
12727	22945574	It is clear that toxicant-induced modulation of the endocrine system can have myriad downstream effects on reproduction and development.	('effects', 'Reg', (96, 103))	('reproduction', 'CPA', (107, 119))	('men', 'Species', '9606', (131, 134))	('development', 'CPA', (124, 135))	('modulation', 'Var', (34, 44))
12756	22945574	According to this hypothesis, perturbations to the developmentally-critical in utero or peri-natal environment, possibly due to EDC exposure, may result in subsequent dysgenesis of the male reproductive tract.	('dysgenesis', 'CPA', (167, 177))	('perturbations', 'Var', (30, 43))	('result in', 'Reg', (146, 155))	('men', 'Species', '9606', (58, 61))	('men', 'Species', '9606', (106, 109))
12759	22945574	While some rare genetic defects and point mutations can lead to altered reproductive structure and function, the overall prevalence of these genetic abnormalities cannot explain the increasing incidence or variable expressivity of the full array of TDS disorders.	('TDS disorders', 'Disease', (249, 262))	('genetic defects', 'Disease', (16, 31))	('genetic defects', 'Disease', 'MESH:D030342', (16, 31))	('function', 'MPA', (99, 107))	('reproductive structure', 'CPA', (72, 94))	('genetic abnormalities', 'Disease', 'MESH:D030342', (141, 162))	('TDS disorders', 'Disease', 'MESH:D030342', (249, 262))	('genetic abnormalities', 'Disease', (141, 162))	('altered', 'Reg', (64, 71))	('point mutations', 'Var', (36, 51))	('lead', 'Reg', (56, 60))
12761	22945574	Previous work in developmental biology has observed TDS-like effects with the loss or disruption of genes regulating reproductive growth and development.	('men', 'Species', '9606', (24, 27))	('men', 'Species', '9606', (148, 151))	('loss', 'NegReg', (78, 82))	('TDS-like', 'Disease', (52, 60))	('genes', 'Gene', (100, 105))	('disruption', 'Var', (86, 96))
12764	22945574	Loss of the gene Insl3 causes bilateral intraabdominal cryptorchidism with secondary infertility and testicular atrophy.	('bilateral intraabdominal cryptorchidism', 'Disease', 'MESH:D003456', (30, 69))	('testicular atrophy', 'Phenotype', 'HP:0000029', (101, 119))	('testicular atrophy', 'Disease', 'MESH:C567108', (101, 119))	('causes', 'Reg', (23, 29))	('Insl3', 'Gene', (17, 22))	('infertility', 'Disease', 'MESH:D007247', (85, 96))	('testicular atrophy', 'Disease', (101, 119))	('cryptorchidism', 'Phenotype', 'HP:0000028', (55, 69))	('bilateral intraabdominal cryptorchidism', 'Disease', (30, 69))	('infertility', 'Phenotype', 'HP:0000789', (85, 96))	('Loss', 'Var', (0, 4))	('infertility', 'Disease', (85, 96))
12772	22945574	As such, phthalates have been suggested to be associated with the development of TDS due to the potential for significant exposure during development and the induction of reproductive tract defects in rats following gestational exposure (Figure 1).	('induction', 'Reg', (158, 167))	('reproductive tract defects', 'CPA', (171, 197))	('men', 'Species', '9606', (145, 148))	('men', 'Species', '9606', (73, 76))	('phthalates', 'Chemical', 'MESH:C032279', (9, 19))	('reproductive tract defects', 'Phenotype', 'HP:0000078', (171, 197))	('rats', 'Species', '10116', (201, 205))	('associated', 'Reg', (46, 56))	('gestational exposure', 'Phenotype', 'HP:0031437', (216, 236))	('phthalates', 'Var', (9, 19))	('TDS', 'Disease', (81, 84))
12776	22945574	While estrogenic properties of phthalates had previously been reported, subsequent research pointed towards an anti-androgenic mechanism, as female rats gestationally exposed to DBP exhibited no change in reproductive organ weights, estrous cyclicity or vaginal opening, as was observed with weakly estrogenic compounds.	('estrous cyclicity', 'CPA', (233, 250))	('anti-androgenic', 'MPA', (111, 126))	('vaginal opening', 'Disease', (254, 269))	('phthalates', 'Chemical', 'MESH:C032279', (31, 41))	('reproductive organ weights', 'CPA', (205, 231))	('change in reproductive organ', 'Phenotype', 'HP:0000078', (195, 223))	('rats', 'Species', '10116', (148, 152))	('estrous cyclicity', 'Phenotype', 'HP:0100608', (233, 250))	('DBP', 'Chemical', 'MESH:D003993', (178, 181))	('DBP', 'Var', (178, 181))	('vaginal opening', 'Disease', 'MESH:D014627', (254, 269))
12799	22945574	The HPG axis is critical for both gonadal development and steroid production; if it is disrupted, a hypogonadal state can result, leading to abnormalities such as the congenital disorders previously described.	('men', 'Species', '9606', (49, 52))	('result', 'Reg', (122, 128))	('steroid', 'Chemical', 'MESH:D013256', (58, 65))	('leading to', 'Reg', (130, 140))	('congenital disorders', 'Disease', 'MESH:D000013', (167, 187))	('abnormalities', 'MPA', (141, 154))	('hypogonadal state', 'Phenotype', 'HP:0000135', (100, 117))	('disrupted', 'Var', (87, 96))	('congenital disorders', 'Disease', (167, 187))
12845	22945574	Many functions have been proposed for these sperm transcripts, including roles in sperm structure and stress response, de novo translational replacement of degraded proteins, oocyte fertilization, embryogenesis/morphogenesis, and epigenetic regulation and establishment/maintenance of the parental imprint.	('roles', 'Reg', (73, 78))	('men', 'Species', '9606', (265, 268))	('men', 'Species', '9606', (148, 151))	('embryogenesis/morphogenesis', 'CPA', (197, 224))	('epigenetic regulation', 'Var', (230, 251))	('oocyte fertilization', 'CPA', (175, 195))
12867	22945574	Overall, EDS induces a depletion of germ cells in the seminiferous epithelium.	('EDS', 'Var', (9, 12))	('induces', 'Reg', (13, 20))	('depletion of', 'MPA', (23, 35))	('EDS', 'Chemical', 'MESH:C002994', (9, 12))
12878	22945574	Overall, CBZ disrupts proper Sertoli cell function and spermatogenesis and ultimately reduces fertility in male rats.	('rats', 'Species', '10116', (112, 116))	('CBZ', 'Chemical', 'MESH:C006698', (9, 12))	('disrupts', 'NegReg', (13, 21))	('reduces', 'NegReg', (86, 93))	('CBZ', 'Var', (9, 12))	('spermatogenesis', 'CPA', (55, 70))	('reduces fertility', 'Phenotype', 'HP:0000144', (86, 103))	('Sertoli', 'MPA', (29, 36))	('fertility', 'CPA', (94, 103))	('Sertoli cell', 'Phenotype', 'HP:0100619', (29, 41))	('reduces fertility in male', 'Phenotype', 'HP:0012041', (86, 111))
12886	22945574	Ubiquitin marks aberrant proteins for 26S-proteasome degradation, and it is believed that a mutated form of ubiquitin (K48R) offers protection from testicular injury in both acute (experimental cryptorchidism) and chronic (aging) cases.	('testicular injury', 'Disease', 'MESH:D013736', (148, 165))	('men', 'Species', '9606', (187, 190))	('K48R', 'Chemical', '-', (119, 123))	('testicular injury', 'Disease', (148, 165))	('mutated', 'Var', (92, 99))	('26S-proteasome degradation', 'MPA', (38, 64))	('cryptorchidism', 'Phenotype', 'HP:0000028', (194, 208))
12887	22945574	This is true for mice with the K48R ubiquitin mutation, who are resistant to the effects of acute and chronic testicular injury.	('mice', 'Species', '10090', (17, 21))	('testicular injury', 'Disease', 'MESH:D013736', (110, 127))	('testicular injury', 'Disease', (110, 127))	('K48R', 'Var', (31, 35))	('ubiquitin', 'Protein', (36, 45))	('K48R', 'Chemical', '-', (31, 35))
12889	22945574	When compared to wild type mice, ubiquitin K48R mutant mice have greater testis weights after both types of injury.	('mice', 'Species', '10090', (27, 31))	('greater', 'PosReg', (65, 72))	('K48R', 'Chemical', '-', (43, 47))	('testis weights', 'CPA', (73, 87))	('mice', 'Species', '10090', (55, 59))	('ubiquitin K48R mutant', 'Var', (33, 54))	('greater testis', 'Phenotype', 'HP:0000053', (65, 79))
12890	22945574	Testis cross sections of experimentally cryptorchid animals indicate that the average number of germ cells per seminiferous tubule is greater in ubiquitin K48R mutant mice than in their WT counterparts.	('K48R', 'Chemical', '-', (155, 159))	('experimentally cryptorchid', 'Phenotype', 'HP:0000028', (25, 51))	('men', 'Species', '9606', (31, 34))	('K48R mutant', 'Var', (155, 166))	('ubiquitin', 'Protein', (145, 154))	('Testis cross', 'Disease', 'MESH:D013736', (0, 12))	('mice', 'Species', '10090', (167, 171))	('greater', 'PosReg', (134, 141))	('Testis cross', 'Disease', (0, 12))
12891	22945574	The seminiferous tubules of aged mutant mice have larger diameters, with a greater number of germ cells, than WT mice, indicating that the K48R mutation does indeed serve to protect against the testicular injury of aging.	('K48R', 'Var', (139, 143))	('K48R', 'Chemical', '-', (139, 143))	('testicular injury', 'Disease', 'MESH:D013736', (194, 211))	('larger', 'PosReg', (50, 56))	('mutant', 'Var', (33, 39))	('mice', 'Species', '10090', (40, 44))	('mice', 'Species', '10090', (113, 117))	('testicular injury', 'Disease', (194, 211))
12897	22945574	Despite this initial surge of testosterone production, prolonged occupation of pituitary LH receptors results in an overall decrease in testosterone.	('testosterone', 'MPA', (136, 148))	('testosterone production', 'MPA', (30, 53))	('testosterone', 'Chemical', 'MESH:D013739', (30, 42))	('testosterone', 'Chemical', 'MESH:D013739', (136, 148))	('LH receptor', 'Gene', (89, 100))	('occupation', 'Var', (65, 75))	('decrease', 'NegReg', (124, 132))	('LH receptor', 'Gene', '25477', (89, 100))	('surge of testosterone', 'Phenotype', 'HP:0030088', (21, 42))	('decrease in testosterone', 'Phenotype', 'HP:0040171', (124, 148))
12924	22945574	They found aberrant protamine ratios and increased mRNA expression of Bcl2 in ejaculates and in testicular biopsies of infertile men compared to controls.	('increased', 'PosReg', (41, 50))	('aberrant', 'Var', (11, 19))	('Bcl2', 'Gene', (70, 74))	('rat', 'Species', '10116', (30, 33))	('men', 'Species', '9606', (129, 132))	('protamine ratios', 'MPA', (20, 36))	('mRNA expression', 'MPA', (51, 66))
12932	22945574	DNA methylation modifies the function of the mammalian genome, and typically results in repression of gene expression.	('mammalian', 'Species', '9606', (45, 54))	('modifies', 'Reg', (16, 24))	('results in', 'Reg', (77, 87))	('methylation', 'Var', (4, 15))	('function', 'MPA', (29, 37))	('repression', 'NegReg', (88, 98))
12934	22945574	It has been suggested that alterations in the epigenetic reprogramming processes during development can lead to adult-onset disease.	('adult-onset disease', 'Disease', (112, 131))	('epigenetic', 'Var', (46, 56))	('men', 'Species', '9606', (95, 98))	('rat', 'Species', '10116', (31, 34))	('lead to', 'Reg', (104, 111))	('alterations', 'Var', (27, 38))
12938	22945574	In addition to regulating gene expression, DNA methylation silences repetitive elements and is important for the stability of the mammalian genome.	('gene expression', 'MPA', (26, 41))	('methylation', 'Var', (47, 58))	('silences', 'NegReg', (59, 67))	('mammalian', 'Species', '9606', (130, 139))	('regulating', 'Reg', (15, 25))	('men', 'Species', '9606', (82, 85))	('repetitive elements', 'MPA', (68, 87))
12939	22945574	Both human and animal studies have shown that abnormal methylation patterns affect fertility.	('affect', 'Reg', (76, 82))	('methylation', 'MPA', (55, 66))	('abnormal', 'Var', (46, 54))	('fertility', 'CPA', (83, 92))	('affect fertility', 'Phenotype', 'HP:0000144', (76, 92))	('human', 'Species', '9606', (5, 10))
12945	22945574	The authors suggest that errors in paternal imprints could affect embryo development and that methylation patterns could be useful as biomarkers for evaluating male fertility.	('embryo development', 'CPA', (66, 84))	('men', 'Species', '9606', (80, 83))	('errors', 'Var', (25, 31))	('affect', 'Reg', (59, 65))
12987	22945574	Results suggest that exposure to Aroclor 1248 causes down-regulation of testicular androgenesis through inhibition of the activity of 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase/lyase and 17beta-hydroxysteroid dehydrogenase.	('inhibition', 'NegReg', (104, 114))	('17beta-hydroxysteroid dehydrogenase', 'Gene', (200, 235))	('17alpha-hydroxylase/lyase', 'Enzyme', (170, 195))	('down-regulation', 'NegReg', (53, 68))	('steroid', 'Chemical', 'MESH:D013256', (147, 154))	('17beta-hydroxysteroid dehydrogenase', 'Gene', '364773', (200, 235))	('Aroclor 1248', 'Chemical', 'MESH:C028617', (33, 45))	('Aroclor', 'Var', (33, 40))	('testicular', 'CPA', (72, 82))	('3beta-hydroxysteroid dehydrogenase', 'Enzyme', (134, 168))	('activity', 'MPA', (122, 130))	('steroid', 'Chemical', 'MESH:D013256', (214, 221))
13002	22945574	The reprogramming of DNA methylation that takes place in primordial germ cells is presumably acting to prevent the passage of DNA methylation defects from one generation to the next.	('defects', 'Var', (142, 149))	('prevent', 'NegReg', (103, 110))	('rat', 'Species', '10116', (163, 166))
13009	22945574	A number of studies have suggested that environmental chemicals, such as endocrine disruptors, promote a transgenerational phenotype due to embryonic or postnatal exposures through an epigenetic mechanism.	('rat', 'Species', '10116', (114, 117))	('epigenetic', 'Var', (184, 194))	('promote', 'PosReg', (95, 102))	('transgenerational phenotype', 'CPA', (105, 132))	('men', 'Species', '9606', (47, 50))
13011	22945574	While many DNA methylation changes are not heritable, it is thought that imprinted genes maintain methylation pattern in a heritable manner, and it has been proposed that alterations in the methylation status of imprinted genes may be a mechanism promoting these disease states.	('promoting', 'PosReg', (247, 256))	('methylation pattern', 'MPA', (98, 117))	('disease', 'Disease', (263, 270))	('rat', 'Species', '10116', (175, 178))	('alterations', 'Var', (171, 182))
13018	22945574	When the vinclozolin F2 generation males were out-crossed to wild-type untreated control females, the male progeny exhibited a similar phenotype of decreased spermatogenic capacity and male infertility, suggesting that the transgenerational phenotype is transmitted through the male germ line, likely through epigenetic changes (because the developmental period used for the endocrine disruptor exposure was during the re-methylation programming of the germ line).	('rat', 'Species', '10116', (232, 235))	('spermatogenic capacity', 'CPA', (158, 180))	('male infertility', 'Disease', 'MESH:D007248', (185, 201))	('men', 'Species', '9606', (348, 351))	('decreased', 'NegReg', (148, 157))	('infertility', 'Phenotype', 'HP:0000789', (190, 201))	('male infertility', 'Phenotype', 'HP:0003251', (185, 201))	('male infertility', 'Disease', (185, 201))	('vinclozolin', 'Chemical', 'MESH:C025643', (9, 20))	('epigenetic', 'Var', (309, 319))	('rat', 'Species', '10116', (28, 31))
13036	22945574	Because dysregulation in secretion, signaling, production, transportation and/or metabolism of steroidogenic pathways could impair germ cell differentiation and the surrounding cellular environment (potentially initiating carcinogenesis), research into the regulation of steroidogenic pathways and their associated hormones is becoming increasingly important.	('dysregulation', 'Var', (8, 21))	('steroid', 'Chemical', 'MESH:D013256', (95, 102))	('transportation', 'MPA', (59, 73))	('signaling', 'MPA', (36, 45))	('production', 'MPA', (47, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (222, 236))	('steroid', 'Chemical', 'MESH:D013256', (271, 278))	('carcinogenesis', 'Disease', (222, 236))	('men', 'Species', '9606', (193, 196))	('secretion', 'MPA', (25, 34))	('metabolism', 'MPA', (81, 91))	('impair', 'NegReg', (124, 130))	('germ cell differentiation', 'CPA', (131, 156))
13052	22945574	Mutations in the Ter gene led to tumors within weeks, related to a decrease in primordial germ cells initiated by the mutation.	('Ter', 'Gene', '191576', (17, 20))	('decrease', 'NegReg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Mutations', 'Var', (0, 9))	('led to', 'Reg', (26, 32))	('mutation', 'Var', (118, 126))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('Ter', 'Gene', (17, 20))
13057	22945574	Another important discovery in spontaneous tumor formation was made after investigating a deficiency in the p53 gene.	('p53', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('deficiency', 'Var', (90, 100))	('p53', 'Gene', '301300', (108, 111))	('tumor', 'Disease', (43, 48))
13058	22945574	Mouse models deficient in this gene form various types of spontaneous tumors, including testicular tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('testicular tumors', 'Disease', 'MESH:D013736', (88, 105))	('testicular tumors', 'Phenotype', 'HP:0010788', (88, 105))	('tumors', 'Disease', (70, 76))	('deficient', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Mouse', 'Species', '10090', (0, 5))	('form', 'Reg', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('testicular tumors', 'Disease', (88, 105))	('spontaneous', 'Disease', (58, 69))	('tumors', 'Disease', (99, 105))
13059	22945574	Mutation in this gene alters the normal cell-cycle control pathway, and is the probable reason for carcinogenesis formation.	('alters', 'Reg', (22, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('cell-cycle control pathway', 'Pathway', (40, 66))	('Mutation', 'Var', (0, 8))	('carcinogenesis', 'Disease', (99, 113))
13061	22945574	It is clear that different genetic backgrounds are capable of predisposing rodents to varying degrees of susceptibility to tumor formation; for example, mice with a 129/Sv background tend to develop a higher proportion of testis tumors (35%) than mice with a mixed C57BL/6 x 129/Sv background (9%).	('testis tumor', 'Phenotype', 'HP:0010788', (222, 234))	('mice', 'Species', '10090', (247, 251))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (123, 128))	('testis tumors', 'Disease', 'MESH:D013736', (222, 235))	('129/Sv', 'Species', '10090', (275, 281))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('testis tumors', 'Phenotype', 'HP:0010788', (222, 235))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (229, 234))	('develop', 'PosReg', (191, 198))	('mice', 'Species', '10090', (153, 157))	('testis tumors', 'Disease', (222, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('129/Sv', 'Var', (165, 171))	('129/Sv', 'Species', '10090', (165, 171))
13066	22945574	Due to the reciprocal nature of this signaling, dysregulation is particularly detrimental and has been implicated in the development of disease states.	('detrimental', 'Disease', 'MESH:D008569', (78, 89))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (128, 131))	('dysregulation', 'Var', (48, 61))	('detrimental', 'Disease', (78, 89))	('implicated', 'Reg', (103, 113))
13071	22945574	While the proposed mechanism remains unclear, data suggests that disruption of the natural hormonal balance of mother and fetus could result in a higher susceptibility to certain cancers.	('result', 'Reg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('susceptibility', 'MPA', (153, 167))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('disruption', 'Var', (65, 75))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
13072	22945574	Androgens are well-known risk factors in certain age-related diseases, such as BPH and carcinoma, however, recent evidence suggests that estrogens may also play a large role in the developing prostate and that disruption of the natural androgen/estrogen hormone balance could lead to abnormal growth.	('growth', 'MPA', (293, 299))	('BPH', 'Disease', (79, 82))	('lead to', 'Reg', (276, 283))	('carcinoma', 'Disease', (87, 96))	('abnormal growth', 'Phenotype', 'HP:0001507', (284, 299))	('disruption', 'Var', (210, 220))	('abnormal', 'CPA', (284, 292))	('carcinoma', 'Disease', 'MESH:D002277', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
13089	22945574	Early studies using animals and the subcutaneous route of exposure (bypassing first-pass metabolism by the liver) showed that low dose exposures to BPA during gestation could impact prostate growth and development by inducing an increase in cellular proliferation as well as the number of buds within the gland.	('BPA', 'Gene', (148, 151))	('exposures', 'Var', (135, 144))	('inducing', 'Reg', (217, 225))	('increase', 'PosReg', (229, 237))	('impact', 'Reg', (175, 181))	('rat', 'Species', '10116', (257, 260))	('men', 'Species', '9606', (209, 212))	('cellular proliferation', 'CPA', (241, 263))	('prostate growth', 'CPA', (182, 197))	('BPA', 'Chemical', 'MESH:C006780', (148, 151))
13257	33668653	Consistent with these observations, modulation of 53BP1 protein expression altered the cell line's resistance to cisplatin, and inhibition of DNA-PKcs activity antagonized cisplatin cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (182, 194))	('DNA-PKcs', 'Gene', (142, 150))	('inhibition', 'NegReg', (128, 138))	('53BP1', 'Gene', '7158', (50, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('cytotoxicity', 'Disease', (182, 194))	('protein', 'Protein', (56, 63))	('altered', 'Reg', (75, 82))	('antagonized', 'NegReg', (160, 171))	('resistance to cisplatin', 'MPA', (99, 122))	('modulation', 'Var', (36, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('DNA-PKcs', 'Gene', '5591', (142, 150))	('activity', 'MPA', (151, 159))	('53BP1', 'Gene', (50, 55))
13258	33668653	Dampening of NHEJ was accompanied by a functional increase in the repair of DNA double-strand breaks (DSBs) by the homologous recombination repair pathway.	('increase', 'PosReg', (50, 58))	('DSBs', 'Chemical', '-', (102, 106))	('NHEJ', 'Gene', (13, 17))	('Dampening', 'Var', (0, 9))	('repair of DNA double-strand breaks', 'MPA', (66, 100))
13259	33668653	As a result, cisplatin-resistant cells were more resistant to PARP inhibitor (PARPi) monotherapy.	('PARP', 'Gene', (78, 82))	('resistant', 'MPA', (49, 58))	('cisplatin-resistant', 'Var', (13, 32))	('PARP', 'Gene', '142', (78, 82))	('PARP', 'Gene', (62, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('PARP', 'Gene', '142', (62, 66))
13289	33668653	However, preventing the utilization of NHEJ in ICL repair-deficient cells has been reported to substantially rescue their sensitivity to cisplatin and also increases survival of wild-type (WT) cells treated with the drug.	('preventing', 'Var', (9, 19))	('increases', 'PosReg', (156, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('rescue', 'PosReg', (109, 115))	('survival', 'CPA', (166, 174))	('sensitivity to cisplatin', 'MPA', (122, 146))
13329	33668653	Cells were permeabilized with PBS 0.5% Triton X-100 plus 0.5% normal goat serum (NGS) at RT, then incubated in PBS 0.2% Triton X-100 and blocked with 0.2% NGS in PBS at RT for 1 h. To identify cells in the S/G2 phase of the cell cycle, cells were stained by the anti-cyclin A antibody (1:250, Santa Cruz Biotechnology, Dallas, TX, USA; H-432).	('cyclin A', 'Gene', (267, 275))	('PBS', 'Chemical', '-', (111, 114))	('Triton X-100', 'Chemical', 'MESH:D017830', (120, 132))	('PBS', 'Chemical', '-', (162, 165))	('cyclin A', 'Gene', '890', (267, 275))	('PBS', 'Chemical', '-', (30, 33))	('Triton X-100', 'Chemical', 'MESH:D017830', (39, 51))	('S/G2', 'Var', (206, 210))	('S/G2', 'SUBSTITUTION', 'None', (206, 210))
13332	33668653	Other primary antibodies used were as follows: anti-H2AX Ser139 (1:250; Cell Signaling 978), anti-RPA1 (1:250; Santa Cruz Biotechnology B6), anti-RAD51 (1:250 H-92; Santa Cruz Biotechnology), anti-BRCA1 (1:100 D9; Santa Cruz Biotechnology), anti-FANCD2 (1:250; Novus Biologicals, Centennial, CO, USA; NB100-182) and anti-53BP1 (1:250; OriGene, Rockville, MD, USA; ta309918).	('53BP1', 'Gene', '7158', (321, 326))	('BRCA1', 'Gene', (197, 202))	('RPA1', 'Gene', '6117', (98, 102))	('RAD51', 'Gene', (146, 151))	('Ser139', 'Chemical', '-', (57, 63))	('H2AX', 'Gene', (52, 56))	('FANCD2', 'Gene', '2177', (246, 252))	('H2AX', 'Gene', '3014', (52, 56))	('FANCD2', 'Gene', (246, 252))	('RAD51', 'Gene', '5888', (146, 151))	('1:250;', 'Var', (254, 260))	('BRCA1', 'Gene', '672', (197, 202))	('RPA1', 'Gene', (98, 102))	('53BP1', 'Gene', (321, 326))
13339	33668653	Cells were seeded in a 96-well plate at the appropriate density (2102EP 3.5 x 103 cells/well; GCT27 2.5 x 103 cells/well) and, the next day, were incubated with the appropriate drugs, accordingly with the experimental setting.	('men', 'Species', '9606', (211, 214))	('2102EP', 'Var', (65, 71))	('GCT27', 'Gene', (94, 99))
13357	33668653	We found that the GCT27cis-r and 2102EPcis-r cell lines were more resistant to cisplatin (Figure S1A,B), with a resistance factor (RF) determined from the ratio of half-maximal inhibitor concentrations (IC50 cis-r/IC50 cis-s) of 4 and 3.6, respectively, and an RF determined from IC90 ratios increased by over fivefold (Table 2).	('GCT27cis-r', 'Var', (18, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('resistant', 'MPA', (66, 75))	('cis-r', 'Chemical', '-', (208, 213))	('cis-r', 'Chemical', '-', (39, 44))	('cis-r', 'Chemical', '-', (23, 28))	('2102EPcis-r', 'Var', (33, 44))
13369	33668653	The analysis of 2102EP paired cell lines revealed that under these experimental conditions, the load of DNA damage induced by cisplatin in 2102EPcis-r was reduced relative to 2102EPcis-s cells (t = 0, Figure S2B).	('2102EPcis-r', 'Var', (139, 150))	('men', 'Species', '9606', (73, 76))	('cis-r', 'Chemical', '-', (145, 150))	('reduced', 'NegReg', (155, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('load', 'MPA', (96, 100))
13372	33668653	In accordance with these results, the percentage of apoptotic cells in the sub-G1 phase of the cell cycle was reduced in both GCT27cis-r and 2102EPcis-r cells, indicating that cells that repaired the damage survived the treatment (Figure S2C,D).	('reduced', 'NegReg', (110, 117))	('cis-r', 'Chemical', '-', (131, 136))	('men', 'Species', '9606', (225, 228))	('2102EPcis-r', 'Var', (141, 152))	('GCT27cis-r', 'Var', (126, 136))	('cis-r', 'Chemical', '-', (147, 152))
13375	33668653	MN can originate from missegregation of whole chromosomes at anaphase or from lagging acentric chromosomes or chromatid fragments caused by misrepaired or unrepaired DNA breaks.	('originate from', 'Reg', (7, 21))	('MN', 'CellLine', 'CVCL:U508', (0, 2))	('missegregation', 'Var', (22, 36))	('men', 'Species', '9606', (124, 127))
13385	33668653	As shown in Figure 1F,G, we observed that the number of FANCD2 foci was much greater in GCT27cis-r cells than in their cis-s counterparts, both after a 6 h pulse of cisplatin and 16 h after drug washout.	('FANCD2', 'Gene', (56, 62))	('cis-r', 'Chemical', '-', (93, 98))	('GCT27cis-r', 'Var', (88, 98))	('greater', 'PosReg', (77, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('FANCD2', 'Gene', '2177', (56, 62))
13387	33668653	We concluded that in GCT27cis-r cells, activation of the FA pathway occurs with a higher efficiency than in GCT27cis-s cells.	('cis-r', 'Chemical', '-', (26, 31))	('GCT27cis-r', 'Var', (21, 31))	('FA pathway', 'Pathway', (57, 67))
13395	33668653	As quantified in Figure 2A,B, we found that in GCT27cis-r cells, RPA and RAD51 foci were increased significantly compared to their cis-s counterparts at both examined time points.	('RPA', 'Gene', (65, 68))	('GCT27cis-r', 'Var', (47, 57))	('RAD51', 'Gene', (73, 78))	('RPA', 'Gene', '6117', (65, 68))	('RAD51', 'Gene', '5888', (73, 78))	('increased', 'PosReg', (89, 98))	('cis-r', 'Chemical', '-', (52, 57))
13400	33668653	We observed that in GCT27cis-r cells, the proficiency in HR repair was increased by twofold relative to GCT27cis-s cells (Figure 2C).	('cis-r', 'Chemical', '-', (25, 30))	('GCT27cis-r', 'Var', (20, 30))	('HR repair', 'CPA', (57, 66))	('increased', 'PosReg', (71, 80))
13401	33668653	We also observed a significant increase in HR in 2102EPcis-r cells, although with a reduced magnitude (Figure 2D).	('2102EPcis-r', 'Var', (49, 60))	('cis-r', 'Chemical', '-', (55, 60))	('increase', 'PosReg', (31, 39))
13404	33668653	As shown in Figure 2E,F, PARPi sensitivity was reduced in cis-r cells compared to their cis-s counterparts, with a greater effect observed in GCT27cis-r cells.	('PARP', 'Gene', (25, 29))	('cis-r cells', 'Var', (58, 69))	('cis-r', 'Chemical', '-', (58, 63))	('reduced', 'NegReg', (47, 54))	('PARP', 'Gene', '142', (25, 29))	('cis-r', 'Chemical', '-', (147, 152))
13406	33668653	We measured a significant increase in the percentage of GFP+ cells in GCT27cis-r cells (Figure 2G), indicating that in resistant cells, HR contributed significantly to the repair of ICL-induced DSBs.	('DSBs', 'Chemical', '-', (194, 198))	('cis-r', 'Chemical', '-', (75, 80))	('ICL-induced DSBs', 'Disease', (182, 198))	('increase', 'PosReg', (26, 34))	('repair', 'MPA', (172, 178))	('GCT27cis-r', 'Var', (70, 80))
13410	33668653	We observed that while RAD51 was evenly expressed across cell lines, the expression of CtIP was increased in GCT27cis-r cells (Figure 3A).	('CtIP', 'Gene', (87, 91))	('increased', 'PosReg', (96, 105))	('cis-r', 'Chemical', '-', (114, 119))	('CtIP', 'Gene', '5932', (87, 91))	('GCT27cis-r', 'Var', (109, 119))	('RAD51', 'Gene', (23, 28))	('expression', 'MPA', (73, 83))	('RAD51', 'Gene', '5888', (23, 28))
13413	33668653	Using Western blotting, we observed that BRCA1 basal expression was higher in GCT27cis-r cells (Figure 3A).	('BRCA1', 'Gene', '672', (41, 46))	('basal expression', 'MPA', (47, 63))	('higher', 'PosReg', (68, 74))	('BRCA1', 'Gene', (41, 46))	('GCT27cis-r', 'Var', (78, 88))	('cis-r', 'Chemical', '-', (83, 88))
13415	33668653	We observed that GCT27cis-r cells could assemble a significantly greater number of BRCA1 foci onto DNA, both in untreated and treated cells (Figure 3C).	('BRCA1', 'Gene', '672', (83, 88))	('greater', 'PosReg', (65, 72))	('cis-r', 'Chemical', '-', (22, 27))	('BRCA1', 'Gene', (83, 88))	('GCT27cis-r', 'Var', (17, 27))
13420	33668653	Loss of 53BP1 alleviates HR repair defects and overcomes PARPi sensitivity of BRCA1-deficient cells by restoring DNA end resection and RAD51 loading.	('restoring', 'PosReg', (103, 112))	('overcomes', 'NegReg', (47, 56))	('PARP', 'Gene', (57, 61))	('53BP1', 'Gene', (8, 13))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (78, 93))	('RAD51', 'Gene', (135, 140))	('HR repair defects', 'MPA', (25, 42))	('PARP', 'Gene', '142', (57, 61))	('DNA end resection', 'MPA', (113, 130))	('RAD51', 'Gene', '5888', (135, 140))	('Loss', 'Var', (0, 4))	('BRCA1-deficient', 'Disease', (78, 93))	('alleviates', 'NegReg', (14, 24))	('53BP1', 'Gene', '7158', (8, 13))
13427	33668653	We found that NHEJ proficiency was reduced in both 2102EPcis-r and GCT27cis-r cells compared to their cis-s counterparts (Figure 4A,B).	('GCT27cis-r', 'Var', (67, 77))	('reduced', 'NegReg', (35, 42))	('cis-r', 'Chemical', '-', (57, 62))	('2102EPcis-r', 'Var', (51, 62))	('NHEJ proficiency', 'CPA', (14, 30))	('cis-r', 'Chemical', '-', (72, 77))
13430	33668653	Thus, to understand if the sensitivity of the cell lines to X-rays was linked to reduced 53BP1 function, we quantified 53BP1 foci in S/G2 phase cells after exposure to 5 Gy of IR.	('53BP1', 'Gene', (89, 94))	('53BP1', 'Gene', '7158', (89, 94))	('53BP1', 'Gene', (119, 124))	('53BP1', 'Gene', '7158', (119, 124))	('S/G2', 'Var', (133, 137))	('S/G2', 'SUBSTITUTION', 'None', (133, 137))	('reduced', 'NegReg', (81, 88))	('function', 'MPA', (95, 103))
13433	33668653	To investigate whether the reduced assembly of 53BP1 during S/G2 might be relevant to 2102EPcis-r and GCT27cis-r response to cisplatin, we quantified 53BP1 foci after drug treatment.	('53BP1', 'Gene', (150, 155))	('53BP1', 'Gene', (47, 52))	('cis-r', 'Chemical', '-', (107, 112))	('53BP1', 'Gene', '7158', (150, 155))	('53BP1', 'Gene', '7158', (47, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('S/G2', 'Var', (60, 64))	('cis-r', 'Chemical', '-', (92, 97))	('men', 'Species', '9606', (177, 180))	('S/G2', 'SUBSTITUTION', 'None', (60, 64))
13434	33668653	To this end, cis-s and cis-r paired cell lines were exposed to cisplatin for 6 h and S/G2-phase cells were stained with anti-53BP1 antibody.	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('cis-r', 'Chemical', '-', (23, 28))	('53BP1', 'Gene', (125, 130))	('S/G2', 'Var', (85, 89))	('53BP1', 'Gene', '7158', (125, 130))	('S/G2', 'SUBSTITUTION', 'None', (85, 89))
13436	33668653	Similarly, a reduction in foci and binding onto chromatin was observed in GCT27cis-r cells after 6 h of treatment (Figure 4H and Figure S4G).	('binding', 'Interaction', (35, 42))	('foci', 'CPA', (26, 30))	('GCT27cis-r', 'Var', (74, 84))	('reduction', 'NegReg', (13, 22))	('men', 'Species', '9606', (109, 112))	('cis-r', 'Chemical', '-', (79, 84))
13438	33668653	These results suggest a correlation between reduced 53BP1 expression/assembly in S/G2 and acquired resistance to cisplatin.	('expression/assembly', 'MPA', (58, 77))	('53BP1', 'Gene', (52, 57))	('53BP1', 'Gene', '7158', (52, 57))	('reduced', 'NegReg', (44, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('S/G2', 'Var', (81, 85))	('S/G2', 'SUBSTITUTION', 'None', (81, 85))
13439	33668653	This assumption predicts that modulation of 53BP1 expression level should alter the response of cell lines to cisplatin.	('alter', 'Reg', (74, 79))	('53BP1', 'Gene', (44, 49))	('53BP1', 'Gene', '7158', (44, 49))	('response', 'MPA', (84, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('modulation', 'Var', (30, 40))
13442	33668653	As shown in Figure 5B and quantified in Figure 5C, we found that upregulation of 53BP1 in 2102EPcis-r cells increased their sensitivity to cisplatin by approximately two- to threefold compared to 2102EPcis-r transfected with a control vector (Ctr).	('cis-r', 'Chemical', '-', (96, 101))	('53BP1', 'Gene', '7158', (81, 86))	('sensitivity to cisplatin', 'MPA', (124, 148))	('increased', 'PosReg', (108, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('2102EPcis-r', 'Var', (90, 101))	('upregulation', 'PosReg', (65, 77))	('cis-r', 'Chemical', '-', (202, 207))	('53BP1', 'Gene', (81, 86))
13444	33668653	Therefore, we investigated whether dampening of the 53BP1 protein level in GCT27cis-s cells could induce cisplatin resistance.	('induce', 'Reg', (98, 104))	('53BP1', 'Gene', (52, 57))	('53BP1', 'Gene', '7158', (52, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('dampening', 'Var', (35, 44))	('cisplatin resistance', 'MPA', (105, 125))
13448	33668653	As shown in Figure 5E, silencing of 53BP1 in GCT27cis-s cells significantly increased their survival following exposure cisplatin at all tested doses of the drug.	('53BP1', 'Gene', (36, 41))	('survival', 'CPA', (92, 100))	('53BP1', 'Gene', '7158', (36, 41))	('increased', 'PosReg', (76, 85))	('silencing', 'Var', (23, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
13455	33668653	Interestingly, treatment of 2102EPcis-r and GCT27cis-r cells (which have a reduced 53BP1 protein level) with 2.5 and 5 microM DNA-PKi doses, respectively, did not reduce cisplatin cytotoxicity (Figure 5F,G).	('cytotoxicity', 'Disease', (180, 192))	('cis-r', 'Chemical', '-', (49, 54))	('cytotoxicity', 'Disease', 'MESH:D064420', (180, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('reduced', 'NegReg', (75, 82))	('GCT27cis-r', 'Var', (44, 54))	('53BP1', 'Gene', (83, 88))	('53BP1', 'Gene', '7158', (83, 88))	('cis-r', 'Chemical', '-', (34, 39))	('reduce', 'NegReg', (163, 169))	('men', 'Species', '9606', (20, 23))
13457	33668653	To further test the consequence of combining cisplatin and DNA-PKi, we compared the effect of the combination with that of each single drug using the combination index (CI), where CI < 1, CI = 1 and CI > 1 indicated synergistic, additive and antagonistic effects, respectively.	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('CI > 1', 'Var', (199, 205))	('CI < 1', 'Var', (180, 186))	('CI = 1', 'Var', (188, 194))
13468	33668653	Conversely, AZD2281 has limited toxicity in patients and in recombination-proficient cells, such as the non-tumorigenic breast epithelial cell line MCF10A, treated with clinically achievable doses (Figure S6A).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MCF10A', 'CellLine', 'CVCL:0598', (148, 154))	('AZD2281', 'Chemical', 'MESH:C531550', (12, 19))	('tumor', 'Disease', (108, 113))	('AZD2281', 'Var', (12, 19))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('toxicity', 'Disease', (32, 40))
13473	33668653	This experiment revealed that in both experimental settings, AZD2281 enhances the cytotoxicity of cisplatin in both cis-r cell lines (Figure 6A,B).	('AZD2281', 'Var', (61, 68))	('cytotoxicity', 'Disease', (82, 94))	('cis-r', 'Chemical', '-', (116, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('enhances', 'PosReg', (69, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('men', 'Species', '9606', (44, 47))	('AZD2281', 'Chemical', 'MESH:C531550', (61, 68))	('men', 'Species', '9606', (11, 14))
13475	33668653	Importantly, the analysis of drugs' interaction revealed that when AZD2281 was given at a dose of 1 microM (a sub-lethal dose in recombination-proficient cells, Figure S6A), the drugs interacted additively, while the interaction was synergistic at concentrations >= 2 microM, regardless of the administration schedule (Table 4).	('AZD2281', 'Var', (67, 74))	('interacted additively', 'Interaction', (184, 205))	('AZD2281', 'Chemical', 'MESH:C531550', (67, 74))
13476	33668653	Finally, we tested whether pre-treatment with AZD2281 could enhance the effect of cisplatin/AZD2281 combined therapy.	('tested', 'Reg', (12, 18))	('AZD2281', 'Chemical', 'MESH:C531550', (46, 53))	('men', 'Species', '9606', (36, 39))	('AZD2281', 'Chemical', 'MESH:C531550', (92, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('AZD2281', 'Var', (46, 53))	('enhance', 'PosReg', (60, 67))
13479	33668653	In the present work, we show that both GCT27cis-r and 2102EPcis-r cell lines have increased proficiency in repairing ICL-induced DSBs compared to their cis-s counterparts.	('GCT27cis-r', 'Var', (39, 49))	('repairing ICL-induced DSBs', 'Disease', (107, 133))	('DSBs', 'Chemical', '-', (129, 133))	('cis-r', 'Chemical', '-', (60, 65))	('cis-r', 'Chemical', '-', (44, 49))
13485	33668653	Moreover, we also observed increased efficiency in DSBs' repair by HR, and this correlates with increased expression and binding onto chromatin of RAD51 and CtIP and loading of RPA and BRCA1 after cisplatin-induced DNA damage.	('RPA', 'Gene', '6117', (177, 180))	('increased', 'PosReg', (96, 105))	('RAD51', 'Gene', (147, 152))	('increased', 'PosReg', (27, 36))	('BRCA1', 'Gene', (185, 190))	('RAD51', 'Gene', '5888', (147, 152))	('expression', 'MPA', (106, 116))	('DSBs', 'Var', (51, 55))	('RPA', 'Gene', (177, 180))	('loading', 'MPA', (166, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (197, 206))	('binding', 'Interaction', (121, 128))	('DSBs', 'Chemical', '-', (51, 55))	('BRCA1', 'Gene', '672', (185, 190))	('CtIP', 'Gene', (157, 161))	('CtIP', 'Gene', '5932', (157, 161))
13489	33668653	Thus, we propose that dampening of the 53BP1 protein level contributes to the improved proficiency in HR repair of GCT27cis-r cells compared to their cis-s counterpart.	('GCT27cis-r', 'Var', (115, 125))	('53BP1', 'Gene', (39, 44))	('cis-r', 'Chemical', '-', (120, 125))	('improved', 'PosReg', (78, 86))	('HR repair', 'CPA', (102, 111))	('53BP1', 'Gene', '7158', (39, 44))
13491	33668653	In agreement with this hypothesis, resection of DSBs (as measured by loading of RPA and RAD51 foci) and HR repair proficiency are significantly increased in 2102EPcis-r cells compared to their cis-s counterpart.	('resection', 'CPA', (35, 44))	('RPA', 'Gene', '6117', (80, 83))	('men', 'Species', '9606', (8, 11))	('cis-r', 'Chemical', '-', (163, 168))	('RPA', 'Gene', (80, 83))	('2102EPcis-r', 'Var', (157, 168))	('HR repair proficiency', 'CPA', (104, 125))	('RAD51', 'Gene', (88, 93))	('RAD51', 'Gene', '5888', (88, 93))	('increased', 'PosReg', (144, 153))	('DSBs', 'Chemical', '-', (48, 52))
13503	33668653	Silencing of 53BP1 in GCT27cis-s cells increases their cisplatin resistance, whereas increased 53BP1 expression in 2102EPcis-r cells sensitizes them to cisplatin.	('cis-r', 'Chemical', '-', (121, 126))	('53BP1', 'Gene', (95, 100))	('53BP1', 'Gene', '7158', (95, 100))	('53BP1', 'Gene', (13, 18))	('53BP1', 'Gene', '7158', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('cisplatin resistance', 'MPA', (55, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('sensitizes', 'Reg', (133, 143))	('increased', 'PosReg', (85, 94))	('increases', 'PosReg', (39, 48))	('expression', 'MPA', (101, 111))	('Silencing', 'Var', (0, 9))
13521	33668653	At the basis of the combinatorial effect, there might be the downregulation, caused by AZD2281, of HR protein expression, with consequent sensitization to cisplatin-induced damage.	('downregulation', 'NegReg', (61, 75))	('AZD2281', 'Chemical', 'MESH:C531550', (87, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('AZD2281', 'Var', (87, 94))	('HR protein', 'Protein', (99, 109))
13534	33668653	Investigation on the response of cis-r cells to treatment with a PARP inhibitor revealed that, beside resistance of these cells in monotherapy, the PARPi AZD2281 exerted an additive/synergistic effect when combined with cisplatin, suggesting the possibility of introducing PARPi(s) in salvage therapy of patients.	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('PARP', 'Gene', (273, 277))	('AZD2281', 'Var', (154, 161))	('PARP', 'Gene', '142', (148, 152))	('patients', 'Species', '9606', (304, 312))	('cis-r', 'Chemical', '-', (33, 38))	('PARP', 'Gene', '142', (273, 277))	('PARP', 'Gene', (65, 69))	('AZD2281', 'Chemical', 'MESH:C531550', (154, 161))	('PARP', 'Gene', (148, 152))	('men', 'Species', '9606', (53, 56))	('PARP', 'Gene', '142', (65, 69))
13619	30847172	2, the cumulative paternity rate in TSS group is significantly higher than in RO group (log-rank test, P=0.0051).	('TSS', 'Chemical', '-', (36, 39))	('higher', 'PosReg', (63, 69))	('RO', 'Chemical', '-', (78, 80))	('TSS', 'Var', (36, 39))
13708	30456190	In a meta-analysis of four studies which included 130 patients F-FDG PET/CT proved to be superior to standard imaging procedures in predicting viable residual tumors.	('F-FDG', 'Chemical', '-', (63, 68))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('F-FDG', 'Var', (63, 68))
13710	30456190	The use of F-FDG PET/CT led to a significant reduction of overtreatment from 72% to 30% and undertreatment was decreased from 14% to 7%.	('to 7', 'Species', '1214577', (130, 134))	('F-FDG', 'Chemical', '-', (11, 16))	('men', 'Species', '9606', (67, 70))	('men', 'Species', '9606', (102, 105))	('overtreatment', 'MPA', (58, 71))	('reduction', 'NegReg', (45, 54))	('F-FDG', 'Var', (11, 16))
13740	26349679	Of note was the impact of rs995030 at 12q21 which was high, at just under 2%.	('12q21', 'Gene', (38, 43))	('rs995030', 'Mutation', 'rs995030', (26, 34))	('rs995030', 'Var', (26, 34))
13744	26349679	In addition rare variants, indels and structural alterations, which all have potential to contribute to the heritable risk of cancer, are not generally well-captured by GWAS.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('contribute', 'Reg', (90, 100))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('indels', 'Var', (27, 33))	('structural alterations', 'Var', (38, 60))
13770	26558006	Patients undergoing L-RPLND on average have shorter hospital stays, a quicker return to normal activity and improved cosmesis.	('cosmesis', 'CPA', (117, 125))	('Patients', 'Species', '9606', (0, 8))	('improved', 'PosReg', (108, 116))	('L-RPLND', 'Var', (20, 27))
13806	26558006	Patients should be aware that manipulation of the sympathetic chain could result in retrograde ejaculation.	('result in', 'Reg', (74, 83))	('manipulation', 'Var', (30, 42))	('Patients', 'Species', '9606', (0, 8))	('retrograde ejaculation', 'Phenotype', 'HP:0012877', (84, 106))	('retrograde ejaculation', 'MPA', (84, 106))
13812	26558006	Induction chemotherapy regimens typically include bleomycin, which has been associated with pulmonary fibrosis; this can cause several postoperative respiratory issues, including respiratory distress syndrome.	('respiratory issues', 'Phenotype', 'HP:0002795', (149, 167))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (92, 110))	('respiratory distress syndrome', 'Disease', 'MESH:D012128', (179, 208))	('pulmonary fibrosis', 'Disease', (92, 110))	('respiratory distress syndrome', 'Disease', (179, 208))	('associated', 'Reg', (76, 86))	('bleomycin', 'Var', (50, 59))	('bleomycin', 'Chemical', 'MESH:D001761', (50, 59))	('cause', 'Reg', (121, 126))	('respiratory distress', 'Phenotype', 'HP:0002098', (179, 199))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (92, 110))
13815	26558006	The use of nephrotoxic medications should be minimised in patients who received cisplatin, given its deleterious effects on renal function.	('renal', 'MPA', (124, 129))	('nephrotoxic', 'Disease', (11, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('nephrotoxic', 'Disease', 'MESH:D007674', (11, 22))	('patients', 'Species', '9606', (58, 66))	('cisplatin', 'Var', (80, 89))
13883	26558006	Although comparative data are limited, L-RPLND appears to be comparable to open RPLND for perioperative complications and oncological efficacy, while providing patients with improved cosmesis and a faster recovery time.	('L-RPLND', 'Var', (39, 46))	('patients', 'Species', '9606', (160, 168))	('improved', 'PosReg', (174, 182))	('cosmesis', 'CPA', (183, 191))
13885	23666239	In the combined analysis, TGCT risk was significantly associated with markers at four novel loci: 4q22.2 in HPGDS (per allele odds ratio (OR) 1.19, 95%CI 1.12-1.26, P = 1.11x10-8); 7p22.3 in MAD1L1 (OR 1.21, 95%CI 1.14-1.29, P = 5.59x10-9); 16q22.3 in RFWD3 (OR 1.26, 95%CI 1.18-1.34, P = 5.15x10-12); and 17q22 (rs9905704; OR 1.27, 95%CI 1.18-1.33; P = 4.32x10-13, and rs7221274; OR 1.20, 95%CI 1.12-1.28 P = 4.04x10-9), a locus which includes TEX14, RAD51C and PPM1E.	('TGCT', 'Disease', (26, 30))	('TEX14', 'Gene', (445, 450))	('HPGDS', 'Gene', '27306', (108, 113))	('RFWD3', 'Gene', (252, 257))	('rs7221274; OR', 'Var', (370, 383))	('TEX14', 'Gene', '56155', (445, 450))	('MAD1L1', 'Gene', '8379', (191, 197))	('rs9905704', 'Mutation', 'rs9905704', (313, 322))	('RAD51C', 'Gene', '5889', (452, 458))	('HPGDS', 'Gene', (108, 113))	('MAD1L1', 'Gene', (191, 197))	('RFWD3', 'Gene', '55159', (252, 257))	('RAD51C', 'Gene', (452, 458))	('rs7221274', 'Mutation', 'rs7221274', (370, 379))
13892	23666239	Initially, two independent genome wide association studies (GWAS) identified allele variation within KITLG on 12q22 as the strongest genetic risk factor for TGCT, with a per allele odds ratio (OR) greater than 3.	('risk factor', 'Reg', (141, 152))	('TGCT', 'Disease', (157, 161))	('KITLG', 'Gene', (101, 106))	('allele variation', 'Var', (77, 93))	('KITLG', 'Gene', '4254', (101, 106))
13893	23666239	Variants on 5p15.33 (TERT- two independent loci), 5q31.3 (SPRY4), 6p21.3 (BAK1), 9p24.3 (DMRT1- two independent loci), and 12p13.1 (ATF7IP) also have been associated with TGCT risk.	('Variants', 'Var', (0, 8))	('TGCT', 'Disease', (171, 175))	('ATF7IP', 'Gene', (132, 138))	('SPRY4', 'Gene', (58, 63))	('TERT', 'Gene', (21, 25))	('DMRT1', 'Gene', '1761', (89, 94))	('TERT', 'Gene', '7015', (21, 25))	('associated with', 'Reg', (155, 170))	('SPRY4', 'Gene', '81848', (58, 63))	('ATF7IP', 'Gene', '55729', (132, 138))	('DMRT1', 'Gene', (89, 94))
13903	23666239	The most significant 4q22.2 SNP marker, rs17021463, is located within the intron of the hematopoietic prostaglandin D synthase gene, HPGDS (P = 1.11x10-8, OR 1.19, 95%CI 1.12-1.26) (Figure 1A, Table 1).	('prostaglandin D synthase', 'Gene', (102, 126))	('HPGDS', 'Gene', '27306', (133, 138))	('rs17021463', 'Mutation', 'rs17021463', (40, 50))	('prostaglandin D synthase', 'Gene', '5730', (102, 126))	('HPGDS', 'Gene', (133, 138))	('rs17021463', 'Var', (40, 50))
13905	23666239	Disruption of hpgds leads to modification of the phenotype of apcMin/+ mice.	('mice', 'Species', '10090', (71, 75))	('phenotype', 'MPA', (49, 58))	('Disruption', 'Var', (0, 10))	('hpgds', 'Gene', (14, 19))	('hpgds', 'Gene', '54486', (14, 19))	('modification', 'Reg', (29, 41))
13906	23666239	Seventy-one surrogate markers highly correlate with HPGDS rs17021463 (r2 >= 0.8, 1000 Genomes CEU data, Supplementary Table 5).	('rs17021463', 'Var', (58, 68))	('HPGDS', 'Gene', (52, 57))	('men', 'Species', '9606', (110, 113))	('rs17021463', 'Mutation', 'rs17021463', (58, 68))	('HPGDS', 'Gene', '27306', (52, 57))
13907	23666239	Notably, rs35744894 (r2 = 0.87) changes a DMRT2 binding motif (Supplementary Table 6); variation in DMRT1 has been associated with TGCT risk.	('changes', 'Reg', (32, 39))	('men', 'Species', '9606', (69, 72))	('DMRT1', 'Gene', (100, 105))	('variation', 'Var', (87, 96))	('DMRT1', 'Gene', '1761', (100, 105))	('binding', 'Interaction', (48, 55))	('associated', 'Reg', (115, 125))	('rs35744894', 'Mutation', 'rs35744894', (9, 19))	('TGCT', 'Disease', (131, 135))	('rs35744894', 'Var', (9, 19))
13908	23666239	Fifty-three of 71 surrogate markers that were highly correlated with HPGDS rs17021463 (r2 >= 0.8, 1000 Genomes CEU data, Supplementary Table 5) across a 200kb window mapped within or near an adjacent gene, SMARCAD1 (SWI/SNF-related, matrix-associated actin-dependent regulator of chromatin, subfamily a, containing DEAD/H box 1).	('SMARCAD1', 'Gene', '56916', (206, 214))	('HPGDS', 'Gene', (69, 74))	('SMARCAD1', 'Gene', (206, 214))	('rs17021463', 'Var', (75, 85))	('rs17021463', 'Mutation', 'rs17021463', (75, 85))	('men', 'Species', '9606', (127, 130))	('HPGDS', 'Gene', '27306', (69, 74))
13910	23666239	Homozygous mutant mice display developmental defects, including impaired fertility.	('mutant', 'Var', (11, 17))	('developmental defects', 'Disease', 'MESH:D003147', (31, 52))	('impaired fertility', 'Phenotype', 'HP:0000144', (64, 82))	('mice', 'Species', '10090', (18, 22))	('impaired fertility', 'Disease', 'MESH:D009422', (64, 82))	('developmental defects', 'Disease', (31, 52))	('impaired fertility', 'Disease', (64, 82))
13911	23666239	Surrogate markers included one nonsynonymous substitution, rs7439869, at codon 301 (r2 = 0.93, 1000 Genomes CEU, T>C, Val>Ala).	('rs7439869', 'Mutation', 'rs7439869', (59, 68))	('rs7439869', 'Var', (59, 68))	('Val', 'Chemical', 'MESH:D014633', (118, 121))	('T>C', 'Var', (113, 116))	('Ala', 'Chemical', 'MESH:D000409', (122, 125))
13918	23666239	Among the 35 SNPs that are highly correlated with MAD1L1 rs12699477 (r2 >= 0.7, 1000 Genomes CEU data, Supplementary Table 5), rs1801368 is a missense mutation at codon 558 (G>A, Arg>His) that resides in the MAD1L1 second leucine zipper domain.	('rs1801368', 'Var', (127, 136))	('MAD1L1', 'Gene', (208, 214))	('MAD1L1', 'Gene', '8379', (208, 214))	('MAD1L1', 'Gene', '8379', (50, 56))	('rs1801368', 'Mutation', 'rs1801368', (127, 136))	('MAD1L1', 'Gene', (50, 56))	('His', 'Chemical', 'MESH:D006639', (183, 186))	('G>A', 'Var', (174, 177))	('men', 'Species', '9606', (109, 112))	('rs12699477', 'Mutation', 'rs12699477', (57, 67))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))
13919	23666239	Arg558His has been reported to be associated with lung cancer risk and may lead to reduced binding of MAD2 to MAD1, resulting in decreased proficiency in enforcing mitotic arrest.	('lung cancer', 'Disease', (50, 61))	('associated', 'Reg', (34, 44))	('mitotic arrest', 'Disease', (164, 178))	('reduced', 'NegReg', (83, 90))	('MAD2', 'Gene', (102, 106))	('MAD1', 'Gene', (110, 114))	('mitotic arrest', 'Disease', 'MESH:D006323', (164, 178))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('MAD2', 'Gene', '4085', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Arg558His', 'Mutation', 'rs1801368', (0, 9))	('MAD1', 'Gene', '8379', (110, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('Arg558His', 'Var', (0, 9))	('binding', 'Interaction', (91, 98))	('proficiency', 'MPA', (139, 150))	('decreased', 'NegReg', (129, 138))
13920	23666239	We observed additional statistically significant associations with TGCT for neighboring SNPs in the MAD1L1 region, including rs10275045 (P=3.78x10-10, OR 1.20, 95%CI (1.13-1.27)) and rs3778991 (P=6.73x10-10, OR 1.21, 95%CI (1.14-1.28)).	('MAD1L1', 'Gene', '8379', (100, 106))	('MAD1L1', 'Gene', (100, 106))	('rs3778991', 'Var', (183, 192))	('rs3778991', 'Mutation', 'rs3778991', (183, 192))	('associations', 'Reg', (49, 61))	('rs10275045', 'Var', (125, 135))	('rs10275045', 'Mutation', 'rs10275045', (125, 135))	('TGCT', 'Disease', (67, 71))
13924	23666239	We observed a significant TGCT association with rs4888262 on 16q22.3 (P = 5.15x10-12, OR 1.26, 95%CI 1.18-1.34), which is a synonymous SNP in codon 404 (G>A, Thr) of the ring finger WD domain 3 (RFWD3) (Table 1, Figure 1C).	('rs4888262', 'Var', (48, 57))	('codon 404 (G>A', 'Mutation', 'c.CODON404G>A', (142, 156))	('WD', 'Disease', 'MESH:D006527', (197, 199))	('TGCT', 'MPA', (26, 30))	('Thr', 'Chemical', 'MESH:D013912', (158, 161))	('WD', 'Disease', 'MESH:D006527', (182, 184))	('RFWD3', 'Gene', (195, 200))	('rs4888262', 'Mutation', 'rs4888262', (48, 57))	('RFWD3', 'Gene', '55159', (195, 200))
13927	23666239	We note that rs3851729, which is highly correlated with rs4888262 (r2 = 0.77, 1000 Genomes CEU), maps to a highly conserved sequence in the 3' UTR of GLG1; similarly, rs4072222 (r2 = 0.87, 1000 Genomes CEU) maps to an intron of MLKL (Supplementary Table 5).	('rs3851729', 'Var', (13, 22))	('rs3851729', 'Mutation', 'rs3851729', (13, 22))	('men', 'Species', '9606', (240, 243))	('GLG1', 'Gene', '2734', (150, 154))	('GLG1', 'Gene', (150, 154))	('MLKL', 'Gene', '197259', (228, 232))	('rs4888262', 'Mutation', 'rs4888262', (56, 65))	('MLKL', 'Gene', (228, 232))	('rs4072222', 'Var', (167, 176))	('rs4072222', 'Mutation', 'rs4072222', (167, 176))	('rs4888262', 'Var', (56, 65))
13928	23666239	Both susceptibility variants are cis-eQTLs that influence MLKL and RFWD3 expression in monocytes.	('variants', 'Var', (20, 28))	('RFWD3', 'Gene', (67, 72))	('MLKL', 'Gene', '197259', (58, 62))	('MLKL', 'Gene', (58, 62))	('RFWD3', 'Gene', '55159', (67, 72))	('expression', 'MPA', (73, 83))	('influence', 'Reg', (48, 57))
13929	23666239	We identified two highly correlated SNPs (r2 = 0.74 in the STEED controls) on 17q22, rs9905704 (P = 4.32x10-13, OR 1.27, 95%CI 1.18-1.33) and rs7221274 (P = 4.04x10-9, OR 1.20, 95%CI 1.12-1.28) (Table 1, Figure 1D).	('rs9905704', 'Mutation', 'rs9905704', (85, 94))	('rs7221274', 'Mutation', 'rs7221274', (142, 151))	('rs7221274', 'Var', (142, 151))	('rs9905704', 'Var', (85, 94))
13931	23666239	Within this LD block are at least six plausible candidate genes: RAD51C (RAD51 homolog C [S. cerevisiae]), TEX14 (testis expressed 14), PPM1E (protein phosphatase, Mg2+/Mn2+ dependent, 1E), SEPT4 (septin 4), TRIM37 (tripartite motif containing 37), and SKA2 (spindle and kinetochore associated complex subunit 2) (Figure 1D).	('PPM1E', 'Var', (136, 141))	('RAD51C', 'Gene', '5889', (65, 71))	('RAD51', 'Gene', '856831', (73, 78))	('SKA2', 'Gene', '348235', (253, 257))	('tripartite', 'Chemical', '-', (216, 226))	('RAD51C', 'Gene', (65, 71))	('S. cerevisiae', 'Species', '4932', (90, 103))	('TRIM37', 'Gene', (208, 214))	('RAD51', 'Gene', (73, 78))	('SEPT4', 'Gene', (190, 195))	('TRIM37', 'Gene', '4591', (208, 214))	('TEX14', 'Gene', (107, 112))	('TEX14', 'Gene', '56155', (107, 112))	('RAD51', 'Gene', '856831', (65, 70))	('Mg2+', 'Chemical', '-', (164, 168))	('Mn2+', 'Chemical', '-', (169, 173))	('SKA2', 'Gene', (253, 257))	('RAD51', 'Gene', (65, 70))
13935	23666239	TEX14 is an essential component of germ cell intercellular bridges, evolutionarily conserved structures from invertebrates to humans that allows clonal development of daughter cells in syncytium; targeted disruption of Tex14 results in male sterility in mice.	('Tex14', 'Gene', '56155', (219, 224))	('TEX14', 'Gene', (0, 5))	('male', 'Disease', (236, 240))	('disruption', 'Var', (205, 215))	('results in', 'Reg', (225, 235))	('Tex14', 'Gene', (219, 224))	('men', 'Species', '9606', (159, 162))	('TEX14', 'Gene', '56155', (0, 5))	('mice', 'Species', '10090', (254, 258))	('humans', 'Species', '9606', (126, 132))
13938	23666239	TRIM37 encodes a RING-B-box-coiled-coil protein; rare mutations in this gene cause the autosomal recessive disease mulibrey nanism (MUL; MIM 253250), in which adult males have testicular failure.	('TRIM37', 'Gene', (0, 6))	('cause', 'Reg', (77, 82))	('TRIM37', 'Gene', '4591', (0, 6))	('autosomal recessive disease mulibrey nanism', 'Disease', (87, 130))	('testicular failure', 'Disease', 'MESH:C543092', (176, 194))	('mutations', 'Var', (54, 63))	('testicular failure', 'Disease', (176, 194))	('autosomal recessive disease mulibrey nanism', 'Disease', 'MESH:D050336', (87, 130))
13939	23666239	Three SNPs - rs8077332, rs11652713, and rs9898048 - map within TRIM37 and are in perfect LD with rs7221274 (r2 = 1, 1000 Genomes CEU, Supplementary Table 5); all are cis-eQTL affecting RAD51C expression in monocytes.	('RAD51C', 'Gene', (185, 191))	('men', 'Species', '9606', (140, 143))	('RAD51C', 'Gene', '5889', (185, 191))	('TRIM37', 'Gene', (63, 69))	('affecting', 'Reg', (175, 184))	('expression', 'MPA', (192, 202))	('rs7221274', 'Mutation', 'rs7221274', (97, 106))	('TRIM37', 'Gene', '4591', (63, 69))	('rs11652713', 'Mutation', 'rs11652713', (24, 34))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('rs11652713', 'Var', (24, 34))	('rs8077332', 'Mutation', 'rs8077332', (13, 22))	('rs9898048 -', 'Var', (40, 51))	('rs9898048', 'Mutation', 'rs9898048', (40, 49))
13943	23666239	None of the four newly identified loci have been previously implicated in GWAS of other cancers, further supporting that there are distinct pathways and regions implicated in TGCT susceptibility; however rare mutations in RAD51C have been implicated in ovarian cancer susceptibility.	('ovarian cancer', 'Disease', 'MESH:D010051', (253, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('ovarian cancer', 'Disease', (253, 267))	('RAD51C', 'Gene', (222, 228))	('cancers', 'Disease', (88, 95))	('RAD51C', 'Gene', '5889', (222, 228))	('implicated', 'Reg', (239, 249))	('mutations', 'Var', (209, 218))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))
13944	23666239	TGCT susceptibility is particularly unique in that many of the associated genes affect male germ cell development and differentiation, thus emphasizing the potential detrimental effect that inherited variation in this developmental process can have on the tumorigenic potential of the primordial germ cell.	('genes', 'Var', (74, 79))	('affect', 'Reg', (80, 86))	('differentiation', 'CPA', (118, 133))	('male germ cell development', 'CPA', (87, 113))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('men', 'Species', '9606', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('variation', 'Var', (200, 209))	('men', 'Species', '9606', (109, 112))	('men', 'Species', '9606', (171, 174))	('tumor', 'Disease', (256, 261))
13945	23666239	This study is the first to implicate variation within genes involved in chromosomal segregation as associated with cancer susceptibility.	('variation', 'Var', (37, 46))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('associated', 'Reg', (99, 109))
13947	23666239	Variation in these genes may lead to chromosomal instability and facilitate the development of aneuploidy.	('aneuploidy', 'Disease', 'MESH:D000782', (95, 105))	('lead to', 'Reg', (29, 36))	('men', 'Species', '9606', (87, 90))	('chromosomal instability', 'CPA', (37, 60))	('facilitate', 'PosReg', (65, 75))	('aneuploidy', 'Disease', (95, 105))	('Variation', 'Var', (0, 9))	('chromosomal instability', 'Phenotype', 'HP:0040012', (37, 60))
13956	23666239	Genomic annotation on high LD surrogates (r2 >= 0.8, 1000 Genomes CEU) of 5 SNPs (rs17021463, rs12699477, rs4888262, rs9905704, and rs7221274) from the four TGCT susceptibility loci identified in the current study was conducted using ENCODE tools - HaploReg and RegulomeDB (Supplementary Table 5).	('rs12699477', 'Var', (94, 104))	('rs17021463', 'Var', (82, 92))	('rs4888262', 'Mutation', 'rs4888262', (106, 115))	('rs7221274', 'Var', (132, 141))	('rs9905704', 'Var', (117, 126))	('rs12699477', 'Mutation', 'rs12699477', (94, 104))	('rs9905704', 'Mutation', 'rs9905704', (117, 126))	('rs4888262', 'Var', (106, 115))	('rs7221274', 'Mutation', 'rs7221274', (132, 141))	('rs17021463', 'Mutation', 'rs17021463', (82, 92))	('men', 'Species', '9606', (280, 283))
13961	23666239	Twenty-nine SNPs that passed one of these criteria also changed a motif, and are annotated further with the motif of interest and their log-odds (LOD) motif score for the specific SNP of interest in Supplementary Table 6.	('changed', 'Reg', (56, 63))	('SNPs', 'Var', (12, 16))	('men', 'Species', '9606', (205, 208))	('motif', 'MPA', (66, 71))
13964	21255381	The calculated per-allele odds ratio for variants in the region of KITLG is the highest reported for any malignancy so far.	('variants', 'Var', (41, 49))	('KITLG', 'Gene', '4254', (67, 72))	('KITLG', 'Gene', (67, 72))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))
13977	21255381	A candidate study has identified a deletion in the Y chromosome azoospermia factor C (AZFc) region (known as the gr/gr deletion) as a TGCT risk locus (odds ratio (OR) = 3.2 and 2.1 in familial and sporadic TGCT, respectively).	('azoospermia', 'Disease', (64, 75))	('TGCT', 'Disease', (134, 138))	('azoospermia', 'Phenotype', 'HP:0000027', (64, 75))	('chromosome azoospermia', 'Phenotype', 'HP:0011961', (53, 75))	('deletion', 'Var', (35, 43))	('azoospermia', 'Disease', 'MESH:D053713', (64, 75))	('familial', 'Disease', (184, 192))
13978	21255381	Single nucleotide polymorphisms (SNPs) with significant associations were located in regions containing the genes KITLG (encoding a ligand for the tyrosine kinase KIT) and SPRY4 (encoding an inhibitor of the mitogen-activated protein kinase pathway acting downstream of KITLG-KIT).	('KITLG', 'Gene', '4254', (114, 119))	('KITLG', 'Gene', (114, 119))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('KITLG', 'Gene', '4254', (270, 275))	('SPRY4', 'Gene', (172, 177))	('KITLG', 'Gene', (270, 275))	('SPRY4', 'Gene', '81848', (172, 177))
13981	21255381	The calculated per-allele OR for variants in the region of KITLG (OR = 2.69) is the highest reported for any malignancy to date.	('malignancy', 'Disease', (109, 119))	('KITLG', 'Gene', '4254', (59, 64))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('KITLG', 'Gene', (59, 64))	('variants', 'Var', (33, 41))
13995	21255381	TGCT has a larger genetic component than many other complex diseases, and recently identified risk marker alleles confer, at least in part, higher relative risks than those identified for other cancers.	('alleles', 'Var', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('TGCT', 'Disease', (0, 4))	('higher', 'PosReg', (140, 146))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))
13997	21255381	General population genetic assessment using genetic variants that modify TGCT risk currently has no proven value for risk prediction.	('TGCT', 'Gene', (73, 77))	('variants', 'Var', (52, 60))	('men', 'Species', '9606', (33, 36))
14000	21255381	GWAS: genome-wide association study; OR: odds ratio; SNP: single nucleotide polymorphism; TGCT: testicular germ cell tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('single nucleotide polymorphism', 'Var', (58, 88))	('germ cell tumor', 'Phenotype', 'HP:0100728', (107, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
14004	32148661	Cisplatin-Based Chemotherapy of Human Cancers Cisplatin (cis-diammine-dichloro-platinum II) was initially discovered to prevent the growth of Escherichia coli and was further recognized for its anti-neoplastic and cytotoxic effects on cancer cells.	('Cisplatin', 'Var', (46, 55))	('Cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('prevent', 'NegReg', (120, 127))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('cis-diammine-dichloro-platinum II', 'Chemical', 'MESH:D002945', (57, 90))	('Cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Cancers', 'Disease', (38, 45))	('Cancers', 'Disease', 'MESH:D009369', (38, 45))	('growth', 'MPA', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Escherichia coli', 'Species', '562', (142, 158))	('Human', 'Species', '9606', (32, 37))
14026	32148661	Evidence from tissue culture studies reveals that drug resistance may stem from epigenetic modifications at both cellular and molecular levels; including high levels of DNA damage repair (DDR), modifications in DNA methylation progress, uprooted and low regulation of mRNA expression levels, impairment in transcriptional regulation, and interference with apoptosis.	('impairment', 'NegReg', (292, 302))	('low', 'NegReg', (250, 253))	('stem from', 'Reg', (70, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (50, 65))	('uprooted', 'PosReg', (237, 245))	('apoptosis', 'CPA', (356, 365))	('modifications', 'Var', (194, 207))	('drug', 'Disease', (50, 54))	('mRNA expression levels', 'MPA', (268, 290))	('DNA methylation progress', 'Gene', (211, 235))	('interference', 'NegReg', (338, 350))	('transcriptional regulation', 'MPA', (306, 332))	('men', 'Species', '9606', (298, 301))	('DNA damage repair', 'MPA', (169, 186))
14029	32148661	Moreover, once ATM is activated it maintains and phosphorylates tumor suppressor gene p53 which may induce transactivation of several genes inclusing p21 gene responsible for cell cycle growth arrest, DNA damage inducible gene 45 (GADD45) involved in DNA repair, and Bax to facilitate in apoptosis.	('ATM', 'Gene', '472', (15, 18))	('arrest', 'Disease', 'MESH:D006323', (193, 199))	('GADD45', 'Gene', '1647', (231, 237))	('p21', 'Gene', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('p21', 'Gene', '644914', (150, 153))	('GADD45', 'Gene', (231, 237))	('p53', 'Gene', '7157', (86, 89))	('p53', 'Gene', (86, 89))	('ATM', 'Gene', (15, 18))	('arrest', 'Disease', (193, 199))	('tumor', 'Disease', (64, 69))	('phosphorylates', 'Var', (49, 63))	('transactivation', 'MPA', (107, 122))	('Bax', 'Gene', (267, 270))	('growth arrest', 'Phenotype', 'HP:0001510', (186, 199))	('apoptosis', 'CPA', (288, 297))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Bax', 'Gene', '581', (267, 270))
14062	32148661	However, cisplatin is also known to induce unfavorable side effects and drug resistance, especially after long-term exposure.	('cisplatin', 'Var', (9, 18))	('drug resistance', 'CPA', (72, 87))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))
14083	32148661	In addition, refusal of cisplatin in PC3 cell lines is assumed to be due to the mutation and/or the nonoperation of p53 gene.	('p53', 'Gene', (116, 119))	('PC3', 'CellLine', 'CVCL:0035', (37, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('mutation', 'Var', (80, 88))	('p53', 'Gene', '7157', (116, 119))
14134	31221747	Thus, in turn, GST P1-1 overexpression and Pt-induced subunit cross-linking could modulate JNK apoptotic signaling, further confirming the role of GST P1-1 as an antiapoptotic protein.	('JNK', 'Gene', (91, 94))	('GST P1-1', 'Gene', (147, 155))	('GST P1-1', 'Gene', '2950', (15, 23))	('modulate', 'Reg', (82, 90))	('overexpression', 'PosReg', (24, 38))	('cross-linking', 'Var', (62, 75))	('JNK', 'Gene', '5599', (91, 94))	('Pt', 'Chemical', 'MESH:D010984', (43, 45))	('GST P1-1', 'Gene', '2950', (147, 155))	('GST P1-1', 'Gene', (15, 23))
14142	31221747	Notably, GSH depletion has been shown to sensitize formerly cis-DDP-resistant cell lines.	('sensitize', 'Reg', (41, 50))	('depletion', 'Var', (13, 22))	('GSH', 'Chemical', 'MESH:D005978', (9, 12))	('cis-DDP', 'Chemical', 'MESH:D002945', (60, 67))	('GSH', 'MPA', (9, 12))
14143	31221747	Furthermore, it has recently been shown that simultaneous administration of GSH and cis-DDP induces cis-DDP resistance in human lung carcinoma A549 cells.	('human', 'Species', '9606', (122, 127))	('induces', 'Reg', (92, 99))	('GSH', 'Chemical', 'MESH:D005978', (76, 79))	('cis-DDP', 'Var', (84, 91))	('cis-DDP', 'Chemical', 'MESH:D002945', (100, 107))	('lung carcinoma A549', 'Disease', (128, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lung carcinoma A549', 'Disease', 'MESH:D008175', (128, 147))	('cis-DDP', 'Chemical', 'MESH:D002945', (84, 91))	('cis-DDP resistance', 'MPA', (100, 118))
14151	31221747	GST Pi class enzymes, including GST P1-1, are characterized by 2 solvent-accessible cysteine residues that affect catalytic activity when modified: C47, located near the G site and fundamental for maintaining the conformation and stability of the G site; and C101, located at the dimer interface, which can form a disulfide bond with C47, requiring a large-scale conformational change that leads to inactivation of the enzyme.	('catalytic activity', 'MPA', (114, 132))	('GST', 'Gene', (0, 3))	('affect', 'Reg', (107, 113))	('GST P1-1', 'Gene', (32, 40))	('GST', 'Gene', '2950', (32, 35))	('GST P1-1', 'Gene', '2950', (32, 40))	('inactivation', 'MPA', (399, 411))	('disulfide', 'Chemical', 'MESH:D004220', (314, 323))	('GST', 'Gene', (32, 35))	('cysteine', 'Chemical', 'MESH:D003545', (84, 92))	('C101', 'Var', (259, 263))	('GST', 'Gene', '2950', (0, 3))	('modified', 'Var', (138, 146))	('C101', 'Chemical', '-', (259, 263))	('C47', 'Var', (148, 151))
14152	31221747	To date, several drugs, such as chlorambucil and ethacrynic acid, have been shown to be effective substrates or inhibitors of GSTs, whereas other drugs, such as doxorubicin, do not interact with this family of enzymes, although inhibition of GST P1-1 increases sensitivity of certain cancer cell lines to this anticancer compound.	('inhibition', 'Var', (228, 238))	('cancer', 'Disease', (314, 320))	('increases', 'PosReg', (251, 260))	('ethacrynic acid', 'Chemical', 'MESH:D004976', (49, 64))	('chlorambucil', 'Chemical', 'MESH:D002699', (32, 44))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('sensitivity', 'MPA', (261, 272))	('doxorubicin', 'Chemical', 'MESH:D004317', (161, 172))	('GST P1-1', 'Gene', '2950', (242, 250))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('inhibitors', 'NegReg', (112, 122))	('GST P1-1', 'Gene', (242, 250))	('GSTs', 'Gene', '27306', (126, 130))	('GSTs', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
14162	31221747	The study presented here investigated the role of GST P1-1 in cellular response to cis-DDP using a neuroblastoma cell line (SH-SY5Y) transfected with GST P1-1 and either C47S, C101S, or C47S/C101S mutant enzymes.	('C101S', 'Var', (176, 181))	('C47S/C101S', 'Var', (186, 196))	('GST P1-1', 'Gene', (50, 58))	('C101S', 'Mutation', 'p.C101S', (191, 196))	('cis-DDP', 'Chemical', 'MESH:D002945', (83, 90))	('C47S', 'Mutation', 'p.C47S', (170, 174))	('GST P1-1', 'Gene', '2950', (50, 58))	('neuroblastoma', 'Disease', 'MESH:D009447', (99, 112))	('GST P1-1', 'Gene', (150, 158))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (124, 131))	('neuroblastoma', 'Disease', (99, 112))	('GST P1-1', 'Gene', '2950', (150, 158))	('C101S', 'Mutation', 'p.C101S', (176, 181))	('C47S', 'Mutation', 'p.C47S', (186, 190))	('neuroblastoma', 'Phenotype', 'HP:0003006', (99, 112))	('C47S', 'Var', (170, 174))
14164	31221747	Of note, high levels of GSTP1 were associated with decreased event-free and overall survival.	('GSTP1', 'Gene', (24, 29))	('GSTP1', 'Gene', '2950', (24, 29))	('overall survival', 'CPA', (76, 92))	('decreased', 'NegReg', (51, 60))	('high levels', 'Var', (9, 20))
14167	31221747	The SH-SY5Y cell line was transfected with plasmids coding for WT GST P1-1 and Cys-modified enzymes (C47S, C101S, C47S/C101S).	('C47S', 'Var', (101, 105))	('C101S', 'Var', (107, 112))	('C47S', 'Mutation', 'p.C47S', (114, 118))	('GST P1-1', 'Gene', '2950', (66, 74))	('C101S', 'Mutation', 'p.C101S', (119, 124))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (4, 11))	('C47S', 'Mutation', 'p.C47S', (101, 105))	('GST P1-1', 'Gene', (66, 74))	('C101S', 'Mutation', 'p.C101S', (107, 112))	('C47S/C101S', 'Var', (114, 124))	('Cys', 'Chemical', 'MESH:D003545', (79, 82))
14169	31221747	There was a significant increase in the expression of GST P1-1 in transfected cell lines in comparison with nontransfected cell lines (SI Appendix, Fig.	('expression', 'MPA', (40, 50))	('transfected', 'Var', (66, 77))	('increase', 'PosReg', (24, 32))	('GST P1-1', 'Gene', (54, 62))	('SI Appendix', 'Disease', 'MESH:D001063', (135, 146))	('SI Appendix', 'Disease', (135, 146))	('GST P1-1', 'Gene', '2950', (54, 62))
14170	31221747	In parallel, the GST specific activity increased in all transfected clones compared with the controls, in the range of 2- to 5-fold (for the mutants) and 9-fold (for WT) (SI Appendix, Fig.	('mutants', 'Var', (141, 148))	('increased', 'PosReg', (39, 48))	('SI Appendix', 'Disease', 'MESH:D001063', (171, 182))	('GST', 'Gene', '2950', (17, 20))	('GST', 'Gene', (17, 20))	('SI Appendix', 'Disease', (171, 182))
14173	31221747	Cell viability of SH-SY5Y cell lines transfected with WT and mutant GSTP1 was assessed using the MTS (3-[4,5,dimethylthiazol-2-yl]-5-[3-carboxymethoxy-phenyl]-2-[4-sulfophenyl]-2H-tetrazolium) assay and fluorescence activated cell sorting (FACS) analysis after treatment with graded doses of cis-DDP for 24 h (Fig.	('cis-DDP', 'Chemical', 'MESH:D002945', (292, 299))	('GSTP1', 'Gene', (68, 73))	('mutant', 'Var', (61, 67))	('GSTP1', 'Gene', '2950', (68, 73))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (18, 25))
14175	31221747	Similar levels of protection were not observed after transfection with the mutated forms of GSTP1.	('mutated', 'Var', (75, 82))	('GSTP1', 'Gene', '2950', (92, 97))	('GSTP1', 'Gene', (92, 97))
14176	31221747	Transfection with GSTP1 C47S afforded some protection toward cell death, which became more significant at the higher cis-DDP doses tested (Fig.	('cell death', 'CPA', (61, 71))	('cis-DDP', 'Chemical', 'MESH:D002945', (117, 124))	('GSTP1', 'Gene', (18, 23))	('C47S', 'Mutation', 'p.C47S', (24, 28))	('C47S', 'Var', (24, 28))	('GSTP1', 'Gene', '2950', (18, 23))
14177	31221747	In contrast, the cells transfected with GSTP1 C101S and the double mutation C47S/C101S showed no protection to cell death.	('GSTP1', 'Gene', (40, 45))	('C101S', 'Mutation', 'p.C101S', (46, 51))	('C101S', 'Var', (46, 51))	('C101S', 'Mutation', 'p.C101S', (81, 86))	('C47S', 'Mutation', 'p.C47S', (76, 80))	('GSTP1', 'Gene', '2950', (40, 45))	('C47S/C101S', 'Var', (76, 86))
14183	31221747	The data show that the spontaneous reaction rate was not affected by the presence of GST P1-1.	('presence', 'Var', (73, 81))	('GST P1-1', 'Gene', '2950', (85, 93))	('GST P1-1', 'Gene', (85, 93))
14185	31221747	cis-DDP was shown to inhibit GST P1-1 activity under certain conditions.	('activity', 'MPA', (38, 46))	('cis-DDP', 'Chemical', 'MESH:D002945', (0, 7))	('GST P1-1', 'Gene', '2950', (29, 37))	('inhibit', 'NegReg', (21, 28))	('cis-DDP', 'Var', (0, 7))	('GST P1-1', 'Gene', (29, 37))
14190	31221747	Inactivation of GST P1-1 occurred more rapidly at low concentrations of NaCl, with the order:in both rate and extent of inactivation:being WT > C47S > C101S.	('GST P1-1', 'Gene', (16, 24))	('C47S', 'Mutation', 'p.C47S', (144, 148))	('GST P1-1', 'Gene', '2950', (16, 24))	('Inactivation', 'MPA', (0, 12))	('NaCl', 'Chemical', 'MESH:D012965', (72, 76))	('C47S > C101S', 'Var', (144, 156))	('C101S', 'Mutation', 'p.C101S', (151, 156))	('C101S', 'Var', (151, 156))
14191	31221747	The C101S mutant retained 60% residual activity after 40 min of incubation, whereas the WT was completely inactivated over the same time period (Fig.	('C101S', 'Var', (4, 9))	('activity', 'MPA', (39, 47))	('C101S', 'Mutation', 'p.C101S', (4, 9))
14192	31221747	To assess the platination of GST P1-1 by cis-DDP, WT GST P1-1 and its mutants, C47S and C101S, were each incubated in a 1:1 protein-to-drug ratio (50 muM) at 37  C for up to 72 h. Subsequent analysis by SDS/PAGE (sodium dodecyl sulphate/polyacrylamide gel electrophoresis) under nonreducing conditions showed that the Pt-free WT and C47S samples migrated, for the most part, as a single species with an approximate molecular mass of 24 kDa.	('muM', 'Gene', (150, 153))	('GST P1-1', 'Gene', (53, 61))	('Pt', 'Chemical', 'MESH:D010984', (318, 320))	('cis-DDP', 'Chemical', 'MESH:D002945', (41, 48))	('C101S', 'Mutation', 'p.C101S', (88, 93))	('C47S', 'Var', (333, 337))	('C47S', 'Mutation', 'p.C47S', (333, 337))	('GST P1-1', 'Gene', '2950', (29, 37))	('C47S', 'Mutation', 'p.C47S', (79, 83))	('GST P1-1', 'Gene', '2950', (53, 61))	('SDS', 'Chemical', 'MESH:D012967', (203, 206))	('muM', 'Gene', '56925', (150, 153))	('GST P1-1', 'Gene', (29, 37))
14198	31221747	Incubation of WT GST P1-1 with cis-DDP resulted in complete cross-linking of the dimer during the first 24 h (Fig.	('cis-DDP', 'Chemical', 'MESH:D002945', (31, 38))	('GST P1-1', 'Gene', (17, 25))	('cross-linking', 'MPA', (60, 73))	('GST P1-1', 'Gene', '2950', (17, 25))	('cis-DDP', 'Var', (31, 38))
14200	31221747	ESI-MS analysis after 8 h of incubation identified equivalent peaks in both the C47S and C101S mutant samples (Fig.	('C101S', 'Var', (89, 94))	('C101S', 'Mutation', 'p.C101S', (89, 94))	('C47S', 'Var', (80, 84))	('C47S', 'Mutation', 'p.C47S', (80, 84))
14205	31221747	3 C, peak L), but multiple monomeric adducts attributed to C101S with 1 or 2 Pt species (Fig.	('Pt', 'Chemical', 'MESH:D010984', (77, 79))	('C101S', 'Mutation', 'p.C101S', (59, 64))	('C101S', 'Var', (59, 64))	('monomeric adducts', 'MPA', (27, 44))
14206	31221747	The data of the C101S mutant are also consistent with the gel electrophoresis experiments in which a band was observed around 50 kDa before the addition of cis-DDP that intensified with time, but did not represent the majority of the protein.	('cis-DDP', 'Chemical', 'MESH:D002945', (156, 163))	('intensified', 'PosReg', (169, 180))	('C101S', 'Mutation', 'p.C101S', (16, 21))	('C101S', 'Var', (16, 21))
14207	31221747	Rather, a laddering effect of higher-molecular-weight species accounts for the majority of the protein species at 72 h. The rate of intersubunit cross-linking of all of the WT, C47S, and C101S proteins was accelerated as the concentration of cis-DDP increased (SI Appendix, Fig.	('SI Appendix', 'Disease', (261, 272))	('C101S', 'Mutation', 'p.C101S', (187, 192))	('C101S', 'Var', (187, 192))	('C47S', 'Var', (177, 181))	('C47S', 'Mutation', 'p.C47S', (177, 181))	('proteins', 'Protein', (193, 201))	('cis-DDP', 'Chemical', 'MESH:D002945', (242, 249))	('accelerated', 'PosReg', (206, 217))	('SI Appendix', 'Disease', 'MESH:D001063', (261, 272))
14208	31221747	The crystal structure of WT GST P1-1 complexed to cis-DDP was determined to a resolution of 1.9 A. Cis-DDP was found to bind to the dimer interface of WT GST P1-1 in 2 different modes.	('GST P1-1', 'Gene', '2950', (28, 36))	('GST P1-1', 'Gene', (154, 162))	('Cis-DDP', 'Var', (99, 106))	('bind', 'Interaction', (120, 124))	('GST P1-1', 'Gene', (28, 36))	('Cis-DDP', 'Chemical', 'MESH:D002945', (99, 106))	('cis-DDP', 'Chemical', 'MESH:D002945', (50, 57))	('GST P1-1', 'Gene', '2950', (154, 162))
14233	31221747	Specifically, posttranslational modifications of C47 are thought to modify the function of the protein, with S-glutathionylation leading to oligomerization and carboxymethylation or S-nitrosylation reducing affinity for GSH through changes in the preequilibrium between the open and closed conformations of helix alpha2.	('GSH', 'Chemical', 'MESH:D005978', (220, 223))	('affinity', 'Interaction', (207, 215))	('C47', 'Gene', (49, 52))	('oligomerization', 'MPA', (140, 155))	('function', 'MPA', (79, 87))	('S-nitrosylation', 'Var', (182, 197))	('leading to', 'Reg', (129, 139))	('preequilibrium', 'MPA', (247, 261))	('modify', 'Reg', (68, 74))	('modifications', 'Var', (32, 45))	('helix alpha2', 'Protein', (307, 319))	('reducing', 'NegReg', (198, 206))	('S-glutathionylation', 'Var', (109, 128))	('GSH', 'Protein', (220, 223))	('changes', 'Reg', (232, 239))
14234	31221747	C101 has also been implicated in regulation of activity, with reports of similar posttranslational modifications to those of C47, but to a lesser extent.	('C101', 'Var', (0, 4))	('activity', 'MPA', (47, 55))	('implicated', 'Reg', (19, 29))	('C101', 'Chemical', '-', (0, 4))
14235	31221747	In addition, C47-C47 intersubunit and C47-C101 intrasubunit disulfide binding can occur, which inactivates the protein for GSH transferase activity.	('protein', 'Protein', (111, 118))	('inactivates', 'NegReg', (95, 106))	('C101', 'Chemical', '-', (42, 46))	('C47-C101', 'Var', (38, 46))	('C47-C47', 'Var', (13, 20))	('activity', 'MPA', (139, 147))	('GSH', 'Chemical', 'MESH:D005978', (123, 126))	('disulfide', 'Chemical', 'MESH:D004220', (60, 69))	('C47-C47', 'CellLine', 'CVCL:L675', (13, 20))
14236	31221747	To investigate the role of C47 and C101 in the direct interaction of GST P1-1 with cis-DDP, plasmids coding for the WT and cysteine mutant enzymes were transfected into neuroblastoma SH-SY5Y cells.	('neuroblastoma', 'Disease', 'MESH:D009447', (169, 182))	('cysteine', 'Chemical', 'MESH:D003545', (123, 131))	('neuroblastoma', 'Disease', (169, 182))	('cis-DDP', 'Chemical', 'MESH:D002945', (83, 90))	('mutant', 'Var', (132, 138))	('neuroblastoma', 'Phenotype', 'HP:0003006', (169, 182))	('GST P1-1', 'Gene', (69, 77))	('C101', 'Chemical', '-', (35, 39))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (183, 190))	('GST P1-1', 'Gene', '2950', (69, 77))
14239	31221747	Of note, single point mutations of the cysteine residues affording the C47S or C101S variants reduce this protection, giving an order of cis-DDP sensitivity, determined by the proliferation assay and FACS analysis, as C101S > C47S > WT GST P1-1.	('cis-DDP', 'Chemical', 'MESH:D002945', (137, 144))	('C47S', 'Var', (71, 75))	('GST P1-1', 'Gene', (236, 244))	('variants', 'Var', (85, 93))	('C101S', 'Mutation', 'p.C101S', (218, 223))	('C47S', 'Var', (226, 230))	('C101S variants', 'Var', (79, 93))	('C47S', 'Mutation', 'p.C47S', (71, 75))	('C47S', 'Mutation', 'p.C47S', (226, 230))	('cysteine', 'Chemical', 'MESH:D003545', (39, 47))	('GST P1-1', 'Gene', '2950', (236, 244))	('C101S', 'Mutation', 'p.C101S', (79, 84))	('reduce', 'NegReg', (94, 100))	('protection', 'MPA', (106, 116))	('C101S > C47S', 'Var', (218, 230))
14240	31221747	Therefore, C101 appears to be more important because mutation of this residue makes cells more sensitive to cis-DDP compared with mutation of C47.	('mutation', 'Var', (53, 61))	('cis-DDP', 'Chemical', 'MESH:D002945', (108, 115))	('sensitive to cis-DDP', 'MPA', (95, 115))	('C101', 'Chemical', '-', (11, 15))	('more', 'PosReg', (90, 94))
14241	31221747	C101 is more solvent accessible than C47, although, surprisingly, it has been relatively overlooked in previous studies compared with C47.	('C101', 'Var', (0, 4))	('C101', 'Chemical', '-', (0, 4))	('solvent accessible', 'MPA', (13, 31))
14242	31221747	Platination of C101 cannot sterically hinder GSH binding based on its location in the crystal structures.	('GSH', 'Chemical', 'MESH:D005978', (45, 48))	('Platination', 'Var', (0, 11))	('C101', 'Var', (15, 19))	('C101', 'Chemical', '-', (15, 19))	('GSH', 'Protein', (45, 48))
14243	31221747	Therefore, the observation that the C101 mutant has a greater effect on cis-DDP resistance compared with mutation of C47 suggests that the mechanism may not involve GSH conjugation.	('GSH', 'Chemical', 'MESH:D005978', (165, 168))	('cis-DDP', 'Chemical', 'MESH:D002945', (72, 79))	('C101', 'Var', (36, 40))	('C101', 'Chemical', '-', (36, 40))	('cis-DDP resistance', 'MPA', (72, 90))
14249	31221747	The major binding mode shows cis-DDP mediating an intersubunit cross-link via the C101 residues, whereas the minor binding mode shows cis-DDP bound to a single C101 and possibly represents an intermediate stage before intersubunit cross-linking is complete.	('C101', 'Chemical', '-', (82, 86))	('cis-DDP', 'Var', (29, 36))	('C101', 'Var', (160, 164))	('intersubunit cross-link', 'MPA', (50, 73))	('cis-DDP', 'Chemical', 'MESH:D002945', (29, 36))	('cis-DDP', 'Chemical', 'MESH:D002945', (134, 141))	('C101', 'Var', (82, 86))	('C101', 'Chemical', '-', (160, 164))
14252	31221747	The order of inactivation follows the order WT-Pt > C47S-Pt > C101S-Pt, which is inversely related to the order of cis-DDP sensitivity as measured by the proliferation assay.	('C101S-Pt', 'Var', (62, 70))	('Pt', 'Chemical', 'MESH:D010984', (47, 49))	('Pt', 'Chemical', 'MESH:D010984', (68, 70))	('cis-DDP', 'Chemical', 'MESH:D002945', (115, 122))	('C47S', 'Mutation', 'p.C47S', (52, 56))	('C47S-Pt', 'Var', (52, 59))	('Pt', 'Chemical', 'MESH:D010984', (57, 59))	('C101S', 'Mutation', 'p.C101S', (62, 67))
14259	31221747	These observations are further confirmed by the altered cytotoxicity of cis-DDP after treating SH-SY5Y cells transfected with the WT enzyme and its cysteine mutants.	('SH-SY5Y', 'CellLine', 'CVCL:0019', (95, 102))	('cis-DDP', 'Chemical', 'MESH:D002945', (72, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('altered', 'Reg', (48, 55))	('cysteine', 'Chemical', 'MESH:D003545', (148, 156))	('cytotoxicity', 'Disease', (56, 68))	('mutants', 'Var', (157, 164))
14260	31221747	In particular, in the absence of C101, cis-DDP is not sequestered by the enzyme and its cytotoxicity is almost comparable to that exerted on nontransfected cells (Fig.	('C101', 'Chemical', '-', (33, 37))	('cytotoxicity', 'Disease', (88, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (88, 100))	('cis-DDP', 'Var', (39, 46))	('cis-DDP', 'Chemical', 'MESH:D002945', (39, 46))
14261	31221747	The removal of both cysteines (C101S/C47S mutant) eliminates all possible cis-DDP anchor points on the enzyme, allowing it to exert its cytotoxic action unperturbed (Fig.	('cis-DDP anchor points', 'MPA', (74, 95))	('eliminates', 'NegReg', (50, 60))	('C47S', 'Mutation', 'p.C47S', (37, 41))	('cysteines', 'Chemical', 'MESH:D003545', (20, 29))	('C101S/C47S', 'Var', (31, 41))	('C101S', 'Mutation', 'p.C101S', (31, 36))	('cytotoxic', 'MPA', (136, 145))	('cis-DDP', 'Chemical', 'MESH:D002945', (74, 81))
14279	31221747	WT GST P1-1 and its cysteine mutants (0.2 mg/mL, 10 muM in active sites) were incubated in 1 mL (final volume) of PBS or in 10 mM phosphate buffer solution plus 2 mM NaCl (pH 7.4) in the presence of 1 mM cis-DDP at 37  C. At fixed times, over a period of 40 min, aliquots of sample (5 muL) were withdrawn from the mixture and assayed for residual GST activity in 100 mM phosphate buffer (pH 6.5) containing 1 mM GSH and 1 mM CDNB.	('GST', 'Gene', '2950', (347, 350))	('GST P1-1', 'Gene', '2950', (3, 11))	('GSH', 'Chemical', 'MESH:D005978', (412, 415))	('GST', 'Gene', (347, 350))	('NaCl', 'Chemical', 'MESH:D012965', (166, 170))	('muM', 'Gene', '56925', (52, 55))	('CDNB', 'Chemical', 'MESH:D004137', (425, 429))	('GST P1-1', 'Gene', (3, 11))	('mutants', 'Var', (29, 36))	('cis-DDP', 'Chemical', 'MESH:D002945', (204, 211))	('muM', 'Gene', (52, 55))	('GST', 'Gene', '2950', (3, 6))	('GST', 'Gene', (3, 6))	('PBS', 'Chemical', '-', (114, 117))	('cysteine', 'Chemical', 'MESH:D003545', (20, 28))
14281	31221747	WT GST P1-1 and the C47S and C101S mutants (50 muM) were each incubated with cis-DDP (50 muM) in potassium phosphate buffer solution (pH 7.0) at 37  C for 8 h. The samples were diluted 1:10 in water, and 5 muL was introduced into the mass spectrometer by infusion at a flow rate of 20 muL/min with a solution of acetonitrile, H2O, and formic acid [55:44.9:0.1, vol/vol/vol)].	('GST P1-1', 'Gene', '2950', (3, 11))	('muM', 'Gene', (89, 92))	('water', 'Chemical', 'MESH:D014867', (193, 198))	('C101S', 'Mutation', 'p.C101S', (29, 34))	('C101S', 'Var', (29, 34))	('muM', 'Gene', (47, 50))	('potassium phosphate', 'Chemical', 'MESH:C013216', (97, 116))	('GST P1-1', 'Gene', (3, 11))	('C47S', 'Var', (20, 24))	('C47S', 'Mutation', 'p.C47S', (20, 24))	('cis-DDP', 'Chemical', 'MESH:D002945', (77, 84))	('muM', 'Gene', '56925', (89, 92))	('muM', 'Gene', '56925', (47, 50))
14337	30531061	demonstrated that all participants with inhibin B >56 pg ml-1 12 months after the end of antineoplastic therapy maintained good semen quality at 3 years, while lower values were predictive of the risk of azoospermia.	('men', 'Species', '9606', (130, 133))	('participants', 'Species', '9606', (22, 34))	('inhibin B', 'Gene', (40, 49))	('azoospermia', 'Disease', 'MESH:D053713', (204, 215))	('>56 pg', 'Var', (50, 56))	('azoospermia', 'Disease', (204, 215))	('semen quality', 'CPA', (128, 141))	('azoospermia', 'Phenotype', 'HP:0000027', (204, 215))
14343	30531061	An inhibin B level <92 pg ml-1 was associated with increased risks of total sperm number below 39 x 106 ml-1 (odds ratio [OR]: 16.93, 95% confidential interval [CI]: 9.82-29.18), asthenozoospermia, and teratozoospermia.	('teratozoospermia', 'Phenotype', 'HP:0012864', (202, 218))	('asthenozoospermia', 'Disease', (179, 196))	('below', 'NegReg', (89, 94))	('teratozoospermia', 'Disease', (202, 218))	('inhibin B', 'Protein', (3, 12))	('<92', 'Var', (19, 22))	('teratozoospermia', 'Disease', 'MESH:D000072660', (202, 218))	('asthenozoospermia', 'Disease', 'MESH:D053627', (179, 196))
14386	30250431	reported in a meta-analysis that approximately 35% of focal 18FDG-PET positive thyroid nodules were cancerous.	('thyroid nodules', 'Disease', (79, 94))	('cancerous', 'Disease', (100, 109))	('thyroid nodules', 'Phenotype', 'HP:0025388', (79, 94))	('18FDG', 'Chemical', 'MESH:D019788', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancerous', 'Disease', 'MESH:D009369', (100, 109))	('focal', 'Var', (54, 59))
14387	30250431	Contrastingly, diffuse 18FDG-PET uptake is associated with benign disease.	('diffuse 18FDG-PET uptake', 'Var', (15, 39))	('18FDG', 'Chemical', 'MESH:D019788', (23, 28))	('benign disease', 'Disease', (59, 73))	('associated', 'Reg', (43, 53))	('benign disease', 'Disease', 'MESH:D009369', (59, 73))
14403	30250431	showed that 68Ga PET/CT may also be highly sensitive to identifying bone metastases in thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (87, 104))	('metastases', 'Disease', (73, 83))	('thyroid carcinoma', 'Disease', (87, 104))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('68Ga PET/CT', 'Var', (12, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (87, 104))	('68Ga', 'Chemical', 'MESH:C000615430', (12, 16))
14412	30250431	For example, in MEN type 1, mutations in menin gene is associated with tumors of parathyroid, pituitary, and pancreatic glands, while MEN 2 is characterized by mutations in the RET proto-oncogene and leads to the development of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (238, 255))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('MEN', 'Species', '9606', (16, 19))	('RET', 'Gene', (177, 180))	('hyperparathyroidism', 'Disease', (279, 298))	('leads to', 'Reg', (200, 208))	('pancreatic glands', 'Disease', (109, 126))	('pheochromocytoma', 'Disease', 'MESH:D010673', (257, 273))	('associated', 'Reg', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (279, 298))	('pheochromocytoma', 'Disease', (257, 273))	('menin', 'Gene', '4221', (41, 46))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (257, 273))	('tumors of parathyroid', 'Disease', (71, 92))	('menin', 'Gene', (41, 46))	('MEN', 'Species', '9606', (134, 137))	('tumors of parathyroid', 'Disease', 'MESH:D010282', (71, 92))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (279, 298))	('mutations', 'Var', (28, 37))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (238, 255))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (228, 255))	('RET', 'Gene', '5979', (177, 180))	('pancreatic glands', 'Disease', 'MESH:D010195', (109, 126))	('thyroid carcinoma', 'Disease', (238, 255))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
14426	30250431	Mutations in cyclin-dependent kinase inhibitor, CDKN1B (p27) or loss of CDKN1B expression have been observed in gastroenteropancreatic neuroendocrine tumors.	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (13, 46))	('CDKN1B', 'Gene', '1027', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('expression', 'MPA', (79, 89))	('CDKN1B', 'Gene', (48, 54))	('CDKN1B', 'Gene', (72, 78))	('cyclin-dependent kinase inhibitor', 'Gene', (13, 46))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (64, 68))	('p27', 'Gene', '3429', (56, 59))	('p27', 'Gene', (56, 59))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (112, 156))	('observed', 'Reg', (100, 108))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (112, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (135, 156))	('CDKN1B', 'Gene', '1027', (48, 54))	('endocrine tumor', 'Phenotype', 'HP:0100568', (140, 155))
14427	30250431	hypothesized that circulating tumor cells (CTC) would suggest a more disseminated disease and found that the presence of CTC was associated with decreased progression-free survival and OS.	('more', 'PosReg', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('progression-free survival', 'CPA', (155, 180))	('presence', 'Var', (109, 117))	('decreased', 'NegReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('disseminated disease', 'Disease', (69, 89))	('tumor', 'Disease', (30, 35))
14447	30250431	Other observed molecular or cytogenetic markers that could be potential biomarkers includes the H-ras gene mutations, the presence or absence of D2 receptors, measured telomerase activity via hTERT expression, the expression of HER-2/neu, the detecting of cyclooxygenase-2 (COX-2) enzymes, and the involvement of the Rb gene.	('D2 receptors', 'Protein', (145, 157))	('activity', 'MPA', (179, 187))	('hTERT', 'Gene', (192, 197))	('absence', 'NegReg', (134, 141))	('mutations', 'Var', (107, 116))	('cyclooxygenase-2', 'Gene', (256, 272))	('H-ras', 'Gene', '3265', (96, 101))	('cyclooxygenase-2', 'Gene', '5743', (256, 272))	('COX-2', 'Gene', (274, 279))	('COX-2', 'Gene', '5743', (274, 279))	('HER-2/neu', 'Gene', (228, 237))	('H-ras', 'Gene', (96, 101))	('hTERT', 'Gene', '7015', (192, 197))	('HER-2/neu', 'Gene', '2064', (228, 237))
14448	30250431	For detecting high risk disease, FGFR4, MMP, PTTG, and deletions in chromosome 11 in addition to identifying levels of Ki-67 and p53 have been suggested as concerns for aggressive disease management.	('PTTG', 'Gene', '9232', (45, 49))	('aggressive disease', 'Disease', (169, 187))	('PTTG', 'Gene', (45, 49))	('MMP', 'Disease', (40, 43))	('FGFR4', 'Gene', '2264', (33, 38))	('FGFR4', 'Gene', (33, 38))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('aggressive disease', 'Disease', 'MESH:D001523', (169, 187))	('deletions', 'Var', (55, 64))
14457	30250431	The initial recommendation is to screen with endoscopic ultrasounds (EUS) and/or MRI for high-risk individuals (i.e., those with cancer in the family or those that are carriers of p16 or BRCA2 mutations).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('BRCA2', 'Gene', (187, 192))	('p16', 'Gene', '1029', (180, 183))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mutations', 'Var', (193, 202))	('BRCA2', 'Gene', '675', (187, 192))	('p16', 'Gene', (180, 183))
14459	30250431	Molecular analyses may supplement EUS by observing for some of the most common mutations in pancreatic cancer, including KRAS, TP53, CDKN2A, and SMAD4.	('SMAD4', 'Gene', (145, 150))	('KRAS', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('KRAS', 'Gene', '3845', (121, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('CDKN2A', 'Gene', (133, 139))	('SMAD4', 'Gene', '4089', (145, 150))	('CDKN2A', 'Gene', '1029', (133, 139))	('pancreatic cancer', 'Disease', (92, 109))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('mutations', 'Var', (79, 88))
14464	30250431	In a study of 260 patients, those with CA 19-9 levels less than 90 U/mL benefited from adjuvant therapy by showing a longer disease-free survival (DFS), while those with higher CA 19-9 levels receiving adjuvant therapy showed no difference in DFS from untreated patients.	('less', 'Var', (54, 58))	('disease-free survival', 'CPA', (124, 145))	('longer', 'PosReg', (117, 123))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (262, 270))
14480	30250431	Therefore, other biomarker candidates have been suggested, such as analyzing the expression of XIST gene and detection of specific miRNAs such as from the miR-371-3 and miR-302/367 clusters.	('miR-371-3', 'Gene', '100500855', (155, 164))	('XIST', 'Gene', '7503', (95, 99))	('miR-302/367', 'Var', (169, 180))	('XIST', 'Gene', (95, 99))	('miR-371-3', 'Gene', (155, 164))
14559	26160035	Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side.	('patient', 'Species', '9606', (74, 81))	('Leydig cell tumor', 'Disease', 'MESH:D007984', (42, 59))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (197, 214))	('Leydig cell tumor', 'Disease', (42, 59))	('variants', 'Var', (238, 246))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (42, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Leydig cell tumor', 'Disease', (197, 214))	('Leydig cell tumor', 'Disease', 'MESH:D007984', (197, 214))	('Klinefelter', 'Gene', (226, 237))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
14563	26160035	By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation.	('variants', 'Var', (56, 64))	('LH', 'Chemical', 'MESH:D007986', (237, 239))	('men', 'Species', '9606', (88, 91))	('Klinefelter', 'Gene', (44, 55))	('destruction', 'NegReg', (149, 160))
14565	26160035	The major endocrine issues of aneuploidies are hyper gonadotropic hypogonadism, testicular degenerative changes and the risk of testicular tumorigenesis.	('testicular tumor', 'Disease', 'MESH:D013736', (128, 144))	('gonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (53, 78))	('hyper gonadotropic hypogonadism', 'Phenotype', 'HP:0000815', (47, 78))	('testicular', 'Disease', (80, 90))	('testicular tumor', 'Phenotype', 'HP:0010788', (128, 144))	('testicular tumor', 'Disease', (128, 144))	('aneuploidies', 'Var', (30, 42))	('testicular degenerative changes', 'Phenotype', 'HP:0000029', (80, 111))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('endocrine issues', 'Phenotype', 'HP:0000818', (10, 26))	('hyper gonadotropic hypogonadism', 'Disease', 'MESH:D007006', (47, 78))	('hyper gonadotropic hypogonadism', 'Disease', (47, 78))	('hypogonadism', 'Phenotype', 'HP:0000135', (66, 78))	('degenerative changes', 'Phenotype', 'HP:0002180', (91, 111))
14600	26160035	The global mortality in aneuploidies in general and in 49,XXXXY in particular, studied in details in 3518 patients of a British cohort included between 1958 and 2003 (48 cases of 49,XXXXY), was elevated (SMR: 1.5-2) with congenital heart diseases, epilepsy and pulmonary embolism as major causes of mortality.	('epilepsy', 'Disease', 'MESH:D004827', (248, 256))	('congenital heart', 'Phenotype', 'HP:0001627', (221, 237))	('elevated', 'PosReg', (194, 202))	('pulmonary embolism', 'Phenotype', 'HP:0002204', (261, 279))	('epilepsy', 'Phenotype', 'HP:0001250', (248, 256))	('pulmonary embolism', 'Disease', (261, 279))	('aneuploidies', 'Var', (24, 36))	('patients', 'Species', '9606', (106, 114))	('epilepsy', 'Disease', (248, 256))	('pulmonary embolism', 'Disease', 'MESH:D011655', (261, 279))	('congenital heart diseases', 'Disease', 'MESH:D006331', (221, 246))	('mortality', 'MPA', (11, 20))	('congenital heart diseases', 'Disease', (221, 246))
14606	26160035	The endocrine profile of KS and the variants is characterized by normal levels of gonadotropins, AMH and Inhibin B with variable levels of testosterone in infancy.	('AMH', 'Gene', (97, 100))	('AMH', 'Gene', '268', (97, 100))	('gonadotropins', 'MPA', (82, 95))	('variants', 'Var', (36, 44))	('testosterone', 'Chemical', 'MESH:D013739', (139, 151))
14608	26160035	Hypogonadism is more profound in the variants than the classical 47,XXY syndrome.	('Hypogonadism', 'Phenotype', 'HP:0000135', (0, 12))	('XXY syndrome', 'Disease', 'MESH:D007713', (68, 80))	('XXY syndrome', 'Disease', (68, 80))	('variants', 'Var', (37, 45))	('Hypogonadism', 'Disease', (0, 12))
14615	26160035	This is supported by the evidence that the chance of fertility or successful retrieval of gametes is limited to Klinefelter patients especially in mosaic forms than other aneuploidies.	('Klinefelter', 'Disease', (112, 123))	('patients', 'Species', '9606', (124, 132))	('mosaic', 'Var', (147, 153))
14626	26160035	Thus, a higher risk of testicular cancers in Klinefelter patients and the other variants has been supposed.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('testicular cancer', 'Phenotype', 'HP:0010788', (23, 40))	('patients', 'Species', '9606', (57, 65))	('testicular cancers', 'Phenotype', 'HP:0010788', (23, 41))	('testicular cancers', 'Disease', 'MESH:D013736', (23, 41))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('Klinefelter', 'Var', (45, 56))	('testicular cancers', 'Disease', (23, 41))
14628	26160035	Indeed, a Danish Study published in 1995 (696 patients) and a British cohort of 3518 patients with Klinefelter variants including 48 patients with 49,XXXX, seem to be the most significant publications to explore the tumor risk.	('tumor', 'Disease', (216, 221))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (133, 141))	('variants', 'Var', (111, 119))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Klinefelter', 'Gene', (99, 110))
14642	26160035	We analysed the literature for the published cases of testicular tumors in aneuploidies, over nearly 4000 patients with KS and its variants, we identified only 34 patients with gonadal and extra gonadal tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('gonadal tumors', 'Disease', 'MESH:D006058', (195, 209))	('patients', 'Species', '9606', (163, 171))	('testicular tumors', 'Phenotype', 'HP:0010788', (54, 71))	('gonadal tumors', 'Phenotype', 'HP:0010785', (195, 209))	('testicular tumors', 'Disease', 'MESH:D013736', (54, 71))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('testicular tumor', 'Phenotype', 'HP:0010788', (54, 70))	('variants', 'Var', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (106, 114))	('testicular tumors', 'Disease', (54, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('gonadal tumors', 'Disease', (195, 209))
14649	26160035	By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering it irresponsive to chronic Luteinizing hormone (LH) stimulation.	('irresponsive', 'MPA', (190, 202))	('LH', 'Chemical', 'MESH:D007986', (235, 237))	('variants', 'Var', (56, 64))	('men', 'Species', '9606', (88, 91))	('Klinefelter', 'Gene', (44, 55))	('destruction', 'NegReg', (149, 160))
14656	26160035	Hyper estrogenic and hypo androgenic status are the most commonly accepted risk factors for testicular cancer and infertility.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('infertility', 'Disease', 'MESH:D007247', (114, 125))	('testicular cancer', 'Phenotype', 'HP:0010788', (92, 109))	('testicular cancer', 'Disease', 'MESH:D013736', (92, 109))	('hypo androgenic status', 'Var', (21, 43))	('infertility', 'Phenotype', 'HP:0000789', (114, 125))	('hypo androgenic status', 'Phenotype', 'HP:0008226', (21, 43))	('infertility', 'Disease', (114, 125))	('testicular cancer', 'Disease', (92, 109))
14662	26160035	This hypothesis was confirmed with the description of activating mutations of LH receptors.	('LH receptor', 'Gene', (78, 89))	('LH receptor', 'Gene', '3973', (78, 89))	('mutations', 'Var', (65, 74))	('activating', 'PosReg', (54, 64))
14664	26160035	The chronic and permanent hyper activation of this receptor leads to inappropriate stimulation of cAMP pathway and Leydig cell hyperplasia.	('Leydig cell hyperplasia', 'Disease', (115, 138))	('cAMP', 'Chemical', '-', (98, 102))	('Leydig cell hyperplasia', 'Disease', 'MESH:D007984', (115, 138))	('cAMP pathway', 'Pathway', (98, 110))	('Leydig cell hyperplasia', 'Phenotype', 'HP:0010791', (115, 138))	('hyper', 'Var', (26, 31))	('stimulation', 'PosReg', (83, 94))
14666	26160035	Actually, Asp578His mutation was identified in more than 50 % of children with Leydig cell tumors (13/24 patients) (reviewed in).	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (79, 97))	('children', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (105, 113))	('Leydig cell tumors', 'Disease', (79, 97))	('Asp578His', 'Var', (10, 19))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (79, 96))	('Asp578His', 'SUBSTITUTION', 'None', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (79, 97))
14669	26160035	Management of Leydig cell tumors Leydig cell tumor/hyperplasia were also linked to many other situations than aneuploidies; these include: McCune-Albright syndrome, Carney complex, fumarate hydratase and cyclin dependent kinase (CDK) mutations.	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (33, 50))	('Leydig cell tumor', 'Disease', 'MESH:D007984', (33, 50))	('Carney complex', 'Disease', (165, 179))	('fumarate hydratase', 'Gene', '2271', (181, 199))	('linked', 'Reg', (73, 79))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (139, 163))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (14, 31))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Leydig cell tumor', 'Disease', 'MESH:D007984', (14, 31))	('CDK', 'Gene', (229, 232))	('McCune-Albright syndrome', 'Disease', (139, 163))	('Leydig cell tumor', 'Disease', (33, 50))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (14, 32))	('mutations', 'Var', (234, 243))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('men', 'Species', '9606', (6, 9))	('hyperplasia', 'Disease', (51, 62))	('fumarate hydratase', 'Gene', (181, 199))	('Leydig cell tumors', 'Disease', (14, 32))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (14, 32))	('hyperplasia', 'Disease', 'MESH:D006965', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
14671	26160035	Their physiopathology is near to that of Klinefelter variants with the activation of LH pathway (Activating mutations of alpha subunit of protein G (GNAS) for McCune-Albright syndrome and hyperactivity of protein kinase A in Carney complex).	('McCune-Albright syndrome', 'Disease', (159, 183))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (159, 183))	('mutations', 'Var', (108, 117))	('LH pathway', 'Pathway', (85, 95))	('hyperactivity', 'Disease', 'MESH:D006948', (188, 201))	('hyperactivity', 'Disease', (188, 201))	('protein kinase A', 'Enzyme', (205, 221))	('GNAS', 'Gene', '2778', (149, 153))	('Carney complex', 'Disease', (225, 239))	('LH', 'Chemical', 'MESH:D007986', (85, 87))	('hyperactivity', 'Phenotype', 'HP:0000752', (188, 201))	('variants', 'Var', (53, 61))	('GNAS', 'Gene', (149, 153))
14681	26160035	The risk of Leydig cell tumors in aneuploidies remains a dogma; it seems to be similar to the general population.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (12, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (12, 29))	('Leydig cell tumors', 'Disease', (12, 30))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (12, 30))	('aneuploidies', 'Var', (34, 46))
14689	22354749	We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells.	('DSBs', 'Disease', (86, 90))	('DSBs', 'Chemical', '-', (86, 90))	('aberrant', 'Var', (13, 21))
14690	22354749	We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma.	('seminoma', 'Disease', 'MESH:D018239', (224, 232))	('Bre1 deficiency', 'Disease', (49, 64))	('BRE1A/B', 'Gene', (179, 186))	('situ carcinoma', 'Disease', (267, 281))	('levels', 'MPA', (169, 175))	('dimethylated', 'Var', (191, 203))	('seminoma', 'Disease', (224, 232))	('BRE1A/B', 'Gene', '56254', (179, 186))	('decreased', 'NegReg', (159, 168))	('Bre1 deficiency', 'Disease', 'MESH:D007153', (49, 64))	('testicular seminoma', 'Phenotype', 'HP:0100617', (213, 232))	('H3K79', 'Protein', (204, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('situ carcinoma', 'Disease', 'MESH:D002278', (267, 281))
14692	22354749	H2B monoubiquitination plays an important role in regulation of transcription, being a prerequisite for normal levels of methylation of histone H3 residues K4 and K79.	('H2B', 'Gene', (0, 3))	('K79', 'Var', (163, 166))	('monoubiquitination', 'MPA', (4, 22))	('H2B', 'Gene', '8349', (0, 3))
14693	22354749	In addition, studies in Saccharomyces showed that mutants deficient in H2B monoubiquitination are radiation sensitive and defective in recombinational repair, cell cycle checkpoints, gene silencing and meiosis (see for review).	('cell cycle checkpoints', 'CPA', (159, 181))	('recombinational repair', 'MPA', (135, 157))	('gene silencing', 'CPA', (183, 197))	('H2B', 'Gene', '8349', (71, 74))	('defective', 'NegReg', (122, 131))	('monoubiquitination', 'MPA', (75, 93))	('deficient', 'NegReg', (58, 67))	('Saccharomyces', 'Species', '4932', (24, 37))	('mutants', 'Var', (50, 57))	('H2B', 'Gene', (71, 74))	('meiosis', 'CPA', (202, 209))
14695	22354749	We have reported that loss of Bre1 in mouse cells compromised homologous recombination (HR) repair, resulting in reduced recruitment of Rad51 to sites of radiation-induced double-strand breaks (DSBs) and increased sensitivity to ionizing radiation and DNA-crosslinking agents.	('sensitivity', 'MPA', (214, 225))	('Rad51', 'Protein', (136, 141))	('mouse', 'Species', '10090', (38, 43))	('radiation-induced double-strand breaks', 'Phenotype', 'HP:0010997', (154, 192))	('homologous recombination', 'MPA', (62, 86))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (204, 247))	('men', 'Species', '9606', (128, 131))	('increased', 'PosReg', (204, 213))	('DSBs', 'Chemical', '-', (194, 198))	('Bre1', 'Gene', (30, 34))	('reduced', 'NegReg', (113, 120))	('compromised', 'NegReg', (50, 61))	('loss', 'Var', (22, 26))	('recruitment', 'MPA', (121, 132))
14704	22354749	We used RNAi to deplete Bre1 from mouse cells and then followed the evolution of genomic instability in Bre1-deficient cells from early replication stress to specific genomic rearrangements, which in turn triggered breakage-fusion-bridge cycles, known to accelerate genomic instability.	('mouse', 'Species', '10090', (34, 39))	('breakage-fusion-bridge cycles', 'MPA', (215, 244))	('Bre1-deficient', 'Var', (104, 118))	('men', 'Species', '9606', (184, 187))	('triggered', 'Reg', (205, 214))	('Bre1-deficient', 'Gene', (104, 118))
14714	22354749	Expression of Bre1a and Bre1b shRNAs in mouse fibrosarcoma RIF-1 cells resulted in a significant reduction of corresponding mRNA transcript levels after seven days of antibiotic selection, as shown by quantitative real-time polymerase chain reaction (qRT-PCR) (Fig.	('mRNA transcript levels', 'MPA', (124, 146))	('reduction', 'NegReg', (97, 106))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (46, 58))	('fibrosarcoma', 'Disease', 'MESH:D005354', (46, 58))	('Bre1a', 'Var', (14, 19))	('fibrosarcoma', 'Disease', (46, 58))	('mouse', 'Species', '10090', (40, 45))	('Bre1b shRNAs', 'Var', (24, 36))
14719	22354749	S1A), while cells grew well after knockdown of either GFP, or tumor suppressor Rb (Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('knockdown', 'Var', (34, 43))	('GFP', 'Gene', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
14720	22354749	In order to monitor the effects of disruption of the Bre1a/Bre1b complex over time, we created RIF-1-derived cell lines, in which the knockdown of Bre1a or Bre1b could be initiated by addition of doxycycline.	('knockdown', 'Var', (134, 143))	('Bre1b', 'Gene', (156, 161))	('doxycycline', 'Chemical', 'MESH:D004318', (196, 207))	('Bre1a', 'Gene', (147, 152))
14729	22354749	Apoptosis also increased after depletion of Bre1 in MES cells (Fig.	('Bre1', 'Gene', (44, 48))	('MES', 'Chemical', '-', (52, 55))	('increased', 'PosReg', (15, 24))	('Apoptosis', 'CPA', (0, 9))	('depletion', 'Var', (31, 40))
14730	22354749	We conclude that the function of Bre1 is critical for homeostasis and that apoptosis contributes to the reduced growth phenotype in cell cultures with low levels of Bre1a and Bre1b.	('Bre1b', 'Var', (175, 180))	('reduced', 'NegReg', (104, 111))	('growth', 'MPA', (112, 118))	('Bre1', 'Gene', (33, 37))	('apoptosis', 'CPA', (75, 84))	('homeostasis', 'Disease', (54, 65))	('homeostasis', 'Disease', 'MESH:D008232', (54, 65))	('Bre1a', 'Gene', (165, 170))
14732	22354749	1E), more subtle changes in Bre1b expression due to the partial knockdown in the uninduced shBre1b1 cell line allowed cells to proliferate and manifest dramatic genomic instability associated with Bre1 deficiency after longer culture periods.	('Bre1 deficiency', 'Disease', 'MESH:D007153', (197, 212))	('genomic instability', 'CPA', (161, 180))	('expression', 'MPA', (34, 44))	('Bre1 deficiency', 'Disease', (197, 212))	('changes', 'Reg', (17, 24))	('Bre1b', 'Gene', (28, 33))	('knockdown', 'Var', (64, 73))
14735	22354749	The chromosomal instability phenotype initiated by partial Bre1b knockdown (shBre1b1 cells grown without doxycycline) for three weeks and longer was more dramatic than the one initiated by complete short-term knockdown of Bre1b at early passage (Fig.	('chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('partial', 'Var', (51, 58))	('doxycycline', 'Chemical', 'MESH:D004318', (105, 116))	('Bre1b', 'Gene', (59, 64))	('chromosomal instability', 'CPA', (4, 27))	('knockdown', 'Var', (65, 74))
14736	22354749	To elucidate how loss of Bre1 contributes to increased DSBs and genomic rearrangements, we measured gammaH2AX levels after Bre1 knockdown.	('gammaH2AX', 'Chemical', '-', (100, 109))	('increased', 'PosReg', (45, 54))	('Bre1', 'Gene', (123, 127))	('genomic rearrangements', 'CPA', (64, 86))	('men', 'Species', '9606', (81, 84))	('gammaH2AX levels', 'MPA', (100, 116))	('Bre1', 'Gene', (25, 29))	('DSBs', 'Disease', (55, 59))	('DSBs', 'Chemical', '-', (55, 59))	('loss', 'Var', (17, 21))
14742	22354749	3A), cells with pan-nuclear staining of gammaH2AX (apoptosis) were restricted to S-phase cells after knockdown of Bre1 (Fig.	('gammaH2AX', 'Chemical', '-', (40, 49))	('gammaH2AX', 'Var', (40, 49))	('Bre1', 'Gene', (114, 118))	('knockdown', 'Var', (101, 110))
14746	22354749	Consistent with increased apoptosis during replication, we also found that loss of Bre1 resulted in depletion of cells primarily from the cluster corresponding to the gammaH2AX-positive S-phase cells (Fig.	('depletion of cells primarily', 'MPA', (100, 128))	('loss', 'Var', (75, 79))	('Bre1', 'Gene', (83, 87))	('gammaH2AX', 'Chemical', '-', (167, 176))
14747	22354749	Consistent with both subunits of Bre1 complex being required for the H2B ubiquitination, we observed a high correlation between expression profiles in the Bre1a and Bre1b knockdowns (Fig.	('Bre1a', 'Gene', (155, 160))	('knockdowns', 'Var', (171, 181))	('H2B', 'Gene', (69, 72))	('Bre1b', 'Gene', (165, 170))	('H2B', 'Gene', '8349', (69, 72))	('expression', 'MPA', (128, 138))
14749	22354749	In a genome-wide siRNA screen for genes whose deregulation leads to elevated levels of gammaH2AX, the mRNA processing module represented the most significantly enriched category of genes, suggesting that abnormal mRNA processing was the most common and direct source of genomic instability.	('deregulation', 'Var', (46, 58))	('levels', 'MPA', (77, 83))	('elevated', 'PosReg', (68, 76))	('gammaH2AX', 'Protein', (87, 96))	('gammaH2AX', 'Chemical', '-', (87, 96))
14757	22354749	We also found a strong signal for H3K79me2 and H3K4me3, the two modifications affected by ubiquitination of H2B.	('H2B', 'Gene', '8349', (108, 111))	('H3K79me2', 'Var', (34, 42))	('H2B', 'Gene', (108, 111))	('H3K4me3', 'Var', (47, 54))
14758	22354749	H3K79me2 was highest in middle meiosis (Fig.	('middle meiosis', 'Disease', (24, 38))	('H3K79me2', 'Var', (0, 8))	('highest', 'Reg', (13, 20))	('middle meiosis', 'Disease', 'MESH:D020244', (24, 38))
14761	22354749	Having demonstrated the importance of Bre1 homologs to maintenance of genomic stability, we hypothesized that suboptimal expression of Bre1 homologs in testis might be associated with testicular cancer.	('suboptimal', 'Var', (110, 120))	('associated', 'Reg', (168, 178))	('testicular cancer', 'Disease', 'MESH:D013736', (184, 201))	('Bre1', 'Gene', (135, 139))	('testicular cancer', 'Disease', (184, 201))	('testicular cancer', 'Phenotype', 'HP:0010788', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
14770	22354749	S6), and by staining the testis tissue microarrays we found that amongst testicular cancers, H3K79me2 was also lowest in seminoma (Fig.	('testicular cancers', 'Disease', 'MESH:D013736', (73, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('testicular cancers', 'Phenotype', 'HP:0010788', (73, 91))	('seminoma', 'Disease', 'MESH:D018239', (121, 129))	('lowest', 'NegReg', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('seminoma', 'Disease', (121, 129))	('testicular cancers', 'Disease', (73, 91))	('testicular cancer', 'Phenotype', 'HP:0010788', (73, 90))	('H3K79me2', 'Var', (93, 101))
14776	22354749	This conclusion is consistent with our previous observation that reduced monoubiquitination of H2B in Saccharomyces bre1null mutants and in mouse cells leads to defective recombinational repair of double-strand breaks (DSBs).	('recombinational repair of double-strand breaks', 'MPA', (171, 217))	('monoubiquitination', 'MPA', (73, 91))	('mouse', 'Species', '10090', (140, 145))	('H2B', 'Gene', '8349', (95, 98))	('reduced', 'NegReg', (65, 72))	('bre1', 'Gene', '851485', (116, 120))	('defective', 'NegReg', (161, 170))	('mutants', 'Var', (125, 132))	('H2B', 'Gene', (95, 98))	('bre1', 'Gene', (116, 120))	('Saccharomyces', 'Species', '4932', (102, 115))	('DSBs', 'Chemical', '-', (219, 223))
14779	22354749	It should be noted that while we interpret the observed Bre1 knockdown phenotype as arising from an impact on the well-known role of Bre1 in H2B ubiquitination, it is formally possible that additional targets for the Bre1 ubiquitin ligase exist, which could contribute to the knockdown phenotype.	('H2B', 'Gene', (141, 144))	('ubiquitination', 'MPA', (145, 159))	('knockdown', 'Var', (61, 70))	('impact', 'Reg', (100, 106))	('H2B', 'Gene', '8349', (141, 144))	('Bre1', 'Gene', (56, 60))
14782	22354749	Also, in Saccharomyces, where chromosomal copies of the H2B gene number only two and can be deleted, H2BK123R mutants do mimic the bre1 deletion phenotype (reviewed in), implying that the phenotypes are likely to be conferred through effects on the H2B target.	('H2B', 'Gene', (101, 104))	('H2B', 'Gene', '8349', (101, 104))	('H2B', 'Gene', '8349', (249, 252))	('mutants', 'Var', (110, 117))	('bre1', 'Gene', (131, 135))	('H2B', 'Gene', (56, 59))	('deletion', 'Var', (136, 144))	('Saccharomyces', 'Species', '4932', (9, 22))	('H2B', 'Gene', (249, 252))	('H2B', 'Gene', '8349', (56, 59))	('bre1', 'Gene', '851485', (131, 135))
14783	22354749	Questions remain, however, as to whether the phenotypes we observed after loss of Bre1 are mediated via the well-known impact of H2B ubiquitination on methylation of histone H3, and specifically whether H3K4me3 and or H3K79me2 are involved.	('methylation', 'MPA', (151, 162))	('ubiquitination', 'MPA', (133, 147))	('H2B', 'Gene', '8349', (129, 132))	('Bre1', 'Gene', (82, 86))	('loss', 'Var', (74, 78))	('histone H3', 'Protein', (166, 176))	('H2B', 'Gene', (129, 132))
14785	22354749	Also, knocking down the H3K79 methyltransferase Dot1 would completely eliminate methylation of H3K79, while loss of Bre1-mediated H2B ubiquitination only eliminates the higher states of methylation of H3K79, so additional phenotypes may be conferred by the Dot1 knockdown beyond those mediated by the impact of uH2B on H3K79.	('H2B', 'Gene', (130, 133))	('H3K79', 'Protein', (95, 100))	('eliminate', 'NegReg', (70, 79))	('H3K79', 'Gene', (24, 29))	('methylation', 'MPA', (80, 91))	('eliminates', 'NegReg', (154, 164))	('Dot1', 'Gene', (257, 261))	('H2B', 'Gene', '8349', (312, 315))	('H2B', 'Gene', '8349', (130, 133))	('Dot1', 'Gene', (48, 52))	('methylation', 'MPA', (186, 197))	('higher states', 'MPA', (169, 182))	('H2B', 'Gene', (312, 315))	('knockdown', 'Var', (262, 271))	('knocking down', 'Var', (6, 19))
14786	22354749	Although the effects of Dot1 knockdown in mice paralleled the impaired cell growth, increased ploidy and centromeric abnormalities we observed after Bre1 knockdown, specific clarification of these issues requires further study.	('ploidy', 'CPA', (94, 100))	('Bre1', 'Gene', (149, 153))	('centromeric abnormalities', 'CPA', (105, 130))	('mice', 'Species', '10090', (42, 46))	('Dot1', 'Gene', (24, 28))	('knockdown', 'Var', (154, 163))	('increased', 'PosReg', (84, 93))
14789	22354749	Consistent with the CIN model, we also show that BRE1A/B deficiency accompanies early steps of testicular cancer development.	('deficiency', 'Var', (57, 67))	('BRE1A/B', 'Gene', (49, 56))	('CIN', 'Disease', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('testicular cancer', 'Phenotype', 'HP:0010788', (95, 112))	('testicular cancer', 'Disease', 'MESH:D013736', (95, 112))	('BRE1A/B', 'Gene', '56254', (49, 56))	('CIN', 'Disease', 'MESH:D007674', (20, 23))	('accompanies', 'Reg', (68, 79))	('testicular cancer', 'Disease', (95, 112))	('men', 'Species', '9606', (120, 123))
14791	22354749	Lack of Bre1 leading to abnormal presence of polyadenylated histone mRNAs, which are not rapidly degraded at the end of S-phase, could interfere with proper incorporation of the variant histones into chromatin, and lead to testicular dysgenesis.	('histones', 'Protein', (186, 194))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (223, 244))	('lead to', 'Reg', (215, 222))	('testicular dysgenesis', 'Disease', (223, 244))	('Bre1', 'Gene', (8, 12))	('Lack', 'Var', (0, 4))	('variant', 'Var', (178, 185))	('testicular dysgenesis', 'Disease', 'MESH:D013733', (223, 244))	('interfere', 'NegReg', (135, 144))	('incorporation', 'MPA', (157, 170))
14799	22354749	Hence, deficiency in BRE1A/B may be among etiological factors in common for both infertility and testicular cancer.	('infertility and testicular cancer', 'Disease', 'MESH:D013736', (81, 114))	('BRE1A/B', 'Gene', (21, 28))	('BRE1A/B', 'Gene', '56254', (21, 28))	('deficiency', 'Var', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('infertility', 'Phenotype', 'HP:0000789', (81, 92))	('testicular cancer', 'Phenotype', 'HP:0010788', (97, 114))
14800	22354749	In addition, mutation of BRE1 (RNF20) has been found among other CIN genes mutated in colorectal cancers suggestive of a more general role of Bre1 in CIN.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('CIN', 'Disease', (150, 153))	('RNF20', 'Gene', (31, 36))	('CIN', 'Disease', 'MESH:D007674', (150, 153))	('mutation', 'Var', (13, 21))	('found', 'Reg', (47, 52))	('colorectal cancers', 'Disease', 'MESH:D015179', (86, 104))	('CIN', 'Disease', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colorectal cancers', 'Disease', (86, 104))	('RNF20', 'Gene', '56254', (31, 36))	('CIN', 'Disease', 'MESH:D007674', (65, 68))
14801	22354749	In conclusion, we propose that the mammalian homologs of the yeast BRE1 gene serve as tumor suppressors by preventing replication stress and chromosomal instability that arise from DSBs associated with incorrect processing of replication-associated histone mRNAs and inefficient HR.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('preventing', 'NegReg', (107, 117))	('mammalian', 'Species', '9606', (35, 44))	('BRE1', 'Gene', (67, 71))	('replication stress', 'MPA', (118, 136))	('yeast', 'Species', '4932', (61, 66))	('tumor', 'Disease', (86, 91))	('chromosomal instability', 'Phenotype', 'HP:0040012', (141, 164))	('DSBs', 'Disease', (181, 185))	('incorrect', 'Var', (202, 211))	('DSBs', 'Chemical', '-', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('chromosomal instability', 'CPA', (141, 164))
14990	31163029	The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%).	('children', 'Species', '9606', (87, 95))	('TGCC', 'Chemical', '-', (120, 124))	('men', 'Species', '9606', (108, 111))	('children', 'Species', '9606', (43, 51))	('TGCC', 'Chemical', '-', (68, 72))	('TGCC', 'Var', (68, 72))	('malformations', 'Disease', 'MESH:D000014', (12, 25))	('malformations', 'Disease', (12, 25))
14994	31163029	However, paternal TGCC per se was associated with modestly increased risk for offspring malformations.	('TGCC', 'Chemical', '-', (18, 22))	('TGCC', 'Gene', (18, 22))	('malformations', 'Disease', 'MESH:D000014', (88, 101))	('paternal', 'Var', (9, 17))	('malformations', 'Disease', (88, 101))
14997	31163029	Chemotherapy and radiotherapy have both been shown to cause mutations and genetic damage in animal studies, leading to fears that men being treated with these therapies might be more prone to have children with genetic diseases and birth defects.	('birth defects', 'Disease', (232, 245))	('genetic diseases', 'Disease', (211, 227))	('children', 'Species', '9606', (197, 205))	('genetic damage', 'Disease', (74, 88))	('genetic damage', 'Disease', 'MESH:D030342', (74, 88))	('genetic diseases', 'Disease', 'MESH:D030342', (211, 227))	('mutations', 'Var', (60, 69))	('birth defects', 'Disease', 'MESH:D000014', (232, 245))	('men', 'Species', '9606', (130, 133))
15008	31163029	A possible pathway for the increased malformations risk might be detrimental genetic alterations of germline DNA by oncological treatment, resulting in more frequent CMs in children conceived after paternal oncological treatment.	('men', 'Species', '9606', (224, 227))	('CMs', 'Disease', (166, 169))	('men', 'Species', '9606', (70, 73))	('genetic alterations', 'Var', (77, 96))	('children', 'Species', '9606', (173, 181))	('men', 'Species', '9606', (133, 136))	('malformations', 'Disease', 'MESH:D000014', (37, 50))	('malformations', 'Disease', (37, 50))	('more', 'PosReg', (152, 156))
15052	31163029	Children to fathers with TGCC had a statistically significantly increased risk for both all and major CMs as compared to children born to fathers without TGCC (OR = 1.28, 95% CI = 1.19-1.38, p = 0.001, 4.4% versus 3.5% and OR = 1.36, 95% CI = 1.24-1.49, p < 0.001, 2.9% versus 2.2%, respectively; Fig 2).	('major CMs', 'Disease', (96, 105))	('Children', 'Species', '9606', (0, 8))	('children', 'Species', '9606', (121, 129))	('TGCC', 'Chemical', '-', (154, 158))	('TGCC', 'Chemical', '-', (25, 29))	('TGCC', 'Var', (25, 29))
15055	31163029	In this study, we found that children of fathers with TGCC had an approximately 30% increased malformation risk as compared to children of fathers without TGCC.	('TGCC', 'Chemical', '-', (155, 159))	('children', 'Species', '9606', (29, 37))	('malformation', 'CPA', (94, 106))	('TGCC', 'Chemical', '-', (54, 58))	('TGCC', 'Var', (54, 58))	('children', 'Species', '9606', (127, 135))
15078	31163029	ROSs were shown to cause postmeiotic oxidative sperm DNA damage during a phase of germ-cell development when sperms lack DNA repair machinery.	('cause', 'Reg', (19, 24))	('ROSs', 'Chemical', 'MESH:D017382', (0, 4))	('ROSs', 'Var', (0, 4))	('postmeiotic', 'MPA', (25, 36))	('men', 'Species', '9606', (99, 102))
15079	31163029	Increased rates of these paternally derived DNA lesions, like single- and double-stranded breaks, have been shown to detrimentally affect embryonic development, rates of miscarriage, and pregnancy and can ultimately lead to offspring with chromosomal aberrations.	('embryonic development', 'CPA', (138, 159))	('detrimentally', 'NegReg', (117, 130))	('men', 'Species', '9606', (155, 158))	('pregnancy', 'CPA', (187, 196))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (239, 262))	('affect', 'Reg', (131, 137))	('lead to', 'Reg', (216, 223))	('miscarriage', 'Phenotype', 'HP:0005268', (170, 181))	('single-', 'Var', (62, 69))	('men', 'Species', '9606', (122, 125))	('double-stranded breaks', 'Var', (74, 96))	('miscarriage', 'CPA', (170, 181))
15082	31163029	These de novo mutations among the offspring have been linked to CMs, schizophrenia, and autism.	('schizophrenia', 'Phenotype', 'HP:0100753', (69, 82))	('CMs', 'Disease', (64, 67))	('autism', 'Phenotype', 'HP:0000717', (88, 94))	('autism', 'Disease', 'MESH:D001321', (88, 94))	('schizophrenia', 'Disease', (69, 82))	('autism', 'Disease', (88, 94))	('linked', 'Reg', (54, 60))	('schizophrenia', 'Disease', 'MESH:D012559', (69, 82))	('mutations', 'Var', (14, 23))
15083	31163029	This indicates that some men experience more mutations in their germ cells and conceivably also in their somatic cells, possibly due to a systemic insufficiency of DNA repair.	('systemic insufficiency', 'Disease', (138, 160))	('mutations', 'Var', (45, 54))	('men', 'Species', '9606', (25, 28))	('systemic insufficiency', 'Disease', 'MESH:D000309', (138, 160))
15114	26421011	In fact, patients affected by Kennedy syndrome have a number of CAG repeats greater than 40 together with decreased virilization, testicular atrophy, reduced sperm production, and infertility.	('decreased', 'NegReg', (106, 115))	('patients', 'Species', '9606', (9, 17))	('testicular atrophy', 'Disease', (130, 148))	('CAG', 'Chemical', '-', (64, 67))	('testicular atrophy', 'Disease', 'MESH:C567108', (130, 148))	('reduced sperm', 'Phenotype', 'HP:0012207', (150, 163))	('infertility', 'Disease', 'MESH:D007247', (180, 191))	('testicular atrophy', 'Phenotype', 'HP:0000029', (130, 148))	('sperm production', 'CPA', (158, 174))	('Kennedy syndrome', 'Disease', 'MESH:D055534', (30, 46))	('infertility', 'Phenotype', 'HP:0000789', (180, 191))	('Kennedy syndrome', 'Disease', (30, 46))	('CAG repeats greater', 'Var', (64, 83))	('reduced', 'NegReg', (150, 157))	('infertility', 'Disease', (180, 191))	('greater', 'Var', (76, 83))	('virilization', 'Disease', (116, 128))
15115	26421011	Similarly, other studies have shown that shorter CAG repeats are associated with prostate disease, specifically cancer and benign hypertrophy, improved seminal parameters, and improved mineral bone density.	('improved mineral bone density', 'Phenotype', 'HP:0011001', (176, 205))	('improved', 'PosReg', (143, 151))	('shorter', 'Var', (41, 48))	('prostate disease', 'Disease', (81, 97))	('seminal parameters', 'MPA', (152, 170))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('prostate disease', 'Disease', 'MESH:D011469', (81, 97))	('improved', 'PosReg', (176, 184))	('CAG', 'Protein', (49, 52))	('CAG', 'Chemical', '-', (49, 52))	('benign hypertrophy', 'Disease', (123, 141))	('benign hypertrophy', 'Disease', 'MESH:D006984', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mineral bone density', 'CPA', (185, 205))
15120	26421011	In particular, our main purpose was to provide an updated contribution able to shed light on the many and often contradictory findings on the influence of CAG repeat polymorphism on the targets of testosterone action (Figure 2).	('testosterone', 'Chemical', 'MESH:D013739', (197, 209))	('polymorphism', 'Var', (166, 178))	('CAG repeat', 'Gene', (155, 165))	('CAG', 'Chemical', '-', (155, 158))
15124	26421011	AR gene CAG repeat number was found to be negatively correlated with all domains of sexual function assessable by IIEF-15.	('CAG', 'Chemical', '-', (8, 11))	('AR', 'Gene', '367', (0, 2))	('CAG repeat number', 'Var', (8, 25))	('negatively', 'NegReg', (42, 52))
15128	26421011	In addition, another study, conducted on 213 41-70-year-old men randomly selected from the Population Registry, reported that the CAG repeat number was positively correlated with depression, whereas men with CAG repeats higher than or equal to 23 reported decreased potency (assessed by Heinemann questionnaire) less often than the others.	('potency', 'MPA', (266, 273))	('men', 'Species', '9606', (199, 202))	('depression', 'Disease', (179, 189))	('CAG', 'Chemical', '-', (208, 211))	('correlated', 'Reg', (163, 173))	('CAG', 'Chemical', '-', (130, 133))	('depression', 'Phenotype', 'HP:0000716', (179, 189))	('CAG', 'Var', (130, 133))	('men', 'Species', '9606', (60, 63))	('depression', 'Disease', 'MESH:D000275', (179, 189))	('decreased', 'NegReg', (256, 265))
15129	26421011	Regarding longitudinal studies, only two reports evaluated the effects of the polymorphism in conditioning sexual function recovery after testosterone replacement therapy in hypogonadal male patients.	('patients', 'Species', '9606', (191, 199))	('hypogonadal male', 'Phenotype', 'HP:0000026', (174, 190))	('conditioning', 'MPA', (94, 106))	('testosterone', 'Chemical', 'MESH:D013739', (138, 150))	('hypogonadal male', 'Disease', 'MESH:D005058', (174, 190))	('hypogonadal male', 'Disease', (174, 190))	('polymorphism', 'Var', (78, 90))	('men', 'Species', '9606', (158, 161))
15135	26421011	The correlation between male infertility and CAG repeat lengths on the AR gene is still unknown, while the link between this polymorphism and quality of spermatogenesis is even more obscure.	('AR', 'Gene', '367', (71, 73))	('CAG repeat lengths', 'Var', (45, 63))	('male infertility', 'Phenotype', 'HP:0003251', (24, 40))	('male infertility', 'Disease', (24, 40))	('male infertility', 'Disease', 'MESH:D007248', (24, 40))	('CAG', 'Chemical', '-', (45, 48))	('infertility', 'Phenotype', 'HP:0000789', (29, 40))
15136	26421011	Numerous studies in recent years have attempted to establish the relationship between CAG repeat length variation and male infertility to find out if this variability in the AR gene could be associated with impaired spermatogenesis.	('male infertility', 'Disease', 'MESH:D007248', (118, 134))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (207, 231))	('variability', 'Var', (155, 166))	('AR', 'Gene', '367', (174, 176))	('CAG', 'Chemical', '-', (86, 89))	('male infertility', 'Phenotype', 'HP:0003251', (118, 134))	('associated', 'Reg', (191, 201))	('infertility', 'Phenotype', 'HP:0000789', (123, 134))	('male infertility', 'Disease', (118, 134))
15138	26421011	In Australian, North American, and Japanese populations, an association between CAG repeat length and male infertility has been reported, but this has not been confirmed in Europe.	('infertility', 'Phenotype', 'HP:0000789', (107, 118))	('male infertility', 'Phenotype', 'HP:0003251', (102, 118))	('male infertility', 'Disease', (102, 118))	('male infertility', 'Disease', 'MESH:D007248', (102, 118))	('association', 'Interaction', (60, 71))	('CAG repeat length', 'Var', (80, 97))	('CAG', 'Chemical', '-', (80, 83))
15139	26421011	The latter might suggest that the association between CAG repeat length and male infertility could be valid for a given ethnic group but not necessarily significant if extended to different populations.	('CAG repeat length', 'Var', (54, 71))	('CAG', 'Chemical', '-', (54, 57))	('infertility', 'Phenotype', 'HP:0000789', (81, 92))	('male infertility', 'Phenotype', 'HP:0003251', (76, 92))	('male infertility', 'Disease', (76, 92))	('male infertility', 'Disease', 'MESH:D007248', (76, 92))
15145	26421011	The authors concluded that the number of CAG and GGC triplets has a combined effect on the AR receptor function and that this was the first evidence of a relationship between particular CAG/GGC haplotypes and male infertility.	('CAG', 'Chemical', '-', (186, 189))	('haplotypes', 'Var', (194, 204))	('GGC', 'Gene', (49, 52))	('AR', 'Gene', '367', (91, 93))	('male infertility', 'Phenotype', 'HP:0003251', (209, 225))	('male infertility', 'Disease', (209, 225))	('male infertility', 'Disease', 'MESH:D007248', (209, 225))	('GGC', 'Gene', '79017', (49, 52))	('CAG', 'Chemical', '-', (41, 44))	('GGC', 'Gene', (190, 193))	('combined', 'Interaction', (68, 76))	('effect', 'Reg', (77, 83))	('infertility', 'Phenotype', 'HP:0000789', (214, 225))	('GGC', 'Gene', '79017', (190, 193))
15147	26421011	The authors suggest that the CAG triplet allele 21 might increase the risk of Sertoli cell-only syndrome, although the mechanism is not yet clear.	('CAG', 'Chemical', '-', (29, 32))	('Sertoli cell', 'Phenotype', 'HP:0100619', (78, 90))	('CAG', 'Var', (29, 32))	('triplet', 'Var', (33, 40))	('Sertoli cell-only syndrome', 'Disease', (78, 104))	('increase', 'PosReg', (57, 65))
15152	26421011	The authors analysed CAG polymorphism in 101 azoospermic and 54 oligozoospermic patients and 96 controls, excluding patients with Y chromosome deletions and chromosome abnormalities from the study.	('azoospermic', 'Disease', (45, 56))	('polymorphism', 'Var', (25, 37))	('analysed', 'Reg', (12, 20))	('patients', 'Species', '9606', (80, 88))	('CAG', 'Gene', (21, 24))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (157, 181))	('patients', 'Species', '9606', (116, 124))	('CAG', 'Chemical', '-', (21, 24))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (157, 181))	('chromosome abnormalities', 'Disease', (157, 181))
15156	26421011	The fact that mutations in the CAG repeat stretch can block this interaction or cause changes to the protein structure demonstrates its crucial role in maintaining the function of the AR protein.	('AR', 'Gene', '367', (184, 186))	('protein structure', 'MPA', (101, 118))	('interaction', 'Interaction', (65, 76))	('CAG repeat', 'Protein', (31, 41))	('function', 'MPA', (168, 176))	('cause changes', 'Reg', (80, 93))	('CAG', 'Chemical', '-', (31, 34))	('block', 'NegReg', (54, 59))	('mutations', 'Var', (14, 23))
15164	26421011	It is likely that the genesis of prostate cancer is not induced by androgens, but that the stronger androgenic stimulation caused by receptors with shorter CAG repeats may contribute to a faster development of malignant cells.	('stronger', 'PosReg', (91, 99))	('CAG', 'Chemical', '-', (156, 159))	('men', 'Species', '9606', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('prostate cancer', 'Disease', (33, 48))	('shorter', 'Var', (148, 155))	('androgenic stimulation', 'MPA', (100, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('CAG', 'Protein', (156, 159))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('faster', 'PosReg', (188, 194))
15167	26421011	Some studies have suggested that short CAG repeats constantly stimulate androgens, with increased cell proliferation and induction of somatic mutations.	('cell proliferation', 'CPA', (98, 116))	('short CAG repeats', 'Var', (33, 50))	('CAG', 'Chemical', '-', (39, 42))	('increased', 'PosReg', (88, 97))	('somatic mutations', 'CPA', (134, 151))	('androgens', 'Protein', (72, 81))	('stimulate', 'PosReg', (62, 71))
15168	26421011	Also, short CAG repeats have been associated with more aggressive forms of prostate cancer.	('associated with', 'Reg', (34, 49))	('CAG', 'Chemical', '-', (12, 15))	('prostate cancer', 'Disease', (75, 90))	('short CAG repeats', 'Var', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))
15171	26421011	These data suggest that short CAG repeats are associated with the development of TMPRSS2:ERG-positive prostate cancer.	('ERG', 'Gene', (89, 92))	('TMPRSS2', 'Gene', (81, 88))	('CAG', 'Chemical', '-', (30, 33))	('men', 'Species', '9606', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Disease', (102, 117))	('TMPRSS2', 'Gene', '7113', (81, 88))	('short CAG repeats', 'Var', (24, 41))	('ERG', 'Gene', '2078', (89, 92))	('associated', 'Reg', (46, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
15175	26421011	Many authors have suggested that the CAG repeat length is inversely correlated with the risk of developing prostate cancer (Table 1).	('prostate cancer', 'Disease', (107, 122))	('CAG repeat length', 'Var', (37, 54))	('CAG', 'Chemical', '-', (37, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
15176	26421011	Coetzee and Ross showed for the first time that the variations of the length of the CAG are associated with prostate cancer and suggested that shorter alleles can lead to increased transactivation of androgen receptor.	('transactivation', 'MPA', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CAG', 'Chemical', '-', (84, 87))	('androgen receptor', 'Gene', (200, 217))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('variations', 'Var', (52, 62))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('androgen receptor', 'Gene', '367', (200, 217))	('associated', 'Reg', (92, 102))	('increased', 'PosReg', (171, 180))	('prostate cancer', 'Disease', (108, 123))
15177	26421011	A meta-analysis of 2004 reported that patients with prostate cancer had shorter CAG repeats and the continuous odds ratio of prostate cancer per one repeat decrement was 1.02 for CAG repeat.	('shorter', 'NegReg', (72, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('patients', 'Species', '9606', (38, 46))	('CAG repeats', 'MPA', (80, 91))	('CAG', 'Chemical', '-', (179, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('CAG repeat', 'Var', (179, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('prostate cancer', 'Disease', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('prostate cancer', 'Disease', (52, 67))	('men', 'Species', '9606', (161, 164))	('CAG', 'Chemical', '-', (80, 83))
15181	26421011	However, it must be acknowledged that not all studies agree in concluding that shorter CAG repeats are associated with an increased risk of cancer.	('shorter CAG repeats', 'Var', (79, 98))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('CAG', 'Chemical', '-', (87, 90))
15182	26421011	While some works fail to show a statistically significant association between shorter CAG repeats and prostate cancer, others report that shorter CAG repeats are associated with a younger age at diagnosis but not with an increased risk of disease.	('shorter CAG repeats', 'Var', (138, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Disease', (102, 117))	('CAG', 'Chemical', '-', (86, 89))	('shorter', 'Var', (78, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (102, 117))	('CAG', 'Chemical', '-', (146, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
15184	26421011	Finally, shorter CAG repeats seem also to be associated with the development of benign prostatic hypertrophy (BPH).	('men', 'Species', '9606', (72, 75))	('shorter', 'Var', (9, 16))	('associated with', 'Reg', (45, 60))	('benign prostatic hypertrophy', 'Disease', 'MESH:D011470', (80, 108))	('CAG', 'Chemical', '-', (17, 20))	('BPH', 'Phenotype', 'HP:0008711', (110, 113))	('CAG repeats', 'Protein', (17, 28))	('benign prostatic hypertrophy', 'Phenotype', 'HP:0008711', (80, 108))	('benign prostatic hypertrophy', 'Disease', (80, 108))
15185	26421011	According to data from the Health Professionals Follow-Up Study, men with AR gene CAG repeat lengths of 19 or less had an OR of benign prostatic hyperplasia of 1.92 relative to men with repeat lengths of 25 or more.	('benign prostatic hyperplasia', 'Disease', (128, 156))	('men', 'Species', '9606', (65, 68))	('CAG', 'Chemical', '-', (82, 85))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (128, 156))	('men', 'Species', '9606', (177, 180))	('AR', 'Gene', '367', (74, 76))	('benign prostatic hyperplasia', 'Disease', 'MESH:D011470', (128, 156))	('repeat lengths of 19', 'Var', (86, 106))
15186	26421011	Also, a work which examined 176 BPH patients who underwent simple prostatectomy and 41 control subjects without benign prostatic enlargement found a statistically significant (P < 0.02) trend for large adenoma size with short CAG repeat length among the adenoma quartiles, thus demonstrating the inverse relationship between prostatic adenoma size and AR gene CAG repeat length.	('adenoma', 'Disease', 'MESH:D000236', (202, 209))	('adenoma', 'Disease', (335, 342))	('large adenoma', 'Phenotype', 'HP:0040261', (196, 209))	('prostatic enlargement', 'Disease', 'MESH:D011472', (119, 140))	('adenoma', 'Disease', 'MESH:D000236', (335, 342))	('AR', 'Gene', '367', (352, 354))	('benign prostatic enlargement', 'Phenotype', 'HP:0008711', (112, 140))	('patients', 'Species', '9606', (36, 44))	('CAG', 'Chemical', '-', (226, 229))	('adenoma quartiles', 'Disease', 'MESH:D000236', (254, 271))	('adenoma', 'Disease', (254, 261))	('adenoma', 'Disease', 'MESH:D000236', (254, 261))	('prostatic adenoma', 'Disease', 'MESH:D011470', (325, 342))	('CAG', 'Chemical', '-', (360, 363))	('BPH', 'Phenotype', 'HP:0008711', (32, 35))	('prostatic enlargement', 'Disease', (119, 140))	('prostatic adenoma', 'Disease', (325, 342))	('large', 'PosReg', (196, 201))	('adenoma quartiles', 'Disease', (254, 271))	('adenoma', 'Disease', (202, 209))	('short CAG repeat length', 'Var', (220, 243))
15192	26421011	Nevertheless, even if intima media thickness of peripheral arteries, lipid parameters, insulin resistance, blood pressure, and family history of early coronary artery disease (CAD) did not differ according to AR length, shorter CAG repeat of the AR gene was found to be associated with more severe CAD.	('CAD', 'Disease', 'None', (298, 301))	('insulin', 'Gene', '3630', (87, 94))	('early coronary artery disease', 'Phenotype', 'HP:0005181', (145, 174))	('thickness of peripheral arteries', 'Phenotype', 'HP:0004950', (35, 67))	('insulin resistance', 'Phenotype', 'HP:0000855', (87, 105))	('CAD', 'Disease', (298, 301))	('AR', 'Gene', '367', (246, 248))	('coronary artery disease', 'Disease', 'MESH:D003324', (151, 174))	('lipid', 'Chemical', 'MESH:D008055', (69, 74))	('shorter CAG repeat', 'Var', (220, 238))	('CAD', 'Disease', 'None', (176, 179))	('AR', 'Gene', '367', (209, 211))	('coronary artery disease', 'Disease', (151, 174))	('associated', 'Reg', (270, 280))	('insulin', 'Gene', (87, 94))	('CAD', 'Disease', (176, 179))	('CAG', 'Chemical', '-', (228, 231))
15193	26421011	On the other hand, independent associations between CAG length and adverse cardiovascular risk factors, such as high LDL, low HDL, and high blood pressure, were demonstrated by other studies; intriguingly, the association between longer CAG repeat length and low total testosterone concentrations was found to exert an adjunctive worsening effect on the metabolic profile.	('CAG', 'Gene', (237, 240))	('total testosterone concentrations', 'MPA', (263, 296))	('low', 'NegReg', (259, 262))	('longer', 'Var', (230, 236))	('CAG', 'Chemical', '-', (237, 240))	('high blood pressure', 'Phenotype', 'HP:0000822', (135, 154))	('testosterone', 'Chemical', 'MESH:D013739', (269, 281))	('low total testosterone concentrations', 'Phenotype', 'HP:0040171', (259, 296))	('high LDL', 'Phenotype', 'HP:0003141', (112, 120))	('low HDL', 'Phenotype', 'HP:0003233', (122, 129))	('metabolic profile', 'MPA', (354, 371))	('CAG', 'Chemical', '-', (52, 55))
15195	26421011	A possible relationship has been suggested between body composition and the CAG repeat polymorphism of the AR gene.	('relationship', 'Reg', (11, 23))	('CAG', 'Chemical', '-', (76, 79))	('CAG repeat polymorphism', 'Var', (76, 99))	('AR', 'Gene', '367', (107, 109))
15196	26421011	In adolescent boys, low CAG repeat numbers in AR may be a genetic risk factor for fat accumulation, particularly intra-abdominal fat.	('low CAG repeat numbers', 'Var', (20, 42))	('fat accumulation', 'MPA', (82, 98))	('AR', 'Gene', '367', (46, 48))	('intra-abdominal fat', 'Disease', (113, 132))	('CAG', 'Chemical', '-', (24, 27))	('boys', 'Species', '9606', (14, 18))
15201	26421011	Somewhat discordant results were however reported in a cohort of 233 men with type 2 diabetes and symptoms of hypogonadism, in which shorter AR CAG was independently associated with waist circumference and body mass index, suggesting an effect in providing healthy anthropomorphic and metabolic features.	('men', 'Species', '9606', (69, 72))	('diabetes', 'Disease', (85, 93))	('diabetes', 'Disease', 'MESH:D003920', (85, 93))	('waist circumference', 'Disease', (182, 201))	('CAG', 'Chemical', '-', (144, 147))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (78, 93))	('shorter', 'Var', (133, 140))	('associated', 'Reg', (166, 176))	('hypogonadism', 'Disease', (110, 122))	('body mass index', 'Disease', (206, 221))	('hypogonadism', 'Disease', 'MESH:D007006', (110, 122))	('hypogonadism', 'Phenotype', 'HP:0000135', (110, 122))	('AR', 'Gene', '367', (141, 143))
15202	26421011	Again, there appears to be a complex relationship between CAG repeat length and body composition, possibly influenced by genetic factors involved in type 2 diabetes, obesity, and cardiovascular disease, as well as environmental factors, including circulating total and free testosterone levels, lifestyle changes, and dietary patterns.	('obesity', 'Disease', (166, 173))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (179, 201))	('cardiovascular disease', 'Disease', 'MESH:D002318', (179, 201))	('CAG', 'Chemical', '-', (58, 61))	('diabetes', 'Disease', 'MESH:D003920', (156, 164))	('diabetes', 'Disease', (156, 164))	('body', 'MPA', (80, 84))	('men', 'Species', '9606', (221, 224))	('CAG repeat length', 'Var', (58, 75))	('obesity', 'Phenotype', 'HP:0001513', (166, 173))	('influenced', 'Reg', (107, 117))	('cardiovascular disease', 'Disease', (179, 201))	('testosterone', 'Chemical', 'MESH:D013739', (274, 286))	('obesity', 'Disease', 'MESH:D009765', (166, 173))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (149, 164))
15206	26421011	suggested that a high number of CAG repeats within the AR gene could attenuate testosterone effects on bone density and bone metabolism: the number of CAG was found to inversely and independently associate with BMD in 110 healthy men aged 20-50 years, and an increase in age-dependent bone loss in subjects with a CAG length of 22-31 compared with 14-21 CAG was reported.	('AR', 'Gene', '367', (55, 57))	('BMD', 'Disease', (211, 214))	('men', 'Species', '9606', (230, 233))	('CAG', 'Chemical', '-', (32, 35))	('repeats', 'Var', (36, 43))	('bone density', 'CPA', (103, 115))	('attenuate', 'NegReg', (69, 78))	('bone metabolism', 'CPA', (120, 135))	('BMD', 'Disease', 'MESH:D020388', (211, 214))	('bone loss', 'Phenotype', 'HP:0002797', (285, 294))	('CAG', 'Chemical', '-', (151, 154))	('testosterone', 'Chemical', 'MESH:D013739', (79, 91))	('bone loss', 'Disease', (285, 294))	('CAG', 'Var', (151, 154))	('bone loss', 'Disease', 'MESH:D016301', (285, 294))	('CAG', 'Chemical', '-', (354, 357))	('associate', 'Reg', (196, 205))	('CAG', 'Chemical', '-', (314, 317))
15216	26421011	The development of testicular cancer is postulated to be due to endocrine disruption, particularly abnormalities in the action of gonadotropins and steroidal sex hormones.	('endocrine disruption', 'Disease', 'MESH:D019958', (64, 84))	('action', 'MPA', (120, 126))	('testicular cancer', 'Phenotype', 'HP:0010788', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('endocrine disruption', 'Disease', (64, 84))	('testicular cancer', 'Disease', 'MESH:D013736', (19, 36))	('testicular cancer', 'Disease', (19, 36))	('abnormalities', 'Var', (99, 112))	('men', 'Species', '9606', (11, 14))
15217	26421011	Men with androgen insensitivity syndrome due to AR gene mutations have a higher risk of developing testicular cancer.	('mutations', 'Var', (56, 65))	('androgen insensitivity syndrome', 'Disease', (9, 40))	('Men', 'Species', '9606', (0, 3))	('testicular cancer', 'Phenotype', 'HP:0010788', (99, 116))	('testicular cancer', 'Disease', 'MESH:D013736', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('androgen insensitivity syndrome', 'Phenotype', 'HP:0008226', (9, 40))	('androgen insensitivity', 'Phenotype', 'HP:0008226', (9, 31))	('AR', 'Gene', '367', (48, 50))	('testicular cancer', 'Disease', (99, 116))
15221	26421011	However, the few published studies analysing the correlation between CAG repeat length and testicular cancer report contradictory results.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('testicular cancer', 'Phenotype', 'HP:0010788', (91, 108))	('CAG repeat length', 'Var', (69, 86))	('testicular cancer', 'Disease', 'MESH:D013736', (91, 108))	('CAG', 'Chemical', '-', (69, 72))	('testicular cancer', 'Disease', (91, 108))
15223	26421011	Many authors have tried to understand if reduced androgen sensitivity due to point mutations, or more often to an excessively long CAG repeat segment, could lead to the development of testicular dysgenesis and, consequently, increase susceptibility to testicular cancer.	('point mutations', 'Var', (77, 92))	('reduced', 'NegReg', (41, 48))	('CAG', 'Chemical', '-', (131, 134))	('men', 'Species', '9606', (145, 148))	('testicular dysgenesis', 'Disease', 'MESH:D013733', (184, 205))	('testicular cancer', 'Phenotype', 'HP:0010788', (252, 269))	('testicular cancer', 'Disease', 'MESH:D013736', (252, 269))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (184, 205))	('androgen sensitivity', 'MPA', (49, 69))	('lead to', 'Reg', (157, 164))	('men', 'Species', '9606', (176, 179))	('testicular dysgenesis', 'Disease', (184, 205))	('androgen sensitivity', 'Phenotype', 'HP:0008226', (49, 69))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('testicular cancer', 'Disease', (252, 269))
15229	26421011	This study therefore seems to suggest that longer CAG repeat lengths may indicate a higher risk of metastasis, and it was the first to demonstrate a correlation between AR CAG repeat length, testicular germ cell cancer histology, and disease progression, albeit in a limited caseload.	('AR', 'Gene', '367', (169, 171))	('CAG', 'Chemical', '-', (50, 53))	('correlation', 'Interaction', (149, 160))	('testicular', 'Disease', (191, 201))	('CAG', 'Chemical', '-', (172, 175))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('metastasis', 'CPA', (99, 109))	('germ cell cancer', 'Phenotype', 'HP:0100728', (202, 218))	('longer', 'Var', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
15230	26421011	analysed 123 stage 1 testicular cancer patients against a control group of 300 fertile men studied for AR mutations, of whom 115 were selected for the CAG and GGC repeats study.	('testicular cancer', 'Disease', (21, 38))	('men', 'Species', '9606', (87, 90))	('GGC', 'Gene', (159, 162))	('patients', 'Species', '9606', (39, 47))	('GGC', 'Gene', '79017', (159, 162))	('CAG', 'Chemical', '-', (151, 154))	('testicular cancer', 'Phenotype', 'HP:0010788', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (106, 115))	('AR', 'Gene', '367', (103, 105))	('testicular cancer', 'Disease', 'MESH:D013736', (21, 38))
15236	26421011	's finding that CAG > 25 was more common in patients with nonseminomatous tumours.	('patients', 'Species', '9606', (44, 52))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('CAG > 25', 'Var', (16, 24))	('nonseminomatous tumours', 'Disease', 'MESH:C537844', (58, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('common', 'Reg', (34, 40))	('nonseminomatous tumours', 'Disease', (58, 81))	('CAG', 'Chemical', '-', (16, 19))
15239	26421011	In other words, the risk of developing testicular cancer would seem to be lower for men with a CAG repeat number between 21 and 24.	('CAG', 'Chemical', '-', (95, 98))	('testicular cancer', 'Phenotype', 'HP:0010788', (39, 56))	('testicular cancer', 'Disease', 'MESH:D013736', (39, 56))	('men', 'Species', '9606', (84, 87))	('CAG repeat number', 'Var', (95, 112))	('testicular cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lower', 'NegReg', (74, 79))
15241	26421011	's study, the proportion of subjects with a long CAG repeat length (>=25) was higher in testicular cancer cases than controls; this was statistically significant for the nonseminoma group compared to controls.	('testicular cancer', 'Phenotype', 'HP:0010788', (88, 105))	('testicular cancer', 'Disease', 'MESH:D013736', (88, 105))	('higher', 'PosReg', (78, 84))	('nonseminoma', 'Disease', (170, 181))	('long CAG repeat length', 'Var', (44, 66))	('CAG', 'Chemical', '-', (49, 52))	('testicular cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('nonseminoma', 'Disease', 'None', (170, 181))
15244	26421011	In this group, the odds ratio of testicular cancer was higher for men in whom the CAG and GGC alleles were both long (CAG > 24 and GGC > 18; OR 2.65) or both short (CAG < 21 and GGC <= 17; OR 2.39).	('GGC', 'Gene', (178, 181))	('CAG > 24', 'Var', (118, 126))	('men', 'Species', '9606', (66, 69))	('testicular cancer', 'Phenotype', 'HP:0010788', (33, 50))	('GGC', 'Gene', '79017', (178, 181))	('GGC', 'Gene', (90, 93))	('CAG', 'Chemical', '-', (82, 85))	('testicular cancer', 'Disease', 'MESH:D013736', (33, 50))	('CAG', 'Chemical', '-', (118, 121))	('GGC', 'Gene', '79017', (90, 93))	('testicular cancer', 'Disease', (33, 50))	('GGC', 'Gene', (131, 134))	('CAG', 'Chemical', '-', (165, 168))	('GGC', 'Gene', '79017', (131, 134))	('higher', 'PosReg', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
15246	26421011	In conclusion, a CAG repeat number of >=25 may be considered a risk factor for the onset of testicular cancer, given its greater frequency in patients compared to controls.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('testicular cancer', 'Phenotype', 'HP:0010788', (92, 109))	('testicular cancer', 'Disease', 'MESH:D013736', (92, 109))	('CAG', 'Chemical', '-', (17, 20))	('CAG', 'Var', (17, 20))	('testicular cancer', 'Disease', (92, 109))	('patients', 'Species', '9606', (142, 150))
15251	26421011	These aspects lead us back to the crucial role played by the length of the polymorphic segment in AR function; a change in the number of repeats can lead to various disorders and, above all, is a risk factor for testicular cancer that should not be ignored.	('change', 'Var', (113, 119))	('number of repeats', 'Var', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('men', 'Species', '9606', (90, 93))	('AR', 'Gene', '367', (98, 100))	('testicular cancer', 'Phenotype', 'HP:0010788', (212, 229))	('testicular cancer', 'Disease', 'MESH:D013736', (212, 229))	('disorders', 'Disease', (165, 174))	('lead to', 'Reg', (149, 156))	('testicular cancer', 'Disease', (212, 229))
15262	26421011	In fact, hormone sensitivity is influenced by the AR CAG polymorphism.	('CAG', 'Chemical', '-', (53, 56))	('influenced', 'Reg', (32, 42))	('hormone sensitivity', 'MPA', (9, 28))	('AR', 'Gene', '367', (50, 52))	('polymorphism', 'Var', (57, 69))
15263	26421011	Some authors have shown an association between shorter CAG repeats and self-report measures of dominance and prestige, all of which are argued to be indices of the mating effort.	('shorter', 'Var', (47, 54))	('CAG', 'Chemical', '-', (55, 58))	('CAG', 'Protein', (55, 58))	('prestige', 'CPA', (109, 117))
15266	26421011	Also, free testosterone levels were found to be significantly related to dominance in boys with shorter CAG repeats, but not in those with medium and long CAG repeats.	('free testosterone levels', 'MPA', (6, 30))	('boys', 'Species', '9606', (86, 90))	('shorter CAG repeats', 'Var', (96, 115))	('related', 'Reg', (62, 69))	('testosterone', 'Chemical', 'MESH:D013739', (11, 23))	('dominance', 'Disease', (73, 82))	('CAG', 'Chemical', '-', (104, 107))	('CAG', 'Chemical', '-', (155, 158))
15268	26421011	Some studies show an association between longer CAG repeats and higher levels of depression, while others find no association.	('depression', 'Disease', (81, 91))	('depression', 'Phenotype', 'HP:0000716', (81, 91))	('longer CAG repeats', 'Var', (41, 59))	('CAG', 'Chemical', '-', (48, 51))	('depression', 'Disease', 'MESH:D000275', (81, 91))
15269	26421011	A relationship between testosterone levels, CAG repeat length, and depression was found in a work, which reported that, in middle-aged men, depression was significantly and inversely associated with total testosterone levels only in men with shorter CAG repeats, but not in those with the medium and long numbers of CAG repeats.	('depression', 'Disease', (140, 150))	('testosterone', 'Chemical', 'MESH:D013739', (23, 35))	('inversely', 'NegReg', (173, 182))	('CAG', 'Chemical', '-', (250, 253))	('CAG', 'Chemical', '-', (44, 47))	('shorter', 'Var', (242, 249))	('depression', 'Disease', (67, 77))	('men', 'Species', '9606', (135, 138))	('depression', 'Disease', 'MESH:D000275', (67, 77))	('depression', 'Phenotype', 'HP:0000716', (67, 77))	('depression', 'Phenotype', 'HP:0000716', (140, 150))	('CAG', 'Chemical', '-', (316, 319))	('testosterone', 'Chemical', 'MESH:D013739', (205, 217))	('depression', 'Disease', 'MESH:D000275', (140, 150))	('total testosterone levels', 'MPA', (199, 224))	('men', 'Species', '9606', (233, 236))	('associated', 'Interaction', (183, 193))
15272	26421011	Finally, it is also worth noting that several studies have shown that the presence of shorter AR CAG tracts is linked to Attention Deficit Hyperactivity Disorder and conduct disorder.	('AR', 'Gene', '367', (94, 96))	('linked', 'Reg', (111, 117))	('shorter', 'NegReg', (86, 93))	('Attention Deficit', 'Phenotype', 'HP:0007018', (121, 138))	('presence', 'Var', (74, 82))	('CAG', 'Chemical', '-', (97, 100))	('Attention Deficit Hyperactivity Disorder and conduct disorder', 'Disease', 'MESH:D001289', (121, 182))	('Hyperactivity', 'Phenotype', 'HP:0000752', (139, 152))
15276	26421011	SBMA patients have AR polyglutamine chain length higher than 40 as well as varying degrees of androgen insensitivity with gynecomastia, testicular atrophy, disorders of spermatogenesis, elevated serum gonadotropins, and diabetes mellitus.	('elevated serum gonadotropins', 'Phenotype', 'HP:0000837', (186, 214))	('testicular atrophy', 'Disease', 'MESH:C567108', (136, 154))	('testicular atrophy', 'Phenotype', 'HP:0000029', (136, 154))	('androgen insensitivity', 'Phenotype', 'HP:0008226', (94, 116))	('elevated', 'PosReg', (186, 194))	('gynecomastia', 'Disease', (122, 134))	('patients', 'Species', '9606', (5, 13))	('gynecomastia', 'Phenotype', 'HP:0000771', (122, 134))	('AR', 'Gene', '367', (19, 21))	('serum gonadotropins', 'MPA', (195, 214))	('diabetes mellitus', 'Disease', (220, 237))	('SBMA', 'Gene', '367', (0, 4))	('testicular atrophy', 'Disease', (136, 154))	('gynecomastia', 'Disease', 'MESH:D006177', (122, 134))	('SBMA', 'Gene', (0, 4))	('polyglutamine', 'Var', (22, 35))	('androgen', 'CPA', (94, 102))	('polyglutamine', 'Chemical', 'MESH:C097188', (22, 35))	('diabetes mellitus', 'Disease', 'MESH:D003920', (220, 237))	('disorders of spermatogenesis', 'Phenotype', 'HP:0008669', (156, 184))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (220, 237))
15278	26421011	Robust evidence suggests that polyglutamine stretch exerts toxic function on neurons leading to neurological phenotypes and neurodegeneration.	('neurodegeneration', 'Disease', (124, 141))	('neurodegeneration', 'Disease', 'MESH:D019636', (124, 141))	('polyglutamine stretch', 'Var', (30, 51))	('polyglutamine', 'Chemical', 'MESH:C097188', (30, 43))	('neurodegeneration', 'Phenotype', 'HP:0002180', (124, 141))
15281	26421011	In particular, the abnormal length of polyglutamine chain induces the formation of intracellular aggregates, a clear signature of SBMA.	('SBMA', 'Gene', (130, 134))	('induces', 'Reg', (58, 65))	('polyglutamine chain', 'Protein', (38, 57))	('intracellular aggregates', 'MPA', (83, 107))	('formation', 'MPA', (70, 79))	('SBMA', 'Gene', '367', (130, 134))	('abnormal length', 'Var', (19, 34))	('polyglutamine', 'Chemical', 'MESH:C097188', (38, 51))
15285	26421011	In 2015, a large body of evidence indicated an important role for AR CAG polymorphism in conditioning the peripheral effect of testosterone, even if its contribution warrants further assessment because of the many controversial findings in each androgen-related action.	('men', 'Species', '9606', (189, 192))	('testosterone', 'Chemical', 'MESH:D013739', (127, 139))	('peripheral effect of', 'MPA', (106, 126))	('polymorphism', 'Var', (73, 85))	('CAG', 'Chemical', '-', (69, 72))	('AR', 'Gene', '367', (66, 68))	('conditioning', 'MPA', (89, 101))
15300	23807173	The presence of ERCC1 was associated with non-CPS (P=0.05) and adjusted in the prognosis groups.	('non-CPS', 'Disease', (42, 49))	('CPS', 'Chemical', '-', (46, 49))	('ERCC1', 'Gene', '2067', (16, 21))	('presence', 'Var', (4, 12))	('ERCC1', 'Gene', (16, 21))	('associated', 'Reg', (26, 36))
15319	23807173	There are several polymorphisms in the ERCC1 gene.	('ERCC1', 'Gene', '2067', (39, 44))	('ERCC1', 'Gene', (39, 44))	('polymorphisms', 'Var', (18, 31))
15320	23807173	Some of these polymorphisms result in silent mutations; however, some allelic variants, such as 8092C>A, have been associated with a decrease in the DNA repair capacity and with lower survival rates in patients with colon cancer and lung cancer.	('survival rates', 'CPA', (184, 198))	('decrease', 'NegReg', (133, 141))	('8092C>A', 'Var', (96, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('lower', 'NegReg', (178, 183))	('lung cancer', 'Disease', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('patients', 'Species', '9606', (202, 210))	('colon cancer', 'Disease', 'MESH:D015179', (216, 228))	('8092C>A', 'Mutation', 'rs3212986', (96, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (216, 228))	('DNA repair capacity', 'MPA', (149, 168))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('colon cancer', 'Disease', (216, 228))
15321	23807173	In addition, the XPA gene can contain a polymorphism in the 5' non-coding region (A G) that is located four nucleotides upstream of the ATG start codon.	('polymorphism', 'Var', (40, 52))	('XPA', 'Gene', '7507', (17, 20))	('XPA', 'Gene', (17, 20))
15322	23807173	In this work, we studied the association between the expression of ERCC1 and XPA, the polymorphisms in ERCC1 (8092C>A) and the 5' UTR of XPA, and the overall survival (OS) and sensitivity of non-seminomatous (ns)-TGCTs patients treated with cisplatin-based chemotherapy.	('patients', 'Species', '9606', (219, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('ERCC1', 'Gene', (103, 108))	('8092C>A', 'Var', (110, 117))	('XPA', 'Gene', '7507', (137, 140))	('ERCC1', 'Gene', '2067', (103, 108))	('non-seminomatous', 'Disease', 'MESH:C537844', (191, 207))	('XPA', 'Gene', '7507', (77, 80))	('XPA', 'Gene', (77, 80))	('8092C>A', 'Mutation', 'rs3212986', (110, 117))	('XPA', 'Gene', (137, 140))	('ERCC1', 'Gene', '2067', (67, 72))	('non-seminomatous', 'Disease', (191, 207))	('ERCC1', 'Gene', (67, 72))	('OS', 'Chemical', '-', (168, 170))
15332	23807173	The patients were classified as sensitive (CPS) if they presented a complete radiological response with no evidence of residual lesions or a biochemical response (negativisation of TM) to BEP, or if they showed negativisation of TM and complete surgical resection of the residual lesions and the histopathology showed necrosis, fibrosis, or mature teratoma.	('fibrosis', 'Disease', 'MESH:D005355', (328, 336))	('fibrosis', 'Disease', (328, 336))	('BEP', 'Chemical', '-', (188, 191))	('negativisation', 'Var', (211, 225))	('teratoma', 'Phenotype', 'HP:0009792', (348, 356))	('teratoma', 'Disease', 'MESH:D013724', (348, 356))	('necrosis', 'Disease', (318, 326))	('patients', 'Species', '9606', (4, 12))	('CPS', 'Chemical', '-', (43, 46))	('teratoma', 'Disease', (348, 356))	('necrosis', 'Disease', 'MESH:D009336', (318, 326))
15347	23807173	The genomic region containing the single-nucleotide polymorphism (SNP) ERCC1 8092C>A was amplified by PCR using the primers 5'-TAG-TTCCTC-AGT-TTC-CCG-3' (forward) and 5'-TGA-GCC-AAT-TCAGCC-ACT-3' (reverse), which generate a 255-bp fragment of the 3' UTR of ERCC1.	('8092C>A', 'Mutation', 'rs3212986', (77, 84))	('TGA', 'Gene', '6899', (170, 173))	('AAT', 'Gene', '5265', (178, 181))	('TGA', 'Gene', (170, 173))	('ERCC1', 'Gene', '2067', (257, 262))	('ERCC1', 'Gene', (257, 262))	('single-nucleotide', 'Var', (34, 51))	('men', 'Species', '9606', (235, 238))	('ERCC1', 'Gene', (71, 76))	('ERCC1', 'Gene', '2067', (71, 76))	('AAT', 'Gene', (178, 181))
15378	23807173	Using a Cox model adjusted in the prognosis groups (IGCCCGC), the multivariate model (goodness of fit, P<0.001 by chi2-test) showed an interaction effect between the presence of ERCC1 and the response to cisplatin-based chemotherapy.	('ERCC1', 'Gene', '2067', (178, 183))	('presence', 'Var', (166, 174))	('ERCC1', 'Gene', (178, 183))	('goodness of fit', 'Disease', (86, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (204, 213))	('Cox', 'Gene', '1351', (8, 11))	('Cox', 'Gene', (8, 11))	('goodness of fit', 'Disease', 'MESH:D012640', (86, 101))	('interaction', 'Interaction', (135, 146))
15392	23807173	The OS was influenced by the response to cisplatin-based chemotherapy (CPS and non-CPS), and we found that this variable was strongly associated with the presence of ERCC1 by immunohistochemistry.	('associated', 'Reg', (134, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('OS', 'Chemical', '-', (4, 6))	('CPS', 'Chemical', '-', (83, 86))	('ERCC1', 'Gene', (166, 171))	('ERCC1', 'Gene', '2067', (166, 171))	('CPS', 'Chemical', '-', (71, 74))	('presence', 'Var', (154, 162))
15395	23807173	The Kaplan-Meier curve showed a lower 5-year OS probability for the ERCC1-negative and non-CPS patients (5.26%) compared with the ERCC1-positive and non-CPS patients (15.38%).	('ERCC1', 'Gene', '2067', (68, 73))	('ERCC1', 'Gene', (68, 73))	('OS', 'Chemical', '-', (45, 47))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (157, 165))	('CPS', 'Chemical', '-', (91, 94))	('CPS', 'Chemical', '-', (153, 156))	('ERCC1', 'Gene', '2067', (130, 135))	('OS probability', 'MPA', (45, 59))	('non-CPS', 'Var', (87, 94))	('lower', 'NegReg', (32, 37))	('ERCC1', 'Gene', (130, 135))
15400	23807173	The results of the Cox model of IGCCCG classification, the presence of ERCC1 and the response to cisplatin-based chemotherapy in ns-TGCTs are shown in Table 3.	('Cox', 'Gene', (19, 22))	('ns-TGCTs', 'Disease', (129, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('ERCC1', 'Gene', (71, 76))	('Cox', 'Gene', '1351', (19, 22))	('ERCC1', 'Gene', '2067', (71, 76))	('presence', 'Var', (59, 67))
15404	23807173	These polymorphisms were not associated with the cisplatin response (Table 1), the OS, or any other clinical-pathological variables studied (data not shown).	('OS', 'Chemical', '-', (83, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('polymorphisms', 'Var', (6, 19))	('associated', 'Reg', (29, 39))	('cisplatin response', 'MPA', (49, 67))
15405	23807173	These polymorphisms were in Hardy-Weinberg equilibrium: the calculated chi2 (3.55 and 3.05 for ERCC1 8092C>A and 5' UTR XPA, respectively)<value of chi2 (3.84), considering one degree of freedom and P=0.05.	('ERCC1', 'Gene', '2067', (95, 100))	('ERCC1', 'Gene', (95, 100))	('8092C>A', 'Var', (101, 108))	('XPA', 'Gene', '7507', (120, 123))	('8092C>A', 'Mutation', 'rs3212986', (101, 108))	('XPA', 'Gene', (120, 123))
15406	23807173	The frequencies of the polymorphic alleles were 0.48 for ERCC1 8092C>A and 0.60 for the XPA 5' UTR in patients with ns-TGCTs; these frequencies were the same as the frequencies observed in a sample of 124 and 161 healthy Mexicans.	('patients', 'Species', '9606', (102, 110))	('ns-TGCTs', 'Disease', (116, 124))	('8092C>A', 'Var', (63, 70))	('XPA', 'Gene', '7507', (88, 91))	('8092C>A', 'Mutation', 'rs3212986', (63, 70))	('XPA', 'Gene', (88, 91))	('ERCC1', 'Gene', (57, 62))	('ERCC1', 'Gene', '2067', (57, 62))
15407	23807173	For the ERCC1 8092C>A SNP analysis, 33 (26.6%) individuals were C/C, 64 (51.6%) were C/A, and 27 (21.8%) were A/A; for the 5' UTR XPA SNP, 27 (16.8%) individuals were A/A, 76 (47.2%) were A/G and 58 (36%) were G/G.	('8092C>A', 'Var', (14, 21))	('ERCC1', 'Gene', (8, 13))	('8092C>A', 'Mutation', 'rs3212986', (14, 21))	('XPA', 'Gene', '7507', (130, 133))	('ERCC1', 'Gene', '2067', (8, 13))	('XPA', 'Gene', (130, 133))
15413	23807173	In this study, we evaluated the association of the DNA repair proteins ERCC1 and XPA and the 8092C>A and 5' UTR polymorphisms in ERCC1 and XPA, respectively, with the CPS and OS of patients with ns-TGCTs.	('OS', 'Chemical', '-', (175, 177))	('polymorphisms', 'Var', (112, 125))	('8092C>A', 'Var', (93, 100))	('CPS', 'Disease', (167, 170))	('XPA', 'Gene', (139, 142))	('XPA', 'Gene', (81, 84))	('patients', 'Species', '9606', (181, 189))	('XPA', 'Gene', '7507', (81, 84))	('XPA', 'Gene', '7507', (139, 142))	('ERCC1', 'Gene', (129, 134))	('ERCC1', 'Gene', (71, 76))	('8092C>A', 'Mutation', 'rs3212986', (93, 100))	('ERCC1', 'Gene', '2067', (129, 134))	('CPS', 'Chemical', '-', (167, 170))	('association', 'Interaction', (32, 43))	('ERCC1', 'Gene', '2067', (71, 76))
15431	23807173	In patients with lung cancer who were treated with cisplatin, it was demonstrated that the 8092C>A polymorphism of ERCC1 is associated with decreased OS.	('8092C>A', 'Mutation', 'rs3212986', (91, 98))	('decreased', 'NegReg', (140, 149))	('lung cancer', 'Disease', (17, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('the 8092C>A', 'Var', (87, 98))	('ERCC1', 'Gene', '2067', (115, 120))	('ERCC1', 'Gene', (115, 120))	('patients', 'Species', '9606', (3, 11))	('OS', 'Chemical', '-', (150, 152))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))
15432	23807173	The polymorphism in the 5' UTR of XPA is associated with both decreased OS and decreased disease-free survival in women with ovarian cancer who were treated with cisplatin-based chemotherapy.	('ovarian cancer', 'Disease', (125, 139))	('women', 'Species', '9606', (114, 119))	('OS', 'Chemical', '-', (72, 74))	('disease-free survival', 'CPA', (89, 110))	('decreased', 'NegReg', (62, 71))	('decreased', 'NegReg', (79, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('polymorphism in', 'Var', (4, 19))	('XPA', 'Gene', '7507', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('XPA', 'Gene', (34, 37))
15435	23807173	The response to cisplatin-based chemotherapy and the presence of the ERCC1 were two prognosis factors in determining the probability of survival in ns-TGCTs.	('ERCC1', 'Gene', (69, 74))	('ERCC1', 'Gene', '2067', (69, 74))	('presence', 'Var', (53, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('ns-TGCTs', 'Disease', (148, 156))
15442	19483682	Common variation in KITLG and at 5q31.3 proximate to SPRY4 predispose to testicular germ cell cancer Evidence suggests that testicular germ cell tumors (TGCT) have a strong underlying genetic component.	('SPRY4', 'Gene', '81848', (53, 58))	('predispose', 'Reg', (59, 69))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (124, 151))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('variation', 'Var', (7, 16))	('testicular germ cell tumors', 'Disease', (124, 151))	('KITLG', 'Gene', '4254', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('germ cell cancer', 'Phenotype', 'HP:0100728', (84, 100))	('germ cell tumors', 'Phenotype', 'HP:0100728', (135, 151))	('SPRY4', 'Gene', (53, 58))	('KITLG', 'Gene', (20, 25))	('germ cell tumor', 'Phenotype', 'HP:0100728', (135, 150))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
15444	19483682	In independent replication, TGCT risk was increased 3-fold per copy of the major allele at rs3782179 and rs4474514 (OR=3.08, 95% CI 2.29, 4.13; OR=3.07, 95% CI 2.29, 4.13, respectively).	('rs4474514', 'Mutation', 'rs4474514', (105, 114))	('TGCT', 'Disease', (28, 32))	('rs3782179', 'Mutation', 'rs3782179', (91, 100))	('rs4474514', 'Var', (105, 114))	('rs3782179', 'Var', (91, 100))
15445	19483682	We also replicated associations with rs4324715 and rs6897876 at 5q31.3 near sprouty 4 (SPRY4; P < 5.0 x 10-6 in discovery).	('rs6897876', 'Mutation', 'rs6897876', (51, 60))	('sprouty 4', 'Gene', (76, 85))	('rs4324715', 'Var', (37, 46))	('SPRY4', 'Gene', (87, 92))	('sprouty 4', 'Gene', '81848', (76, 85))	('SPRY4', 'Gene', '81848', (87, 92))	('rs4324715', 'Mutation', 'rs4324715', (37, 46))	('rs6897876', 'Var', (51, 60))
15447	19483682	These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as TGCT susceptibility genes.	('affect', 'Reg', (55, 61))	('TGCT', 'Disease', (62, 66))	('SPRY4', 'Gene', (96, 101))	('variants', 'Var', (46, 54))	('SPRY4', 'Gene', '81848', (96, 101))	('KITLG', 'Gene', '4254', (86, 91))	('KITLG', 'Gene', (86, 91))
15457	19483682	Seven of these (rs995030, rs1352947, rs1472899, rs3782179, rs3782181, rs4474514, rs11104952) including the most significant association (P = 3.54 x 10-10) at rs4474514 occurred within the KITLG (c-KIT ligand) gene region on 12q22 (Supplementary Fig.	('rs4474514', 'Mutation', 'rs4474514', (158, 167))	('rs995030', 'Var', (16, 24))	('KITLG', 'Gene', (188, 193))	('rs4474514', 'Mutation', 'rs4474514', (70, 79))	('rs1352947', 'Mutation', 'rs1352947', (26, 35))	('c-KIT ligand', 'Gene', '4254', (195, 207))	('rs995030', 'Mutation', 'rs995030', (16, 24))	('rs3782181', 'Var', (59, 68))	('KITLG', 'Gene', '4254', (188, 193))	('rs3782181', 'Mutation', 'rs3782181', (59, 68))	('rs4474514', 'Var', (158, 167))	('men', 'Species', '9606', (237, 240))	('rs11104952', 'Mutation', 'rs11104952', (81, 91))	('rs4474514', 'Var', (70, 79))	('rs11104952', 'Var', (81, 91))	('c-KIT ligand', 'Gene', (195, 207))	('rs3782179', 'Var', (48, 57))	('rs1472899', 'Mutation', 'rs1472899', (37, 46))	('rs1472899', 'Var', (37, 46))	('rs1352947', 'Var', (26, 35))	('rs3782179', 'Mutation', 'rs3782179', (48, 57))
15458	19483682	The eighth marker (rs3770112, P = 4.93 x 10-8) mapped to the integrin alpha 4 (ITGA4) gene on 2q31.3.	('integrin alpha 4', 'Gene', '3676', (61, 77))	('rs3770112', 'Var', (19, 28))	('integrin alpha 4', 'Gene', (61, 77))	('ITGA4', 'Gene', (79, 84))	('rs3770112', 'Mutation', 'rs3770112', (19, 28))	('ITGA4', 'Gene', '3676', (79, 84))
15461	19483682	The correlation between observed and imputed P values for the 23 markers that were in the same linkage disequilibrium block with rs3770112 was very high (r=0.96), and information content and maximum posterior call probability for rs3770112 were both > 0.998.	('rs3770112', 'Mutation', 'rs3770112', (129, 138))	('rs3770112', 'Mutation', 'rs3770112', (230, 239))	('rs3770112', 'Var', (129, 138))	('rs3770112', 'Var', (230, 239))
15463	19483682	We selected two markers in KITLG (rs3782179, rs4474514) to bring forward into replication.	('rs3782179', 'Var', (34, 43))	('rs4474514', 'Var', (45, 54))	('KITLG', 'Gene', '4254', (27, 32))	('rs3782179', 'Mutation', 'rs3782179', (34, 43))	('rs4474514', 'Mutation', 'rs4474514', (45, 54))	('KITLG', 'Gene', (27, 32))
15465	19483682	Of these, three (rs12521013, rs4324715, rs6897876) mapped 2.4 kb downstream of the SPRY4 (sprouty homolog 4) coding region on 5q31.3 (Fig.	('sprouty homolog 4', 'Gene', (90, 107))	('rs12521013', 'Var', (17, 27))	('rs12521013', 'Mutation', 'rs12521013', (17, 27))	('rs4324715', 'Var', (29, 38))	('SPRY4', 'Gene', (83, 88))	('sprouty homolog 4', 'Gene', '81848', (90, 107))	('rs6897876', 'Var', (40, 49))	('rs4324715', 'Mutation', 'rs4324715', (29, 38))	('SPRY4', 'Gene', '81848', (83, 88))	('rs6897876', 'Mutation', 'rs6897876', (40, 49))
15467	19483682	3), and two (rs17031166, rs1549383) mapped to a gene free region on 2p14 that is 500kb centromeric of SPRED2 (sprouty-related, EVH1 domain containing 2) (Supplementary Fig.	('rs17031166', 'Var', (13, 23))	('SPRED2', 'Gene', '200734', (102, 108))	('rs17031166', 'Mutation', 'rs17031166', (13, 23))	('SPRED2', 'Gene', (102, 108))	('sprouty-related, EVH1 domain containing 2', 'Gene', '200734', (110, 151))	('rs1549383', 'Mutation', 'rs1549383', (25, 34))	('men', 'Species', '9606', (160, 163))	('rs1549383', 'Var', (25, 34))
15468	19483682	As both SPRY4 and SPRED2 have been implicated in the KIT/KITLG signaling pathway, and as these two regions were the only ones that contained more than one marker surpassing threshold significance, we also chose two markers at each of these loci (SPRY4: rs4324715, rs6897876; 2p14: rs17031166, rs1549383) to bring forward for replication.	('rs6897876', 'Var', (264, 273))	('rs6897876', 'Mutation', 'rs6897876', (264, 273))	('SPRY4', 'Gene', '81848', (246, 251))	('KITLG', 'Gene', '4254', (57, 62))	('SPRY4', 'Gene', '81848', (8, 13))	('rs17031166', 'Mutation', 'rs17031166', (281, 291))	('KITLG', 'Gene', (57, 62))	('SPRED2', 'Gene', '200734', (18, 24))	('rs4324715', 'Mutation', 'rs4324715', (253, 262))	('SPRY4', 'Gene', (8, 13))	('rs1549383', 'Mutation', 'rs1549383', (293, 302))	('SPRY4', 'Gene', (246, 251))	('SPRED2', 'Gene', (18, 24))	('implicated', 'Reg', (35, 45))	('rs1549383', 'Var', (293, 302))
15469	19483682	We observed associations with rs3782179 (Ptrend= 5.88 x 10-15) and rs4474514 (Ptrend= 5.88 x 10-15) in KITLG and with rs4324715 (Ptrend= 6.77 x 10-4) and rs6897876 (Ptrend= 3.67 x 10-4) proximal to SPRY4 (Table 2), but not with rs17031166 (Ptrend= 0.90) or rs1549383 (Ptrend= 0.88) near SPRED2.	('SPRY4', 'Gene', '81848', (198, 203))	('SPRED2', 'Gene', (287, 293))	('rs4474514', 'Mutation', 'rs4474514', (67, 76))	('rs4324715', 'Var', (118, 127))	('rs17031166', 'Mutation', 'rs17031166', (228, 238))	('rs4474514', 'Var', (67, 76))	('rs4324715', 'Mutation', 'rs4324715', (118, 127))	('associations', 'Interaction', (12, 24))	('rs1549383', 'Mutation', 'rs1549383', (257, 266))	('rs3782179', 'Mutation', 'rs3782179', (30, 39))	('KITLG', 'Gene', '4254', (103, 108))	('rs6897876', 'Var', (154, 163))	('SPRY4', 'Gene', (198, 203))	('SPRED2', 'Gene', '200734', (287, 293))	('rs6897876', 'Mutation', 'rs6897876', (154, 163))	('KITLG', 'Gene', (103, 108))	('rs3782179', 'Var', (30, 39))
15470	19483682	TGCT risk was increased three-fold per copy of the major A-allele in KITLG rs3782179 and rs4474514 (odds ratio (OR) = 3.08, 95% CI 2.29, 4.13; and OR=3.07, 95% CI 2.29, 4.13, respectively).	('TGCT', 'Disease', (0, 4))	('rs4474514', 'Mutation', 'rs4474514', (89, 98))	('rs3782179', 'Mutation', 'rs3782179', (75, 84))	('KITLG', 'Gene', '4254', (69, 74))	('rs3782179', 'Var', (75, 84))	('rs4474514', 'Var', (89, 98))	('KITLG', 'Gene', (69, 74))
15472	19483682	TGCT risk was increased nearly 40% per copy of the major T-allele in rs4324715 (OR=1.37, 95% CI 1.14, 1.64) and major C-allele in rs6897876 (OR=1.39, 95% CI 1.16, 1.66); and risk was increased 65-80% with homozygous carriage of the major alleles (OR=1.81, 95% CI 1.26, 2.58; and OR=1.68, 95% CI 1.17, 2.42, respectively) compared with homozygous carriage of their corresponding minor alleles.	('increased', 'PosReg', (14, 23))	('rs4324715', 'Mutation', 'rs4324715', (69, 78))	('TGCT', 'Disease', (0, 4))	('rs6897876', 'Var', (130, 139))	('rs6897876', 'Mutation', 'rs6897876', (130, 139))	('rs4324715', 'Var', (69, 78))
15474	19483682	The per allele relative risks (RR) for rs3782179 and rs4474514 (KITLG) were 2.5 (95% CI 1.6, .9) and 2.6 (95% CI 1.6, 4.0), respectively, and for rs4324715 and rs6897876 (proximal to SPRY4) 1.5 (95% CI 1.2, 2.1) and 1.5 (95% CI 1.1, 2.0), respectively.	('rs6897876', 'Var', (160, 169))	('rs4474514', 'Mutation', 'rs4474514', (53, 62))	('rs4324715', 'Mutation', 'rs4324715', (146, 155))	('rs6897876', 'Mutation', 'rs6897876', (160, 169))	('rs3782179', 'Mutation', 'rs3782179', (39, 48))	('rs4474514', 'Var', (53, 62))	('KITLG', 'Gene', '4254', (64, 69))	('SPRY4', 'Gene', (183, 188))	('KITLG', 'Gene', (64, 69))	('rs3782179', 'Var', (39, 48))	('rs4324715', 'Var', (146, 155))	('SPRY4', 'Gene', '81848', (183, 188))
15476	19483682	In the replication set, marker genotypes in KITLG and SPRY4 were associated with both seminoma and non-seminoma germ cell tumors without indication that genotype associations differed between the two subtypes (Table 3).	('SPRY4', 'Gene', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('germ cell tumors', 'Phenotype', 'HP:0100728', (112, 128))	('non-seminoma germ cell tumors', 'Disease', (99, 128))	('germ cell tumor', 'Phenotype', 'HP:0100728', (112, 127))	('seminoma', 'Disease', 'MESH:D018239', (86, 94))	('SPRY4', 'Gene', '81848', (54, 59))	('seminoma', 'Disease', 'MESH:D018239', (103, 111))	('genotypes', 'Var', (31, 40))	('non-seminoma germ cell tumors', 'Disease', 'MESH:D009373', (99, 128))	('associated with', 'Reg', (65, 80))	('KITLG', 'Gene', (44, 49))	('KITLG', 'Gene', '4254', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('seminoma', 'Disease', (86, 94))	('seminoma', 'Disease', (103, 111))
15480	19483682	For rs3782179 and rs4474514, we observed a three-fold increased risk of disease per major allele and a 4.5-fold increased risk of disease for homozygous carriage of the major allele.	('rs3782179', 'Var', (4, 13))	('rs4474514', 'Var', (18, 27))	('rs4474514', 'Mutation', 'rs4474514', (18, 27))	('rs3782179', 'Mutation', 'rs3782179', (4, 13))	('disease', 'Disease', (72, 79))
15487	19483682	Furthermore, loss of the transmembrane form of Kitl, which leads to decreased PGC number, has been identified as a TGCT susceptibility locus in the 129/Sv mouse.	('decreased', 'NegReg', (68, 77))	('PGC', 'Protein', (78, 81))	('129/Sv', 'Species', '10090', (148, 154))	('mouse', 'Species', '10090', (155, 160))	('Kitl', 'Gene', (47, 51))	('loss', 'Var', (13, 17))
15489	19483682	Thus, both germline variation and somatic mutations in the KITLG/KIT signaling pathway are associated with TGCT.	('germline variation', 'Var', (11, 29))	('KITLG', 'Gene', '4254', (59, 64))	('TGCT', 'Disease', (107, 111))	('KITLG', 'Gene', (59, 64))	('associated', 'Reg', (91, 101))
15490	19483682	In addition, KITLG/KIT signaling plays an important role in male fertility, and mutations in Kitl lead to decreased germ cell number.	('decreased', 'NegReg', (106, 115))	('mutations', 'Var', (80, 89))	('Kitl', 'Gene', (93, 97))	('KITLG', 'Gene', '4254', (13, 18))	('KITLG', 'Gene', (13, 18))	('germ cell number', 'CPA', (116, 132))
15492	19483682	As KITLG plays a role in determining level of pigmentation, we postulated that inherited variation at this locus could provide a genetic explanation for the observed differences in TGCT incidence in whites and blacks.	('men', 'Species', '9606', (49, 52))	('variation', 'Var', (89, 98))	('TGCT', 'Disease', (181, 185))	('KITLG', 'Gene', '4254', (3, 8))	('KITLG', 'Gene', (3, 8))
15494	19483682	Data from HapMap Phase 3 show significant differences (P = 4.3 x 10-20) in the frequency of the risk alleles of KITLG (rs3782179 and rs4474514) when comparing the CEU (major allele frequency = 0.80) and ASW (African ancestry in Southwest USA: major allele frequency = 0.25) populations.	('rs4474514', 'Mutation', 'rs4474514', (133, 142))	('KITLG', 'Gene', '4254', (112, 117))	('KITLG', 'Gene', (112, 117))	('rs3782179', 'Mutation', 'rs3782179', (119, 128))	('rs4474514', 'Var', (133, 142))	('rs3782179', 'Var', (119, 128))
15496	19483682	We also observed an association between TGCT risk and variation at 5q31 just downstream of SPRY4.	('SPRY4', 'Gene', '81848', (91, 96))	('TGCT', 'Disease', (40, 44))	('5q31', 'Gene', (67, 71))	('variation', 'Var', (54, 63))	('SPRY4', 'Gene', (91, 96))
15500	19483682	In summary, our results demonstrate that common genetic variants at the 12p22 and 5q31 loci are associated with TGCT and strongly implicate KITLG as a susceptibility gene in the pathogenesis of TGCT.	('associated', 'Reg', (96, 106))	('KITLG', 'Gene', '4254', (140, 145))	('variants', 'Var', (56, 64))	('KITLG', 'Gene', (140, 145))	('TGCT', 'Disease', (112, 116))
15520	31434192	Immunohistochemical Review of Leydig Cell Lesions in Ochratoxin A-Treated Fischer Rats and Controls Ochratoxin A is best known as a potent renal carcinogen in male rats and mice after necessarily protracted ingestion, although valid extrapolation to any human disease has not been verified.	('Leydig Cell Lesions', 'Disease', 'MESH:D007984', (30, 49))	('human', 'Species', '9606', (254, 259))	('Leydig Cell Lesions', 'Disease', (30, 49))	('rats', 'Species', '10116', (164, 168))	('Ochratoxin A', 'Chemical', 'MESH:C025589', (53, 65))	('Ochratoxin A', 'Var', (100, 112))	('Ochratoxin A', 'Chemical', 'MESH:C025589', (100, 112))	('Rats', 'Species', '10116', (82, 86))	('mice', 'Species', '10090', (173, 177))
15603	31434192	In our study, seminoma was ruled out by the absent reaction for germ cell markers (OCT3/4, PLAP) and D2-40 & CD117 (usually positive in seminoma).	('CD', 'Disease', 'MESH:D006223', (109, 111))	('seminoma', 'Disease', 'MESH:D018239', (14, 22))	('PLAP', 'Gene', '116645', (91, 95))	('OCT3/4', 'Gene', '83500', (83, 89))	('seminoma', 'Disease', (136, 144))	('PLAP', 'Gene', (91, 95))	('D2-40 &', 'Var', (101, 108))	('seminoma', 'Disease', (14, 22))	('OCT3/4', 'Gene', (83, 89))	('seminoma', 'Disease', 'MESH:D018239', (136, 144))
15700	30739914	Comparison of the primary tumours with the matched normal provided a set of 1239 somatic putative DNA variants (SNV) for these cases (Fig.	('variants', 'Var', (102, 110))	('primary tumours', 'Disease', (18, 33))	('primary tumours', 'Disease', 'MESH:D009369', (18, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
15708	30739914	This signature 3 is strongly associated with mutations in BRCA1 or BRCA2, genomic deletion and insertion events smaller than 100 kb, and a deficiency in homologous recombination repair in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('mutations', 'Var', (45, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('homologous recombination repair', 'MPA', (153, 184))	('breast cancer', 'Disease', (188, 201))	('BRCA1', 'Gene', (58, 63))	('deficiency', 'Disease', (139, 149))	('BRCA2', 'Gene', (67, 72))	('associated', 'Reg', (29, 39))	('deficiency', 'Disease', 'MESH:D007153', (139, 149))	('BRCA2', 'Gene', '675', (67, 72))	('BRCA1', 'Gene', '672', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
15710	30739914	Furthermore, pathogenic somatic mutations in BRCA1 or BRCA2 were not observed in the four included TGCC, although case T1382 carried a predicted, non-pathogenic BRCA1 missense variant (Supplementary Table S6), nor in the cases of the Taylor-Weiner study.	('missense variant', 'Var', (167, 183))	('BRCA1', 'Gene', (161, 166))	('BRCA1', 'Gene', '672', (45, 50))	('men', 'Species', '9606', (191, 194))	('BRCA2', 'Gene', (54, 59))	('BRCA1', 'Gene', (45, 50))	('BRCA1', 'Gene', '672', (161, 166))	('BRCA2', 'Gene', '675', (54, 59))
15727	30739914	Presence of chromosome arm 12p gain (Supplementary Fig.	('chromosome', 'Var', (12, 22))	('gain', 'PosReg', (31, 35))	('men', 'Species', '9606', (43, 46))
15767	30739914	The single SNV identified in the GCNIS of T6107 was present in high relative read frequencies (up to 50%), suggesting that this mutational event preceded genome duplication (Fig.	('T6107', 'Var', (42, 47))	('genome', 'MPA', (154, 160))	('GCNIS', 'Chemical', '-', (33, 38))
15781	30739914	In agreement with their extreme sensitivity to cisplatin-based therapies, TP53 mutations are extremely rare in primary TGCC indicating no selective pressure.	('primary TGCC', 'Disease', (111, 123))	('men', 'Species', '9606', (8, 11))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
15783	30739914	S9) may have provided an alternative route for inactivation of TP53 and therapy resistance.	('inactivation', 'Var', (47, 59))	('TP53', 'Gene', (63, 67))	('therapy resistance', 'CPA', (72, 90))	('TP53', 'Gene', '7157', (63, 67))
15787	30739914	It is tempting to speculate that other components of this homologous recombination repair pathway may be affected and responsible for the specific base substitution signature in the absence of direct involvement of BRCA genes.	('responsible', 'Reg', (118, 129))	('affected', 'Reg', (105, 113))	('base substitution', 'Var', (147, 164))	('men', 'Species', '9606', (207, 210))	('BRCA', 'Gene', '672', (215, 219))	('BRCA', 'Gene', (215, 219))
15789	30739914	Alternatively, BRCA-related repair functions may be low or turned off intrinsically in the embryonic PGC/gonocytes and during early TGCC development, and thus contribute to the accumulation of this specific pattern of base substitutions.	('repair functions', 'CPA', (28, 44))	('men', 'Species', '9606', (144, 147))	('base substitutions', 'Var', (218, 236))	('BRCA', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (15, 19))	('contribute', 'Reg', (159, 169))	('low', 'NegReg', (52, 55))	('accumulation', 'PosReg', (177, 189))
15796	30739914	The BRCA-like mutational signature in TGCC indicative for reduced homologous recombination repair, may be suggestive for combined use of poly ADP ribose polymerase (PARP) inhibitors and platinum-based therapy but requires additional support.	('TGCC', 'Gene', (38, 42))	('BRCA', 'Gene', '672', (4, 8))	('mutational', 'Var', (14, 24))	('BRCA', 'Gene', (4, 8))	('PARP', 'Gene', (165, 169))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('poly ADP ribose polymerase', 'Gene', '142', (137, 163))	('PARP', 'Gene', '142', (165, 169))	('reduced', 'NegReg', (58, 65))	('poly ADP ribose polymerase', 'Gene', (137, 163))	('homologous recombination repair', 'MPA', (66, 97))
15818	27551266	Alterations occurring in any of them could lead to the production of abnormal spermatozoa and reduce proliferation of spermatozoa.	('rat', 'Species', '10116', (108, 111))	('Alterations', 'Var', (0, 11))	('lead to', 'Reg', (43, 50))	('proliferation of spermatozoa', 'CPA', (101, 129))	('production', 'MPA', (55, 65))	('reduce', 'NegReg', (94, 100))	('rat', 'Species', '10116', (4, 7))	('abnormal spermatozoa', 'Phenotype', 'HP:0012864', (69, 89))
15885	27551266	cDNA was subjected to PCR (30 cycles) for CYP1A1, AhR, Apaf1, Fas, FasL, Bcl2, Bax and beta Actin in 20 muL reaction mixture [10x PCR buffer, 2.5 mM dNTP (deoxyribonucleotide triphosphate), Taq-polymerase 1U, and forward and reverse primers].	('Bcl2', 'Gene', '24224', (73, 77))	('dNTP', 'Chemical', '-', (149, 153))	('beta Actin', 'Gene', '81822', (87, 97))	('deoxyribonucleotide triphosphate', 'Chemical', '-', (155, 187))	('Bcl2', 'Gene', (73, 77))	('Fas', 'Chemical', 'MESH:C038178', (67, 70))	('CYP1A1', 'Var', (42, 48))	('Apaf1', 'Gene', '78963', (55, 60))	('Fas', 'Chemical', 'MESH:C038178', (62, 65))	('Apaf1', 'Gene', (55, 60))	('beta Actin', 'Gene', (87, 97))	('Bax', 'Gene', (79, 82))	('Bax', 'Gene', '24887', (79, 82))	('FasL', 'Gene', (67, 71))	('FasL', 'Gene', '25385', (67, 71))
15921	27551266	H&E staining of rat testis showed that B(a)P caused significant degenerative changes.	('degenerative changes', 'Phenotype', 'HP:0002180', (64, 84))	('rat', 'Species', '10116', (70, 73))	('significant degenerative', 'CPA', (52, 76))	('that B', 'Var', (34, 40))	('rat', 'Species', '10116', (16, 19))	('H&E', 'Chemical', '-', (0, 3))
15962	27551266	tBid translocates to mitochondrial membrane and facilitates cytochrome c release, thus activates the mitochondrial apoptotic pathway.	('tBid', 'Var', (0, 4))	('mitochondrial apoptotic pathway', 'Pathway', (101, 132))	('cytochrome c', 'Gene', (60, 72))	('facilitates', 'PosReg', (48, 59))	('cytochrome c', 'Gene', '54205', (60, 72))	('activates', 'PosReg', (87, 96))	('tBid', 'Chemical', '-', (0, 4))
16048	27551266	Phosphorylation at serine 15 residue of p53 is an important post-translational modification responsible for the functional efficacy and stability of p53.	('p53', 'Gene', '301300', (40, 43))	('p53', 'Gene', (149, 152))	('Phosphorylation', 'Var', (0, 15))	('p53', 'Gene', (40, 43))	('p53', 'Gene', '301300', (149, 152))	('serine', 'Chemical', 'MESH:D012694', (19, 25))
16085	19429394	In addition, cis-DCCA and trans-DCCA were inversely associated with inhibin B (p for trend = 0.03 and 0.02, respectively).	('inhibin B', 'Protein', (68, 77))	('trans-DCCA', 'Chemical', '-', (26, 36))	('cis-DCCA', 'Chemical', '-', (13, 21))	('trans-DCCA', 'Var', (26, 36))	('associated', 'Interaction', (52, 62))	('inversely', 'NegReg', (42, 51))	('cis-DCCA', 'Var', (13, 21))
16086	19429394	Finally, there was evidence that trans-DCCA was inversely associated with testosterone and free androgen index (the ratio of testosterone to sex hormone binding globulin; p for trend = 0.09 and 0.05, respectively).	('testosterone', 'Chemical', 'MESH:D013739', (125, 137))	('trans-DCCA', 'Chemical', '-', (33, 43))	('testosterone', 'Chemical', 'MESH:D013739', (74, 86))	('trans-DCCA', 'Var', (33, 43))	('associated', 'Interaction', (58, 68))	('inversely', 'NegReg', (48, 57))	('free androgen index', 'MPA', (91, 110))	('testosterone', 'MPA', (74, 86))
16137	19429394	In multivariate linear regression (Table 3), serum hormone levels were regressed on categories of SG-adjusted pyrethroid insecticide metabolite concentrations (<50th, >=50th - 75th, and >=75th percentile).	('serum hormone levels', 'MPA', (45, 65))	('pyrethroid', 'Chemical', 'MESH:D011722', (110, 120))	('<50th', 'Var', (160, 165))
16142	19429394	Men in the highest cis-DCCA, trans-DCCA, or summed metabolite categories had elevated FSH and LH compared to men with concentrations of these metabolites below the median, with most of these relationships demonstrating a dose-dependent trend.	('trans-DCCA', 'Chemical', '-', (29, 39))	('cis-DCCA', 'Chemical', '-', (19, 27))	('trans-DCCA', 'Var', (29, 39))	('Men', 'Species', '9606', (0, 3))	('elevated', 'PosReg', (77, 85))	('FSH', 'CPA', (86, 89))	('elevated FSH', 'Phenotype', 'HP:0008232', (77, 89))	('men', 'Species', '9606', (109, 112))	('LH', 'Chemical', 'MESH:D007986', (94, 96))	('cis-DCCA', 'Var', (19, 27))
16144	19429394	For trans-DCCA, the middle and high metabolite categories were associated with 4.8% (95% CI -23.9% to +14.2%) and 22.7% (95% CI -41.8% to -3.7%) declines in inhibin B, respectively, compared to the population median for inhibin B (153 pg/ml).	('declines', 'NegReg', (145, 153))	('trans-DCCA', 'Chemical', '-', (4, 14))	('inhibin B', 'MPA', (157, 166))	('trans-DCCA', 'Var', (4, 14))
16146	19429394	In multiple linear regression (Table 3) the high trans-DCCA category was associated with a 10% (95% CI -21.3% to +1.1%; p-value = 0.08) decline in testosterone relative to the population median for testosterone (373 ng/dl).	('testosterone', 'MPA', (147, 159))	('testosterone', 'Chemical', 'MESH:D013739', (198, 210))	('testosterone', 'Chemical', 'MESH:D013739', (147, 159))	('high trans-DCCA', 'Var', (44, 59))	('decline', 'NegReg', (136, 143))	('trans-DCCA', 'Chemical', '-', (49, 59))
16148	19429394	Finally, there was an inverse association between cis-DCCA categories and total T3, but the relationship did not follow a monotonic dose-dependent pattern.	('cis-DCCA', 'Var', (50, 58))	('cis-DCCA', 'Chemical', '-', (50, 58))	('inverse', 'NegReg', (22, 29))
16174	19429394	The authors also reported that cis-permethrin caused structural abnormalities in the seminiferous tubules, which may be consistent with our hypothesis of pyrethroid effects on Sertoli cells based on the observed associations with increased FSH and declined inhibin B levels in the present study.	('cis-permethrin', 'Var', (31, 45))	('cis-permethrin', 'Chemical', 'MESH:D026023', (31, 45))	('increased FSH', 'Phenotype', 'HP:0008232', (230, 243))	('inhibin B levels', 'MPA', (257, 273))	('increased', 'PosReg', (230, 239))	('FSH', 'MPA', (240, 243))	('Sertoli cells', 'Phenotype', 'HP:0100619', (176, 189))	('declined', 'NegReg', (248, 256))	('pyrethroid', 'Chemical', 'MESH:D011722', (154, 164))	('declined inhibin B levels', 'Phenotype', 'HP:0031100', (248, 273))
16175	19429394	There is experimental evidence for endocrine disruption in relation to pyrethroids other than permethrin that are metabolized to 3PBA, cis-DCCA and/or trans-DCCA.	('pyrethroids', 'Chemical', 'MESH:D011722', (71, 82))	('endocrine disruption', 'MPA', (35, 55))	('cis-DCCA', 'Chemical', '-', (135, 143))	('men', 'Species', '9606', (15, 18))	('3PBA', 'Chemical', 'MESH:C017618', (129, 133))	('trans-DCCA', 'Chemical', '-', (151, 161))	('permethrin', 'Chemical', 'MESH:D026023', (94, 104))	('trans-DCCA', 'Var', (151, 161))
16178	19429394	Conversely, another study that simultaneously dosed male rats with cypermethrin and the organophosphorus pesticide methyl parathion reported significant increases in serum FSH levels in relation to exposure.	('cypermethrin', 'Chemical', 'MESH:C017160', (67, 79))	('increases in serum FSH levels', 'Phenotype', 'HP:0008232', (153, 182))	('increases', 'PosReg', (153, 162))	('methyl parathion', 'Chemical', 'MESH:D008743', (115, 131))	('cypermethrin', 'Var', (67, 79))	('organophosphorus', 'Chemical', '-', (88, 104))	('rats', 'Species', '10116', (57, 61))	('serum FSH levels', 'MPA', (166, 182))
16191	31454181	We conducted a search in PubMed, Google Scholar and Web of Science to select studies on the association between rs10069690 and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs10069690', 'Mutation', 'rs10069690', (112, 122))	('rs10069690', 'Var', (112, 122))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
16193	31454181	The result demonstrated that rs10069690 was significantly associated with an increased risk of cancer overall (OR = 1.09, 95% CI: 1.06-1.12, p < .001) under the allele model.	('rs10069690', 'Var', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs10069690', 'Mutation', 'rs10069690', (29, 39))
16203	31454181	Recently, genome-wide association studies (GWAS) have demonstrated that single nucleotide polymorphisms (SNPs) in Chromosome 5p15.33, which is a crucial genomic region for telomere biology and contains two well-known genes: telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L), are significantly associated with cancer risk (Bojesen et al., 2013; Haiman et al., 2011; Rafnar et al., 2009; Wolpin et al., 2014).	('CLPTM1L', 'Gene', '81037', (311, 318))	('telomerase reverse transcriptase', 'Gene', (224, 256))	('cleft lip', 'Phenotype', 'HP:0410030', (268, 277))	('CLPTM1L', 'Gene', (311, 318))	('cleft lip and palate', 'Disease', 'MESH:D002972', (268, 288))	('telomerase reverse transcriptase', 'Gene', '7015', (224, 256))	('cleft lip and palate', 'Phenotype', 'HP:0000202', (268, 288))	('single nucleotide', 'Var', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('TERT', 'Gene', (258, 262))	('TERT', 'Gene', '7015', (258, 262))	('cancer', 'Disease', (355, 361))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('associated', 'Reg', (339, 349))
16207	31454181	Mutations in the coding regions of TERT can affect telomerase activity and telomere length, and generate severe clinical phenotypes, including a substantive increase in cancer frequency (Baird, 2010).	('cancer', 'Disease', (169, 175))	('activity', 'MPA', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Mutations', 'Var', (0, 9))	('telomere length', 'CPA', (75, 90))	('affect', 'Reg', (44, 50))	('TERT', 'Gene', (35, 39))	('increase', 'PosReg', (157, 165))	('TERT', 'Gene', '7015', (35, 39))	('telomerase', 'CPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
16208	31454181	Previous studies have demonstrated that rs10069690 (C>T) polymorphism in the TERT is associated with susceptibility to multiple types of cancer, such as breast cancer (Bojesen et al., 2013; Haiman et al., 2011; Huo et al., 2016; Michailidou et al., 2015, 2017), ovarian cancer (Bojesen et al., 2013; Earp et al., 2016; Kuchenbaecker et al., 2015; Lee et al., 2016; Phelan et al., 2017), lung cancer (Landi et al., 2009; Ye et al., 2017), and thyroid cancer (Gong et al., 2016; Gudmundsson et al., 2017).	('cancer', 'Disease', (392, 398))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('thyroid cancer', 'Disease', 'MESH:D013964', (442, 456))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (450, 456))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rs10069690', 'Mutation', 'rs10069690', (40, 50))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (270, 276))	('lung cancer', 'Disease', (387, 398))	('ovarian cancer', 'Disease', 'MESH:D010051', (262, 276))	('thyroid cancer', 'Phenotype', 'HP:0002890', (442, 456))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (450, 456))	('lung cancer', 'Disease', 'MESH:D008175', (387, 398))	('ovarian cancer', 'Disease', (262, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('rs10069690', 'Var', (40, 50))	('thyroid cancer', 'Disease', (442, 456))	('lung cancer', 'Phenotype', 'HP:0100526', (387, 398))	('cancer', 'Phenotype', 'HP:0002664', (450, 456))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
16209	31454181	A quantitative synthesis of the accumulated data from different studies is important to provide evidence on the association of rs10069690 polymorphism with cancer risk.	('association', 'Interaction', (112, 123))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('rs10069690', 'Mutation', 'rs10069690', (127, 137))	('rs10069690', 'Var', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
16225	31454181	Subgroup analysis based on cancer type indicated that the TERT rs10069690 polymorphism was associated with an increased risk of breast cancer (OR = 1.07, 95% CI: 1.03-1.11, p-heterogeneity < .001, I 2 = 89.5%), ovarian cancer (OR = 1.14, 95% CI: 1.10-1.19, p-heterogeneity = .002, I 2 = 70.8%), lung cancer (OR = 1.19, 95% CI: 1.03-1.36, p-heterogeneity = .019, I 2 = 66%), thyroid cancer (OR = 1.23, 95% CI: 1.11-1.38, p-heterogeneity = .243, I 2 = 26.8%), and RCC (OR = 1.29, 95% CI: 1.07-1.55, p-heterogeneity < .001, I 2 = 0.0%).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancer', 'Disease', (295, 306))	('cancer type', 'Disease', (27, 38))	('cancer type', 'Disease', 'MESH:D009369', (27, 38))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('RCC', 'Disease', (462, 465))	('ovarian cancer', 'Disease', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('ovarian cancer', 'Phenotype', 'HP:0100615', (211, 225))	('lung cancer', 'Disease', 'MESH:D008175', (295, 306))	('thyroid cancer', 'Disease', (374, 388))	('polymorphism', 'Var', (74, 86))	('rs10069690', 'Mutation', 'rs10069690', (63, 73))	('RCC', 'Disease', 'MESH:D002292', (462, 465))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('TERT', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('thyroid cancer', 'Disease', 'MESH:D013964', (374, 388))	('thyroid cancer', 'Phenotype', 'HP:0002890', (374, 388))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('ovarian cancer', 'Disease', 'MESH:D010051', (211, 225))
16232	31454181	For a prior probability of 0.1, assuming that the statistical power was 1.00, the FPRP values were 4.44E-09 for an association of rs10069690 allele with an increased risk of cancer.	('rs10069690', 'Mutation', 'rs10069690', (130, 140))	('rs10069690', 'Var', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('association', 'Interaction', (115, 126))
16233	31454181	Positive associations with the rs10069690 observed in the subgroups of ethnicity (European and Asian), cancer type (breast cancer, ovarian cancer, lung cancer, thyroid cancer, RCC, and pancreatic cancer), cancer classification (gynecological cancer, gastrointestinal cancer, and head and neck cancer), source of control (PB and HB), sample size (large and small), and genotype method (Illumina and MassArray) were significant (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('thyroid cancer', 'Phenotype', 'HP:0002890', (160, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('head and neck cancer', 'Disease', 'MESH:D006258', (279, 299))	('cancer', 'Disease', (168, 174))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('ovarian cancer', 'Disease', (131, 145))	('cancer', 'Disease', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rs10069690', 'Mutation', 'rs10069690', (31, 41))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('cancer', 'Disease', (293, 299))	('breast cancer', 'Disease', (116, 129))	('RCC', 'Disease', (176, 179))	('cancer', 'Disease', (267, 273))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('cancer', 'Disease', (205, 211))	('head and neck cancer', 'Phenotype', 'HP:0012288', (279, 299))	('lung cancer', 'Disease', (147, 158))	('thyroid cancer', 'Disease', (160, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer type', 'Disease', (103, 114))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer type', 'Disease', 'MESH:D009369', (103, 114))	('cancer', 'Disease', (139, 145))	('pancreatic cancer', 'Disease', (185, 202))	('gastrointestinal cancer', 'Disease', (250, 273))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (250, 273))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('RCC', 'Disease', 'MESH:D002292', (176, 179))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (250, 273))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (123, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (131, 145))	('thyroid cancer', 'Disease', 'MESH:D013964', (160, 174))	('rs10069690', 'Var', (31, 41))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
16234	31454181	A single nucleotide polymorphism (SNP) rs10069690 located in intron 4 of TERT, has been hypothesized to be associated with the risk of cancers development by many researchers, however, the results are conflicting and heterogeneous.	('single nucleotide polymorphism', 'Var', (2, 32))	('rs10069690', 'Mutation', 'rs10069690', (39, 49))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('rs10069690', 'Var', (39, 49))	('cancers', 'Disease', (135, 142))	('associated', 'Reg', (107, 117))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TERT', 'Gene', (73, 77))	('TERT', 'Gene', '7015', (73, 77))
16239	31454181	The significant association between rs10069690 and cancer risk was also found in the stratification by cancer classification, source of controls, sample size, and genotype method.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rs10069690', 'Mutation', 'rs10069690', (36, 46))	('rs10069690', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
16245	31454181	A growing number of epidemiological studies have provided evidence that TERT polymorphisms contribute to cancer development (Jin et al., 2013; Li et al., 2012; Rafnar et al., 2009).	('polymorphisms', 'Var', (77, 90))	('contribute', 'Reg', (91, 101))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
16246	31454181	It has been reported that rs10069690 was associated with an increased risk of breast cancer (Bojesen et al., 2013; Haiman et al., 2011; Huo et al., 2016; Michailidou et al., 2015, 2017), ovarian cancer (Bojesen et al., 2013; Earp et al., 2016; Kuchenbaecker et al., 2015; Lee et al., 2016; Phelan et al., 2017), thyroid cancer (Gudmundsson et al., 2017), prostate cancer (Panagiotou et al., 2015), and glioma (Kinnersley et al., 2015; Melin et al., 2017; Ostrom et al., 2018; Rajaraman et al., 2012), through GWASs, but other studies have shown that the T allele was associated with a remarkably decreased risk of prostate cancer (Schumacher et al., 2011; Thomas et al., 2008), bladder cancer (Rothman et al., 2010), and testicular germ cell tumor (Schumacher et al., 2013).	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('rs10069690', 'Mutation', 'rs10069690', (26, 36))	('glioma', 'Disease', 'MESH:D005910', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('tumor', 'Disease', (742, 747))	('prostate cancer', 'Disease', (614, 629))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (742, 747))	('breast cancer', 'Disease', (78, 91))	('ovarian cancer', 'Disease', (187, 201))	('glioma', 'Phenotype', 'HP:0009733', (402, 408))	('thyroid cancer', 'Disease', (312, 326))	('germ cell tumor', 'Phenotype', 'HP:0100728', (732, 747))	('decreased', 'NegReg', (596, 605))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('tumor', 'Phenotype', 'HP:0002664', (742, 747))	('rs10069690', 'Var', (26, 36))	('prostate cancer', 'Disease', 'MESH:D011471', (355, 370))	('prostate cancer', 'Phenotype', 'HP:0012125', (355, 370))	('prostate cancer', 'Disease', (355, 370))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('thyroid cancer', 'Disease', 'MESH:D013964', (312, 326))	('bladder cancer', 'Disease', 'MESH:D001749', (678, 692))	('bladder cancer', 'Disease', (678, 692))	('cancer', 'Phenotype', 'HP:0002664', (623, 629))	('decreased risk of prostate', 'Phenotype', 'HP:0008687', (596, 622))	('glioma', 'Disease', (402, 408))	('thyroid cancer', 'Phenotype', 'HP:0002890', (312, 326))	('prostate cancer', 'Disease', 'MESH:D011471', (614, 629))	('bladder cancer', 'Phenotype', 'HP:0009725', (678, 692))	('prostate cancer', 'Phenotype', 'HP:0012125', (614, 629))
16247	31454181	Additionally, a recent study composed of 386 patients and 495 controls suggested that the rs10069690 T allele was associated with increased risk of lung cancer (Ye et al., 2017), while other studies did not find any significant association between rs10069690 and risk of lung cancer (Gao et al., 2014; Landi et al., 2011; Wang et al., 2016).	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('lung cancer', 'Disease', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('lung cancer', 'Disease', (148, 159))	('patients', 'Species', '9606', (45, 53))	('rs10069690', 'Mutation', 'rs10069690', (248, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('rs10069690', 'Mutation', 'rs10069690', (90, 100))	('rs10069690 T', 'Var', (90, 102))	('lung cancer', 'Disease', 'MESH:D008175', (271, 282))
16248	31454181	Other studies reported that the rs10069690 T allele was also not associated with risk of nasopharyngeal carcinoma (Zhang et al., 2016), melanoma (Llorca-Cardenosa et al., 2014), colorectal cancer (Li et al., 2017), non-Hodgkin's lymphoma (Prescott et al., 2010), and endometrial cancer (Burghaus et al., 2017; Prescott et al., 2010).	('colorectal cancer', 'Disease', (178, 195))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (215, 237))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (219, 237))	('endometrial cancer', 'Phenotype', 'HP:0012114', (267, 285))	('rs10069690', 'Mutation', 'rs10069690', (32, 42))	('nasopharyngeal carcinoma', 'Disease', (89, 113))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (215, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('endometrial cancer', 'Disease', (267, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('rs10069690 T', 'Var', (32, 44))	('endometrial cancer', 'Disease', 'MESH:D016889', (267, 285))	('lymphoma', 'Phenotype', 'HP:0002665', (229, 237))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	("non-Hodgkin's lymphoma", 'Disease', (215, 237))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (89, 113))	('nasopharyngeal carcinoma', 'Disease', 'MESH:C538339', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))
16250	31454181	These results suggested that the the role of polymorphism is potentially influenced by the tumor origins, and that stratified analysis is reasonable.	('polymorphism', 'Var', (45, 57))	('influenced', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
16251	31454181	Therefore, we can infer that rs10069690 had cancer-specific contributions and may play different roles in the etiology of different tumor sites.	('rs10069690', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('play', 'Reg', (82, 86))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('rs10069690', 'Mutation', 'rs10069690', (29, 39))
16252	31454181	More recently, a meta-analysis study showed that rs10069690 polymorphism was associated with an increased breast cancer risk (Li, Dong, Feng, Zhang, & Cao, 2016).	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('rs10069690', 'Mutation', 'rs10069690', (49, 59))	('rs10069690', 'Var', (49, 59))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
16253	31454181	An agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34,248 cases and 45,036 controls identified that rs10069690 T allele was positively associated with glioma, while being negatively associated with testicular, prostate, bladder and pancreatic cancer (Wang et al., 2014).	('bladder and pancreatic cancer', 'Disease', 'MESH:D001749', (279, 308))	('prostate', 'Disease', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (291, 308))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('cancers', 'Disease', (99, 106))	('rs10069690 T', 'Var', (159, 171))	('associated', 'Reg', (194, 204))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('rs10069690', 'Mutation', 'rs10069690', (159, 169))	('testicular', 'Disease', (257, 267))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('glioma', 'Disease', (210, 216))
16254	31454181	The association between TERT rs10069690 polymorphism and longer telomere length has been recently reported (Pellatt, Wolff, Lundgreen, Cawthon, & Slattery, 2012).	('TERT', 'Gene', (24, 28))	('polymorphism', 'Var', (40, 52))	('longer', 'MPA', (57, 63))	('TERT', 'Gene', '7015', (24, 28))	('rs10069690', 'Mutation', 'rs10069690', (29, 39))
16256	31454181	TERT rs10069690 polymorphism may contribute directly to disease predisposition by modifying the function of TERT, or it is in linkage disequilibrium (LD) with other disease-causing mutations.	('contribute', 'Reg', (33, 43))	('function', 'MPA', (96, 104))	('rs10069690', 'Mutation', 'rs10069690', (5, 15))	('polymorphism', 'Var', (16, 28))	('TERT', 'Gene', (0, 4))	('modifying', 'Reg', (82, 91))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', (108, 112))	('TERT', 'Gene', '7015', (108, 112))
16262	31454181	Overall, these results would help in understanding the role of this variant rs10069690 in cancer development and can aid in identifying new molecular targets focusing on cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rs10069690', 'Mutation', 'rs10069690', (76, 86))	('rs10069690', 'Var', (76, 86))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
16264	31454181	Considering the limitations of the present meta-analysis, future studies with standardized unbiased methods, larger sample studies and well-matched controls are required to validate the current findings and functional studies are warranted to reveal the role of the polymorphism rs10069690 in carcinogenesis.	('rs10069690', 'Var', (279, 289))	('carcinogenesis', 'Disease', (293, 307))	('carcinogenesis', 'Disease', 'MESH:D063646', (293, 307))	('rs10069690', 'Mutation', 'rs10069690', (279, 289))
16300	28430626	For example, in the study by Mao et al, which involved 128 non-small cell lung cancer patients, multivariate analyses demonstrated that PD-L1 expression was an independent predictor of poor survival in patients with NSCLC (HR=2.02, 95% CI 1.67-2.46; P< 0.001).	('expression', 'Var', (142, 152))	('NSCLC', 'Disease', (216, 221))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('small cell lung cancer', 'Disease', 'MESH:D055752', (63, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('small cell lung cancer', 'Disease', (63, 85))	('PD-L1', 'Gene', (136, 141))	('patients', 'Species', '9606', (202, 210))	('poor', 'NegReg', (185, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('patients', 'Species', '9606', (86, 94))
16303	28430626	In 2016, Roberto et al analyzed the prognostic value of PD-L1 in renal cell carcinoma in a meta-analysis based on 6 studies including 1,323 patients, which demonstrated that positive PD-L1 expression was a negative predictor of OS.	('PD-L1', 'Gene', (183, 188))	('positive', 'Var', (174, 182))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (65, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('negative', 'NegReg', (206, 214))	('patients', 'Species', '9606', (140, 148))	('renal cell carcinoma', 'Disease', (65, 85))	('PD-L1', 'Gene', (56, 61))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))
16420	23169338	Furthermore, increased drug detoxification in the cytoplasm by the glutathione system and changes in DNA repair leading to an increased removal of cisplatin-induced lesions from the DNA have been described in drug resistance.	('DNA repair', 'MPA', (101, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('drug detoxification', 'MPA', (23, 42))	('changes', 'Var', (90, 97))	('removal of cisplatin-induced lesions', 'MPA', (136, 172))	('glutathione', 'Chemical', 'MESH:D005978', (67, 78))	('increased', 'PosReg', (126, 135))	('increased', 'PosReg', (13, 22))	('drug resistance', 'Phenotype', 'HP:0020174', (209, 224))
16421	23169338	Mismatch repair deficiency and microsatellite instability seem to have a pivotal role.	('deficiency', 'Disease', (16, 26))	('Mismatch repair', 'Protein', (0, 15))	('microsatellite instability', 'Var', (31, 57))	('deficiency', 'Disease', 'MESH:D007153', (16, 26))
16479	23169338	After 48 h of incubation with HP-2 (0-20 muM) or HP-14 (0-20 muM), only a non-significant growth inhibition<5% was observed for both compounds (data not shown).	('HP', 'Chemical', 'MESH:C035699', (30, 32))	('muM', 'Gene', '56925', (41, 44))	('0-20', 'Var', (56, 60))	('muM', 'Gene', (41, 44))	('muM', 'Gene', (61, 64))	('HP-14', 'Gene', (49, 54))	('HP-14', 'Chemical', '-', (49, 54))	('HP', 'Chemical', 'MESH:C035699', (49, 51))	('muM', 'Gene', '56925', (61, 64))
16494	23169338	Strikingly, a number of genes known to be directly or indirectly involved in DNA damage detection and repair, such as topoisomerase I, GADD45a/b and BRCA1, were altered by cisplatin in 2102EP, but not in 2102EP-R when cells were treated with cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('topoisomerase I', 'Enzyme', (118, 133))	('BRCA1', 'Gene', '672', (149, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (242, 251))	('GADD45a', 'Gene', (135, 142))	('GADD45a', 'Gene', '1647', (135, 142))	('cisplatin', 'Var', (172, 181))	('BRCA1', 'Gene', (149, 154))	('altered', 'Reg', (161, 168))
16506	23169338	Cisplatin-sensitive (2102EP) and -resistant (2102EP-R) TGCT cells were inoculated onto the CAM of 8-day-old chicken embryos and quantitatively examined for HP-induced growth reduction after 72 h of treatment.	('2102EP-R', 'Var', (45, 53))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('chicken', 'Species', '9031', (108, 115))	('reduction', 'NegReg', (174, 183))	('HP', 'Chemical', 'MESH:C035699', (156, 158))
16507	23169338	Both 2102EP and 2102EP-R cells formed substantial tumours (Figure 5B and C) with mean tumour areas of 7.66 (2102EP) and 8.01 mm2 (2102EP-R) after 3 days.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumour', 'Disease', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Disease', (50, 57))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('2102EP-R', 'Var', (16, 24))	('tumour', 'Disease', (86, 92))
16540	23169338	Furthermore, cisplatin and HP-14 treatment in combination also altered the expression of other genes, such as BRCA1, ERCC3 or DNAJB11, each of them being implicated in the regulation of DNA repair and stress response, suggesting that cisplatin and HP-14 treatment leads to a more pronounced DNA-damaging effect in the sensitive cell line.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('HP-14', 'Chemical', '-', (27, 32))	('ERCC3', 'Gene', '2071', (117, 122))	('DNAJB11', 'Gene', (126, 133))	('HP-14', 'Chemical', '-', (248, 253))	('BRCA1', 'Gene', '672', (110, 115))	('altered', 'Reg', (63, 70))	('DNA-damaging effect', 'MPA', (291, 310))	('BRCA1', 'Gene', (110, 115))	('ERCC3', 'Gene', (117, 122))	('cisplatin', 'Var', (234, 243))	('HP-14', 'Var', (248, 253))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('expression', 'MPA', (75, 85))
16543	23169338	Furthermore, the expression of the cell growth regulator dihydrofolate reductase was much more enhanced in 2102EP-R cells than in 2102EP cells.	('dihydrofolate reductase', 'Gene', '1719', (57, 80))	('2102EP-R', 'Var', (107, 115))	('expression', 'MPA', (17, 27))	('dihydrofolate reductase', 'Gene', (57, 80))	('enhanced', 'PosReg', (95, 103))
16552	23169338	HP-14 treatment significantly reduced tumour growth by up to 64%, and was at least not less effective in tumours formed by 2102EP-R cells compared with tumours formed by 2102EP.	('HP-14', 'Gene', (0, 5))	('HP-14', 'Chemical', '-', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumour growth', 'Disease', (38, 51))	('tumours', 'Disease', (105, 112))	('2102EP-R cells', 'Var', (123, 137))	('tumour growth', 'Disease', 'MESH:D006130', (38, 51))	('reduced', 'NegReg', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
16556	21617256	Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour Familial testicular germ cell tumours (TGCTs) and bilateral TGCTs comprise 1-2% and 5% of all TGCTs, respectively, but their genetic basis remains largely unknown.	('Variants', 'Var', (0, 8))	('predispose to', 'Reg', (57, 70))	('BAK1', 'Gene', '578', (27, 31))	('testicular germ cell tumour', 'Phenotype', 'HP:0010788', (80, 107))	('CLPTM1L', 'Gene', (49, 56))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('BAK1', 'Gene', (27, 31))	('germ cell tumour', 'Phenotype', 'HP:0100728', (128, 144))	('KITLG', 'Gene', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('DMRT1', 'Gene', '1761', (33, 38))	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('tumour', 'Disease', (101, 107))	('testicular germ cell tumour', 'Phenotype', 'HP:0010788', (117, 144))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('KITLG', 'Gene', '4254', (20, 25))	('TGCT', 'Phenotype', 'HP:0010788', (168, 172))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('Familial testicular germ cell tumours', 'Disease', 'MESH:D009373', (108, 145))	('tumour', 'Disease', (138, 144))	('Familial testicular germ cell tumours', 'Disease', (108, 145))	('DMRT1', 'Gene', (33, 38))	('germ cell tumour', 'Phenotype', 'HP:0100728', (91, 107))	('CLPTM1L', 'Gene', '81037', (49, 56))	('TGCT', 'Phenotype', 'HP:0010788', (202, 206))	('TGCT', 'Phenotype', 'HP:0010788', (147, 151))
16557	21617256	To investigate the contribution of known testicular cancer risk variants in familial and bilateral TGCTs.	('testicular cancer', 'Disease', (41, 58))	('bilateral TGCTs', 'Disease', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('testicular cancer', 'Phenotype', 'HP:0010788', (41, 58))	('testicular cancer', 'Disease', 'MESH:D013736', (41, 58))	('TGCT', 'Phenotype', 'HP:0010788', (99, 103))	('familial', 'Disease', (76, 84))	('variants', 'Var', (64, 72))
16558	21617256	The study genotyped 106 single nucleotide polymorphisms (SNPs) in four regions (BAK1, DMRT1, KITLG, TERT-CLPTM1L) previously identified from genome-wide association studies of TGCT, including risk single nucleotide polymorphisms (SNPs) rs210138 (BAK1), rs755383 (DMRT1), rs4635969 (TERT-CLPTM1L) in 97 cases with familial TGCT and 22 affected individuals with sporadic bilateral TGCT as well as 871 controls.	('KITLG', 'Gene', (93, 98))	('rs4635969', 'Mutation', 'rs4635969', (271, 280))	('CLPTM1L', 'Gene', '81037', (287, 294))	('DMRT1', 'Gene', (86, 91))	('CLPTM1L', 'Gene', (105, 112))	('TERT', 'Gene', (100, 104))	('TERT', 'Gene', '7015', (100, 104))	('KITLG', 'Gene', '4254', (93, 98))	('DMRT1', 'Gene', '1761', (263, 268))	('TGCT', 'Phenotype', 'HP:0010788', (176, 180))	('CLPTM1L', 'Gene', (287, 294))	('TERT', 'Gene', (282, 286))	('TGCT', 'Disease', (176, 180))	('TERT', 'Gene', '7015', (282, 286))	('rs755383', 'Mutation', 'rs755383', (253, 261))	('rs210138', 'Mutation', 'rs210138', (236, 244))	('rs755383', 'Var', (253, 261))	('DMRT1', 'Gene', (263, 268))	('BAK1', 'Gene', '578', (80, 84))	('DMRT1', 'Gene', '1761', (86, 91))	('BAK1', 'Gene', '578', (246, 250))	('BAK1', 'Gene', (80, 84))	('CLPTM1L', 'Gene', '81037', (105, 112))	('TGCT', 'Phenotype', 'HP:0010788', (379, 383))	('BAK1', 'Gene', (246, 250))	('TGCT', 'Phenotype', 'HP:0010788', (322, 326))	('rs4635969', 'Var', (271, 280))	('rs210138', 'Var', (236, 244))
16559	21617256	Three previously identified risk SNPs were found to be associated with familial and bilateral TGCT (rs210138: OR 1.80, CI 1.35 to 2.41, p = 7.03x10-5; rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70x10-4; rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07x10-3).	('TGCT', 'Phenotype', 'HP:0010788', (94, 98))	('rs755383', 'Mutation', 'rs755383', (151, 159))	('rs4635969', 'Mutation', 'rs4635969', (200, 209))	('rs210138:', 'Var', (100, 109))	('rs755383', 'Var', (151, 159))	('rs210138', 'Mutation', 'rs210138', (100, 108))	('rs4635969', 'Var', (200, 209))
16560	21617256	Evidence for a second independent association was found for an SNP in TERT (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24x10-3).	('rs4975605', 'Mutation', 'rs4975605', (76, 85))	('TERT', 'Gene', '7015', (70, 74))	('TERT', 'Gene', (70, 74))	('rs4975605:', 'Var', (76, 86))
16561	21617256	Another association with an SNP was identified in KITLG (rs2046971: OR 2.33, p=1.28x10-3); this SNP is in high linkage disequilibrium (LD) with reported risk variant rs995030.	('rs995030', 'Mutation', 'rs995030', (166, 174))	('rs995030', 'Var', (166, 174))	('KITLG', 'Gene', '4254', (50, 55))	('KITLG', 'Gene', (50, 55))	('rs2046971', 'Mutation', 'rs2046971', (57, 66))	('rs2046971:', 'Var', (57, 67))
16562	21617256	This study provides evidence for replication of recent genome-wide association studies results and shows that variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT.	('TGCT', 'Phenotype', 'HP:0010788', (204, 208))	('TERT', 'Gene', (143, 147))	('predispose to', 'Reg', (167, 180))	('DMRT1', 'Gene', '1761', (136, 141))	('BAK1', 'Gene', (130, 134))	('variants', 'Var', (110, 118))	('TERT', 'Gene', '7015', (143, 147))	('KITLG', 'Gene', (161, 166))	('KITLG', 'Gene', '4254', (161, 166))	('CLPTM1L', 'Gene', '81037', (148, 155))	('DMRT1', 'Gene', (136, 141))	('CLPTM1L', 'Gene', (148, 155))	('BAK1', 'Gene', '578', (130, 134))
16584	21617256	Of the previously identified gene regions, four were genotyped in this study, including three of the identified risk SNPs, rs210138 (within an intron of BAK1), rs755383 (near DMRT1), and rs4635969 (near TERT-CLPTM1L).	('CLPTM1L', 'Gene', '81037', (208, 215))	('BAK1', 'Gene', (153, 157))	('rs210138', 'Mutation', 'rs210138', (123, 131))	('CLPTM1L', 'Gene', (208, 215))	('DMRT1', 'Gene', '1761', (175, 180))	('TERT', 'Gene', (203, 207))	('rs4635969', 'Mutation', 'rs4635969', (187, 196))	('rs210138', 'Var', (123, 131))	('BAK1', 'Gene', '578', (153, 157))	('TERT', 'Gene', '7015', (203, 207))	('DMRT1', 'Gene', (175, 180))	('rs755383', 'Mutation', 'rs755383', (160, 168))	('rs4635969', 'Var', (187, 196))	('rs755383', 'Var', (160, 168))
16586	21617256	We found all four SNPs to be associated with familial and bilateral TGCT under a log-additive genetic model (rs210138: OR 1.80, CI 1.35 to 2.41, p=7.03x10-5, non-risk/risk allele: A/G; rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70x10-4, non-risk/risk allele: C/T; rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07x10-3, non-risk/risk allele: C/T; rs2046971: OR 2.33, CI 1.39 to 3.85, p=1.28x10-3, non-risk/risk allele: G/C).	('C/T; rs4635969', 'Var', (256, 270))	('familial', 'Disease', (45, 53))	('rs755383', 'Mutation', 'rs755383', (185, 193))	('TGCT', 'Phenotype', 'HP:0010788', (68, 72))	('C/T; rs2046971: OR', 'Var', (333, 351))	('bilateral TGCT', 'Disease', (58, 72))	('rs210138', 'Var', (109, 117))	('rs2046971', 'Mutation', 'rs2046971', (338, 347))	('associated', 'Reg', (29, 39))	('rs210138', 'Mutation', 'rs210138', (109, 117))	('rs4635969', 'Mutation', 'rs4635969', (261, 270))
16587	21617256	We found several SNPs in BAK1 that were strongly associated with case status; the strongest association was for rs210162 (p=9.11x10-6) (figure 1A).	('rs210162', 'Var', (112, 120))	('BAK1', 'Gene', '578', (25, 29))	('associated', 'Reg', (49, 59))	('BAK1', 'Gene', (25, 29))	('rs210162', 'Mutation', 'rs210162', (112, 120))
16588	21617256	Notably, rs210138 and rs210162 were in LD (r2=0.74), and conditional analysis suggested that these associations were correlated and driven by one signal (data not shown).	('rs210138', 'Mutation', 'rs210138', (9, 17))	('rs210138', 'Var', (9, 17))	('rs210162', 'Mutation', 'rs210162', (22, 30))	('rs210162', 'Var', (22, 30))
16589	21617256	No additional associations that were stronger than rs755383 were identified in DMRT1 (figure 1B).	('rs755383', 'Var', (51, 59))	('DMRT1', 'Gene', (79, 84))	('DMRT1', 'Gene', '1761', (79, 84))	('rs755383', 'Mutation', 'rs755383', (51, 59))
16590	21617256	However, we identified a second associated SNP in the TERT locus (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24x10-03) (figure 1C).	('rs4975605:', 'Var', (66, 76))	('rs4975605', 'Mutation', 'rs4975605', (66, 75))	('TERT', 'Gene', (54, 58))	('TERT', 'Gene', '7015', (54, 58))
16591	21617256	rs4975605 is located within an intron of TERT and is not in LD with rs4635969 (r2=0.04) or with rs2736100 (r2=0.013; this is calculated from HapMap data), another reported TGCT risk variant in the TERT locus.	('TERT', 'Gene', (197, 201))	('rs4635969', 'Var', (68, 77))	('TGCT', 'Phenotype', 'HP:0010788', (172, 176))	('rs2736100', 'Var', (96, 105))	('TERT', 'Gene', '7015', (197, 201))	('rs4975605', 'Mutation', 'rs4975605', (0, 9))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('rs2736100', 'Mutation', 'rs2736100', (96, 105))	('rs4635969', 'Mutation', 'rs4635969', (68, 77))	('rs4975605', 'Var', (0, 9))
16592	21617256	Conditional analysis suggested that both signals in rs4975605 and rs4635969 were independent because their effects remain detectable after correction for each other (rs4975605 adjusting for rs4635969: OR 1.60, CI 1.15 to 2.21, p=4.66x10-3; rs4635969 adjusting for rs4975605: OR 1.43, CI 1.02 to 1.99, p=3.63x10-2).	('rs4975605', 'Var', (52, 61))	('rs4635969', 'Var', (240, 249))	('rs4635969', 'Mutation', 'rs4635969', (190, 199))	('rs4635969', 'Var', (66, 75))	('rs4975605', 'Var', (166, 175))	('rs4975605', 'Mutation', 'rs4975605', (264, 273))	('rs4975605', 'Mutation', 'rs4975605', (52, 61))	('rs4975605', 'Mutation', 'rs4975605', (166, 175))	('rs4635969', 'Mutation', 'rs4635969', (240, 249))	('rs4635969', 'Mutation', 'rs4635969', (66, 75))
16593	21617256	An analysis by adaptive combination of p values was then performed to assess the significance of association signals from multiple SNPs within an entire gene, and the results showed p=6.01x10-5, p=0.0144, p=0.0403, and p=0.0028 for BAK1, DMRT1, TERT and KITLG, respectively.	('DMRT1', 'Gene', '1761', (238, 243))	('TERT', 'Gene', '7015', (245, 249))	('BAK1', 'Gene', (232, 236))	('p=0.0028', 'Var', (219, 227))	('DMRT1', 'Gene', (238, 243))	('KITLG', 'Gene', '4254', (254, 259))	('KITLG', 'Gene', (254, 259))	('TERT', 'Gene', (245, 249))	('BAK1', 'Gene', '578', (232, 236))
16602	21617256	We compared the ORs obtained from our study with those reported in the previous GWAS, and found that they are quite similar; the reported ORs for rs4635969 in TERT were 1.65 and 1.54 and ours is 1.59; for KITLG, the reported ORs were 2.29 and 2.59 for rs995030 and we obtained an OR of 2.33 for rs2046971, which is in high LD with rs995030; for DMRT1 and BAK1, we obtained slightly higher ORs compared to the previous findings; for rs210138 in BAK1, the reported OR was 1.5 while ours is 1.8; for rs755383 in DMRT1, we have an OR of 1.67, which is larger than 1.57 and 1.37 which were previously reported.	('rs210138', 'Var', (432, 440))	('KITLG', 'Gene', (205, 210))	('DMRT1', 'Gene', (345, 350))	('KITLG', 'Gene', '4254', (205, 210))	('DMRT1', 'Gene', '1761', (509, 514))	('rs2046971', 'Mutation', 'rs2046971', (295, 304))	('rs4635969', 'Mutation', 'rs4635969', (146, 155))	('rs995030', 'Mutation', 'rs995030', (331, 339))	('rs210138', 'Mutation', 'rs210138', (432, 440))	('rs995030', 'Mutation', 'rs995030', (252, 260))	('BAK1', 'Gene', '578', (444, 448))	('rs755383', 'Mutation', 'rs755383', (497, 505))	('rs755383', 'Var', (497, 505))	('DMRT1', 'Gene', (509, 514))	('BAK1', 'Gene', (444, 448))	('BAK1', 'Gene', '578', (355, 359))	('DMRT1', 'Gene', '1761', (345, 350))	('TERT', 'Gene', (159, 163))	('TERT', 'Gene', '7015', (159, 163))	('BAK1', 'Gene', (355, 359))
16603	21617256	Also, previous studies reported that <1% of sporadic cases were homozygous for the non-risk minor allele in rs4474514 in KITLG, and we found that such a pattern was observed in familial cases in our data; one of 97 familial cases (1%) was homozygous for non-risk minor allele in rs2046971 in KITLG and none of 22 sporadic cases were homozygous in this SNP.	('KITLG', 'Gene', (121, 126))	('rs2046971', 'Var', (279, 288))	('rs4474514', 'Var', (108, 117))	('rs4474514', 'Mutation', 'rs4474514', (108, 117))	('rs2046971', 'Mutation', 'rs2046971', (279, 288))	('KITLG', 'Gene', '4254', (292, 297))	('KITLG', 'Gene', '4254', (121, 126))	('KITLG', 'Gene', (292, 297))
16619	33317510	The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was <= 0.10 and the relapse rate of the high-risk group was >= 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy.	('toxicity', 'Disease', 'MESH:D064420', (391, 399))	('toxicity', 'Disease', (391, 399))	('patients', 'Species', '9606', (290, 298))	('lower', 'NegReg', (202, 207))	('>= 0.40', 'Var', (152, 159))	('exposure to chemotherapy', 'MPA', (208, 232))	('relapse', 'Disease', (304, 311))
16670	30625331	Importantly, the transcriptomic changes associated with TSG inactivation events were stronger than the cancer lineage difference, and the same TSGs inactivated in different cancer types tended to cluster together.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('transcriptomic changes', 'MPA', (17, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TSG', 'Gene', (56, 59))	('cancer', 'Disease', (173, 179))	('stronger', 'PosReg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('inactivation', 'Var', (60, 72))
16674	30625331	Activation of oncogenes and inactivation of tumor-suppressor genes (TSGs) are two major driving forces in cancer.	('tumor-suppressor', 'Gene', '7248', (44, 60))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('inactivation', 'Var', (28, 40))	('tumor-suppressor', 'Gene', (44, 60))	('cancer', 'Disease', (106, 112))	('Activation', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('oncogenes', 'Protein', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
16678	30625331	In principle, both copies of a TSG need to be mutated for a TSG to completely lose its function, whereas haploinsufficient TSGs work in a dosage-sensitive manner.	('haploinsufficient TSGs', 'Disease', 'MESH:D058495', (105, 127))	('lose', 'NegReg', (78, 82))	('mutated', 'Var', (46, 53))	('function', 'MPA', (87, 95))	('haploinsufficient TSGs', 'Disease', (105, 127))
16679	30625331	Our study provides a landscape view of TSG alterations and their potential impact in 30 cancer types.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('impact', 'Reg', (75, 81))	('TSG', 'Gene', (39, 42))	('alterations', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
16684	30625331	Specifically, 1,020 (83.0%, 1,020/1,229) TSGs had L2 or L1 genetic inactivation events in at least five samples from the same cancer type among a total of 5,510 samples (76.0% of 7,248 samples with qualified data; Figures 2A and S2).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('L1 genetic', 'Var', (56, 66))	('TSGs', 'Disease', (41, 45))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
16686	30625331	Several clusters were observed, such as 8p21-23, 9p (containing CDKN2A/CDKN2B), and 13q (containing RB1), consistent with previous reports.	('RB1', 'Gene', (100, 103))	('CDKN2B', 'Gene', (71, 77))	('CDKN2A', 'Gene', (64, 70))	('RB1', 'Gene', '5925', (100, 103))	('CDKN2B', 'Gene', '1030', (71, 77))	('CDKN2A', 'Gene', '1029', (64, 70))	('8p21-23', 'Var', (40, 47))
16687	30625331	Although several TSGs located in these regions could be driver genes, such as SOX7, NKX3-1, CLU, and TRIM35, many were likely passenger events because of large CNV segments.	('SOX7', 'Gene', (78, 82))	('NKX3-1', 'Gene', (84, 90))	('TRIM35', 'Gene', (101, 107))	('NKX3-1', 'Gene', '4824', (84, 90))	('CLU', 'Gene', (92, 95))	('TRIM35', 'Gene', '23087', (101, 107))	('CLU', 'Gene', '1191', (92, 95))	('SOX7', 'Gene', '83595', (78, 82))	('CNV', 'Var', (160, 163))
16697	30625331	Although deleterious missense mutations were included, they were found mainly in a few genes, such as TP53 (multiple cancer types), PTEN (GBM), KEAP1 (LUAD), and VHL (KIRC).	('VHL', 'Gene', (162, 165))	('KEAP1', 'Gene', '9817', (144, 149))	('TP53', 'Gene', (102, 106))	('PTEN', 'Gene', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PTEN', 'Gene', '5728', (132, 136))	('VHL', 'Gene', '7428', (162, 165))	('KEAP1', 'Gene', (144, 149))	('missense mutations', 'Var', (21, 39))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('TP53', 'Gene', '7157', (102, 106))	('cancer', 'Disease', (117, 123))
16703	30625331	It is commonly recognized that the passenger mutations irrelevant to cancer development would not have much impact on other genes, whereas driver mutations are expected to interrupt signaling pathways that are critical to cancer.	('mutations', 'Var', (45, 54))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('signaling pathways', 'Pathway', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (222, 228))	('interrupt', 'NegReg', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
16708	30625331	Mutations in these events are more likely to contribute to cancer.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Mutations', 'Var', (0, 9))	('contribute', 'Reg', (45, 55))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
16711	30625331	MAP3K1 had inactivation mutations in 44 BRCA_LumA samples but no sign of decreased expression: all with truncation mutations (L1).	('inactivation mutations', 'Var', (11, 33))	('MAP3K1', 'Gene', (0, 6))	('BRCA_LumA', 'Disease', (40, 49))	('MAP3K1', 'Gene', '4214', (0, 6))	('truncation', 'MPA', (104, 114))
16713	30625331	A similar trend was observed for GATA3 in both BRCA_LumA (51 inactivated samples with truncation mutations (L1), not shown in the figure) and BRCA_LumB (29 inactivated samples with truncation mutations, L1).	('GATA3', 'Gene', (33, 38))	('GATA3', 'Gene', '2625', (33, 38))	('truncation mutations', 'Var', (86, 106))
16720	30625331	Examples included RB1 in LUAD (nmut = 28, #DEGs = 627), VHL in KIRC (nmut = 110, #DEGs = 3,765), PBRM1 in KIRC (nmut = 98, #DEGs = 2,865), SETD2 in KIRC (nmut = 40, #DEGs = 2,409), BAP1 in KIRC (nmut = 39, #DEGs = 2,339), and SMAD4 in PAAD (nmut = 51, #DEGs = 1,154).	('VHL', 'Gene', (56, 59))	('nmut', 'Var', (69, 73))	('RB1', 'Gene', (18, 21))	('BAP1', 'Gene', (181, 185))	('SETD2', 'Gene', (139, 144))	('VHL', 'Gene', '7428', (56, 59))	('SMAD4', 'Gene', (226, 231))	('RB1', 'Gene', '5925', (18, 21))	('PBRM1', 'Gene', '55193', (97, 102))	('PBRM1', 'Gene', (97, 102))	('BAP1', 'Gene', '8314', (181, 185))	('SMAD4', 'Gene', '4089', (226, 231))	('SETD2', 'Gene', '29072', (139, 144))
16725	30625331	Next, we explored whether inactivation of the same TSG would lead to similar transcriptional footprints in different cancer types.	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('inactivation', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))
16730	30625331	Although some cancer types were occasionally enriched in local subclusters (e.g., LGG and KIRC), the overall cluster showed enrichment independent of cancer types, suggesting common pathways might be disturbed upon the inactivation of the same TSGs in different cancer types.	('LGG', 'Disease', (82, 85))	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', (14, 20))	('inactivation', 'Var', (219, 231))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('disturbed', 'Reg', (200, 209))	('TSGs', 'Gene', (244, 248))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
16734	30625331	To control potential confounding effects, we restricted RB1 mutant and WT samples both in CDKN2A WT samples and vice versa.	('CDKN2A', 'Gene', '1029', (90, 96))	('RB1', 'Gene', (56, 59))	('mutant', 'Var', (60, 66))	('RB1', 'Gene', '5925', (56, 59))	('CDKN2A', 'Gene', (90, 96))
16737	30625331	However, all other genes were positively correlated, indicating that inactivating either RB1 or CDKN2A had a similar downstream impact on the cell-cycle pathway.	('impact', 'Reg', (128, 134))	('inactivating', 'Var', (69, 81))	('RB1', 'Gene', '5925', (89, 92))	('CDKN2A', 'Gene', '1029', (96, 102))	('RB1', 'Gene', (89, 92))	('CDKN2A', 'Gene', (96, 102))	('cell-cycle pathway', 'Pathway', (142, 160))
16761	30625331	We performed a systematic analysis and characterized the functional features of TSG inactivation events in more than 5,000 tumor genomes of 33 cancer types/subtypes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (123, 128))	('TSG', 'Gene', (80, 83))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('inactivation', 'Var', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
16763	30625331	In addition to the well-studied TSGs, such as RB1 and TP53, our results pinpointed TSGs functioning in various processes of epigenomic regulation (e.g., ARID1A, ARID1B, and KDM6A).	('KDM6A', 'Gene', '7403', (173, 178))	('ARID1B', 'Gene', (161, 167))	('RB1', 'Gene', (46, 49))	('ARID1B', 'Gene', '57492', (161, 167))	('TSGs', 'Var', (83, 87))	('TP53', 'Gene', '7157', (54, 58))	('KDM6A', 'Gene', (173, 178))	('ARID1A', 'Gene', '8289', (153, 159))	('RB1', 'Gene', '5925', (46, 49))	('ARID1A', 'Gene', (153, 159))	('TP53', 'Gene', (54, 58))	('functioning', 'Reg', (88, 99))
16765	30625331	These results have critical implications for identification and interpretation of TSG inactivation events in cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('inactivation', 'Var', (86, 98))	('TSG', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
16766	30625331	For example, loss of heterozygosity (LOH) is a common event associated with inactivation of TSGs in many cancer types.	('loss of heterozygosity', 'Var', (13, 35))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TSGs', 'Gene', (92, 96))
16768	30625331	In addition, if one sample contained multiple NS_FS mutations in one TSG, the sample was considered as inactivated only once and would not be assigned a stronger weight, which might underestimate the severity of the inactivation mutations in some cases.	('mutations', 'Var', (52, 61))	('NS_FS', 'Disease', (46, 51))	('TSG', 'Gene', (69, 72))	('NS_FS', 'Disease', 'MESH:D018223', (46, 51))
16779	30625331	The results from wANNOVAR provided twelve ways to predict the impact of missense mutations, including SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, MutationTaster, Mutation Assessor, FATHMM, RadialSVM, LR, GERP, phyloP46way, and SiPhy_29way_logOdds.	('Mutation', 'Var', (161, 169))	('MutationTaster', 'Var', (145, 159))	('HDIV', 'Disease', 'None', (118, 122))	('missense mutations', 'Var', (72, 90))	('HDIV', 'Disease', (118, 122))	('GERP', 'Gene', (203, 207))	('GERP', 'Gene', '81603', (203, 207))
16781	30625331	The probability of L2 mutations in each cancer type, regardless of the sample variation, ranged between 6.202 x 10-4 (READ) and 0.106 (LAML), and the probability of L1 mutations ranged between 3.617 x 10-4 (PRAD) and 5.086 x 10-3 (COAD).	('COAD', 'Disease', 'MESH:D029424', (231, 235))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('mutations', 'Var', (22, 31))	('COAD', 'Disease', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
16783	30625331	This test was conducted for inactivation mutations L2 and L1, respectively, in cancer types where the number of eligible samples was >= 20.	('inactivation mutations', 'Var', (28, 50))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
16790	30625331	There were 19 BRCA_Basal samples with RB1 inactivation mutations, including 15 samples with deep deletion (L2), 3 samples with copy loss accompanied with truncation mutations (L2), and 1 sample with truncation mutations (L1).	('RB1', 'Gene', '5925', (38, 41))	('inactivation mutations', 'Var', (42, 64))	('RB1', 'Gene', (38, 41))	('deep deletion', 'Var', (92, 105))
16791	30625331	However, a visualization inspection revealed that two samples with deep deletion had quite high expression of RB1, implying these deep deletion events did not function as expected.	('RB1', 'Gene', (110, 113))	('high', 'PosReg', (91, 95))	('deep deletion', 'Var', (67, 80))	('expression', 'MPA', (96, 106))	('RB1', 'Gene', '5925', (110, 113))
16793	30625331	With the quantitative assessment of potential outlier samples, the two samples with RB1 in BRCA_Basal (Figure S7A) were identified as outlier samples, i.e., removing each of them could lead to an increase of the impact score T by > 5%.	('RB1', 'Gene', '5925', (84, 87))	('S7', 'Gene', '6264', (110, 112))	('impact score T', 'MPA', (212, 226))	('RB1', 'Gene', (84, 87))	('increase', 'PosReg', (196, 204))	('removing', 'Var', (157, 165))
16893	31263452	These genes can promote cellular transformation and alter the pathways related to the immune response, leading to carcinogenesis in a plethora of human tissues including vulva, vagina, penis, anus, head, neck, and oropharyngeal cavity.	('carcinogenesis', 'Disease', (114, 128))	('genes', 'Var', (6, 11))	('oropharyngeal', 'Disease', (214, 227))	('human', 'Species', '9606', (146, 151))	('pathways', 'Pathway', (62, 70))	('plethora', 'Phenotype', 'HP:0001050', (134, 142))	('alter', 'Reg', (52, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('leading to', 'Reg', (103, 113))	('promote', 'PosReg', (16, 23))	('cellular transformation', 'CPA', (24, 47))
16907	31263452	The most common oncogenic DNA modifications associated with EBV are phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, extreme DNA hypermethylation, and amplification of the Janus activated kinase2 (JAK2).	('mutations', 'Var', (148, 157))	('PIK3CA', 'Gene', (140, 146))	('amplification', 'Var', (193, 206))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (68, 105))	('EBV', 'Species', '10376', (60, 63))
16924	31263452	In immunosuppressed hosts (including pregnant women), Parvovirus B-19 may cause severe complications including glomerulonephritis, vasculitis, peripheral neuropathies, myocarditis, fulminant hepatic failure, and aplastic anemia.	('Parvovirus B-19', 'Var', (54, 69))	('aplastic anemia', 'Disease', 'MESH:D000741', (212, 227))	('hepatic failure', 'Phenotype', 'HP:0001399', (191, 206))	('vasculitis', 'Disease', (131, 141))	('aplastic anemia', 'Disease', (212, 227))	('fulminant hepatic failure', 'Disease', (181, 206))	('glomerulonephritis', 'Disease', 'MESH:D005921', (111, 129))	('aplastic anemia', 'Phenotype', 'HP:0001915', (212, 227))	('women', 'Species', '9606', (46, 51))	('vasculitis', 'Disease', 'MESH:D014657', (131, 141))	('peripheral neuropathies', 'Disease', 'MESH:D010523', (143, 166))	('myocarditis', 'Phenotype', 'HP:0012819', (168, 179))	('anemia', 'Phenotype', 'HP:0001903', (221, 227))	('fulminant hepatic failure', 'Phenotype', 'HP:0004448', (181, 206))	('glomerulonephritis', 'Disease', (111, 129))	('myocarditis', 'Disease', (168, 179))	('peripheral neuropathies', 'Phenotype', 'HP:0009830', (143, 166))	('fulminant hepatic failure', 'Disease', 'MESH:D017114', (181, 206))	('cause', 'Reg', (74, 79))	('glomerulonephritis', 'Phenotype', 'HP:0000099', (111, 129))	('myocarditis', 'Disease', 'MESH:D009205', (168, 179))	('Parvovirus B-19', 'Species', '10798', (54, 69))	('peripheral neuropathies', 'Disease', (143, 166))	('vasculitis', 'Phenotype', 'HP:0002633', (131, 141))
16975	29515973	Inclusion criteria in the DaTeCa database covers the diagnosis of a germ cell cancer (International Classification of Diseases, 10th revision, ICD-10: DC 62.1-62.9, DC38.3, and DC48.0, the latter two together with germ cell histology), Danish citizenship, follow-up and medical treatment conducted at an oncology ward in Denmark.	('DC48.0', 'Var', (177, 183))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('men', 'Species', '9606', (283, 286))	('germ cell cancer', 'Phenotype', 'HP:0100728', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('oncology', 'Phenotype', 'HP:0002664', (304, 312))
17034	24887064	This study aims at identifying epigenetic footprints in SE and EC cell lines in genome-wide profiles by studying the interaction between gene expression, DNA CpG methylation and histone modifications, and their function in the pathophysiology and etiology of GCC.	('interaction', 'Interaction', (117, 128))	('methylation', 'Var', (162, 173))	('SE', 'Disease', 'None', (56, 58))	('GCC', 'Disease', (259, 262))
17048	24887064	Epigenetic processes have a clear role in both the initiation and protection of pluripotency.	('pluripotency', 'Disease', (80, 92))	('Epigenetic', 'Var', (0, 10))	('pluripotency', 'Disease', 'None', (80, 92))
17049	24887064	Deregulation of these tightly controlled processes is known to be involved in the formation and progression of various cancer types, including GCC.	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('involved', 'Reg', (66, 74))	('GCC', 'Disease', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
17052	24887064	Epigenetic deregulation through genetic and environmental parameters (referred to as genvironment) could disrupt physiological embryonic germ cell development, resulting in delayed or blocked maturation, thereby facilitating the formation of CIS, and potentially progression to an invasive GCC.	('blocked', 'NegReg', (184, 191))	('invasive GCC', 'Disease', (281, 293))	('Epigenetic deregulation', 'Var', (0, 23))	('men', 'Species', '9606', (51, 54))	('men', 'Species', '9606', (93, 96))	('physiological embryonic germ cell development', 'CPA', (113, 158))	('men', 'Species', '9606', (154, 157))	('maturation', 'CPA', (192, 202))	('facilitating', 'PosReg', (212, 224))	('delayed', 'NegReg', (173, 180))	('disrupt', 'NegReg', (105, 112))
17056	24887064	Two types of epigenetic modifications were investigated and related to genome wide expression analysis: CpG DNA methylation status, and enrichment of activating histone marks (H3K4me3, H3K27ac).	('H3K27ac', 'Var', (185, 192))	('activating', 'PosReg', (150, 160))	('H3K4me3', 'Var', (176, 183))	('men', 'Species', '9606', (142, 145))
17058	24887064	Cells were washed once with Hanks balanced Salt Solution (HBSS, #14175-053, Thermo Fisher Scientific/Life Technologies, Carlsbad, CA, USA), and lysed with 7 ml of ice-cold RNA-Bee (#Cs-105B, TEL-TEST Inc, Friendswood, Texas, USA).	('#Cs-105B', 'Var', (181, 189))	('TEL', 'Gene', '2120', (191, 194))	('TEL', 'Gene', (191, 194))
17085	24887064	In line with this, SOX17 and SOX2 were differentially enriched for both H3K4me3 and H3K27ac in TCam-2 and NCCIT respectively (Figure 1).	('H3K4me3', 'Protein', (72, 79))	('SOX17', 'Gene', '64321', (19, 24))	('TCam-2', 'Chemical', '-', (95, 101))	('H3K27ac', 'Var', (84, 91))	('SOX17', 'Gene', (19, 24))
17092	24887064	For NCCIT, there were substantially more genes selected for H3K4me3 compared to H3K27ac (nTCam-2 = 215, NNCCIT = 325).	('H3K27ac', 'Var', (80, 87))	('TCam-2', 'Chemical', '-', (90, 96))	('H3K4me3', 'Var', (60, 67))
17100	24887064	For example, for H3K4me3 the top enriched motif was MAZ for both TCam-2 and NCCIT, a transcription factor associated with MYC (binds to two sites in its promoter) and known to be involved in transcription initiation as well as termination (Figure 2A,B; Table S3).	('MYC', 'Gene', (122, 125))	('NCCIT', 'Gene', (76, 81))	('MYC', 'Gene', '4609', (122, 125))	('H3K4me3', 'Var', (17, 24))	('MAZ', 'Gene', (52, 55))	('MAZ', 'Gene', '4150', (52, 55))	('TCam-2', 'Chemical', '-', (65, 71))	('TCam-2', 'Gene', (65, 71))
17105	24887064	For H3K27ac, there were four differentiating motifs, of which three were ranked higher in TCam-2 and one higher in NCCIT.	('H3K27ac', 'Var', (4, 11))	('TCam-2', 'Chemical', '-', (90, 96))	('higher', 'PosReg', (80, 86))
17106	24887064	The OCT4/SOX2/TCF/NANOG motif was the most significantly enriched motif for H3K27ac in NCCIT (ranked 20 in TCam-2).	('OCT4', 'Gene', (4, 8))	('TCF', 'Gene', (14, 17))	('TCF', 'Gene', '3172', (14, 17))	('NANOG', 'Gene', '79923', (18, 23))	('H3K27ac', 'Var', (76, 83))	('NANOG', 'Gene', (18, 23))	('TCam-2', 'Chemical', '-', (107, 113))	('OCT4', 'Gene', '5460', (4, 8))
17108	24887064	Moreover, for H3K27ac, AP-2alpha and AP-2gamma were ranked as 3rd and 4th most enriched motif in TCam-2 (compared to 29th and 31st in NCCIT) reflecting their (embryonic) germ cell origin (Figure 2C,D).	('AP-2gamma', 'Gene', '7022', (37, 46))	('AP-2gamma', 'Gene', (37, 46))	('TCam-2', 'Chemical', '-', (97, 103))	('H3K27ac', 'Var', (14, 21))	('AP-2alpha', 'Gene', '7020', (23, 32))	('AP-2alpha', 'Gene', (23, 32))	('TCam-2', 'Gene', (97, 103))
17111	24887064	As the investigated chromatin marks (H3K4me3 & H3K27ac) are considered to be associated with active chromatin, we explored whether their presence was associated with another characteristic of active chromatin: DNaseI-hypersensitivity.	('H3K4me3 & H3K27ac', 'Var', (37, 54))	('hypersensitivity', 'Disease', (217, 233))	('hypersensitivity', 'Disease', 'MESH:D004342', (217, 233))
17112	24887064	Using a DNaseI-MLPA approach we targeted 14 regions which showed the greatest differences in either H3K4me3 and/or H3K27ac enrichment between the same two cell lines.	('men', 'Species', '9606', (129, 132))	('H3K4me3', 'Protein', (100, 107))	('H3K27ac', 'Var', (115, 122))
17114	24887064	In contrast, only one H3K27ac-negative locus in NCCIT (Figure S2A, S1), and no H3K27ac-negative loci in TCam-2 (Figure S2B), showed DNaseI-hypersensitivity.	('hypersensitivity', 'Disease', (139, 155))	('H3K27ac-negative', 'Var', (22, 38))	('hypersensitivity', 'Disease', 'MESH:D004342', (139, 155))	('TCam-2', 'Chemical', '-', (104, 110))
17116	24887064	After DMR identification using DMRforPairs, a total of 99 DMRs (annotating to 170 unique gene symbols) were hypomethylated in TCam-2, compared to 44 in NCCIT (annotating to 64 unique gene symbols) (Table S1).	('DMRs', 'Chemical', '-', (58, 62))	('TCam-2', 'Chemical', '-', (126, 132))	('hypomethylated', 'Var', (108, 122))	('TCam-2', 'Gene', (126, 132))
17126	24887064	In general, 33% (47/143) DMRs were annotated to TSSs (File S1, according to Illumina's manifest) which is similar to the fraction of TSS associated regions identified by DMRforPairs (12,652/30,306).	('DMRs', 'Chemical', '-', (25, 29))	('TSSs', 'Disease', (48, 52))	('DMRs', 'Var', (25, 29))
17133	24887064	In total, 257 genes were expressed higher in TCam-2, compared to 149 in NCCIT (Table S1).	('TCam-2', 'Chemical', '-', (45, 51))	('higher', 'PosReg', (35, 41))	('TCam-2', 'Var', (45, 51))	('expressed', 'MPA', (25, 34))
17143	24887064	H19 and CHCHD5 were differentially hypomethylated in TCam-2 and showed high expression compared to NCCIT, but no differential enrichment for H3K27ac or H3K4me3.	('CHCHD5', 'Gene', '84269', (8, 14))	('TCam-2', 'Chemical', '-', (53, 59))	('TCam-2', 'Gene', (53, 59))	('H3K27ac', 'Var', (141, 148))	('CHCHD5', 'Gene', (8, 14))	('men', 'Species', '9606', (132, 135))	('expression', 'MPA', (76, 86))
17148	24887064	Analysis of the histone marks matched the classification of the cell-lines: SOX17 was strongly enriched for H3K4me3 and H3K27ac in TCam-2 compared to NCCIT cells, whereas the opposite pattern was observed for SOX2.	('TCam-2', 'Chemical', '-', (131, 137))	('H3K27ac', 'Var', (120, 127))	('SOX17', 'Gene', (76, 81))	('H3K4me3', 'Var', (108, 115))	('SOX17', 'Gene', '64321', (76, 81))
17166	24887064	found significant enrichment of hypermethylated AR target genes in androgen insensitivity syndrome (AIS) patients versus controls.	('AIS', 'Disease', 'OMIM:181800', (100, 103))	('men', 'Species', '9606', (24, 27))	('patients', 'Species', '9606', (105, 113))	('hypermethylated', 'Var', (32, 47))	('AIS', 'Disease', (100, 103))	('androgen insensitivity syndrome', 'Disease', (67, 98))	('androgen insensitivity', 'Phenotype', 'HP:0008226', (67, 89))	('AR', 'Gene', '367', (48, 50))
17167	24887064	This is consistent with earlier reports that diminished gene activation (due to an AR mutation) results in subsequent increased DNA methylation of target genes, linking DSD and GCC at the epigenetic level.	('AR', 'Gene', '367', (83, 85))	('DSD', 'Disease', 'MESH:D058533', (169, 172))	('DSD', 'Disease', (169, 172))	('increased', 'PosReg', (118, 127))	('DNA methylation', 'MPA', (128, 143))	('diminished', 'NegReg', (45, 55))	('gene activation', 'MPA', (56, 71))	('mutation', 'Var', (86, 94))
17180	24887064	AP-2y expression is induced by estrogens and AP-2alpha and AP-2y are able to induce changes in the chromatin structure known to be associated with ERalpha (ESR1) transcription.	('ESR1', 'Gene', '2099', (156, 160))	('changes', 'Reg', (84, 91))	('chromatin structure', 'MPA', (99, 118))	('ERalpha', 'Gene', (147, 154))	('AP-2alpha', 'Gene', '7020', (45, 54))	('ERalpha', 'Gene', '2099', (147, 154))	('AP-2alpha', 'Gene', (45, 54))	('AP-2y', 'Var', (59, 64))	('ESR1', 'Gene', (156, 160))	('AP-2y', 'Gene', (0, 5))
17182	24887064	Recently it was shown that overexpression of ETS, combined with loss of PTEN, increases AR binding and restores AR transcriptional activity in prostate.	('restores', 'PosReg', (103, 111))	('PTEN', 'Gene', (72, 76))	('PTEN', 'Gene', '5728', (72, 76))	('AR', 'Gene', '367', (112, 114))	('AR', 'Gene', '367', (88, 90))	('loss', 'Var', (64, 68))	('increases', 'PosReg', (78, 87))	('overexpression', 'PosReg', (27, 41))
17183	24887064	Indeed, disruption of the PTEN pathway has been suggested to be part of the pathogenesis of GCC.	('disruption', 'Var', (8, 18))	('PTEN', 'Gene', '5728', (26, 30))	('GCC', 'Disease', (92, 95))	('PTEN', 'Gene', (26, 30))
17277	24204171	Polymorphisms in 17-beta hydroxydehydrogenase-4, the ESR2 gene (encoding estrogen receptor beta [ERbeta]), and finally the increased transactivation of the androgen receptor gene AR, are also associated with a testicular cancer risk.	('increased', 'PosReg', (123, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (210, 227))	('androgen receptor', 'Gene', (156, 173))	('associated with', 'Reg', (192, 207))	('Polymorphisms', 'Var', (0, 13))	('estrogen receptor beta', 'Gene', (73, 95))	('ESR2', 'Gene', (53, 57))	('testicular cancer', 'Disease', (210, 227))	('estrogen receptor beta', 'Gene', '2100', (73, 95))	('androgen receptor', 'Gene', '367', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('transactivation', 'MPA', (133, 148))	('testicular cancer', 'Phenotype', 'HP:0010788', (210, 227))	('ESR2', 'Gene', '2100', (53, 57))
17278	24204171	Recently, evidence for an epigenetic role has also been suggested in testicular cancer.	('testicular cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epigenetic', 'Var', (26, 36))	('testicular cancer', 'Phenotype', 'HP:0010788', (69, 86))	('testicular cancer', 'Disease', 'MESH:D013736', (69, 86))
17284	24204171	Furthermore, many other factors collectively known as the environmental endocrine disrupters (eg, poly-chlorinated biphenyls, organochlorines, nonionizing radiation, agricultural work, and tobacco) have been correlated with an increased risk of testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (245, 262))	('testicular cancer', 'Disease', 'MESH:D013736', (245, 262))	('men', 'Species', '9606', (65, 68))	('correlated', 'Reg', (208, 218))	('organochlorines', 'Chemical', 'MESH:D006843', (126, 141))	('poly-chlorinated', 'Var', (98, 114))	('poly-chlorinated biphenyls', 'Chemical', 'MESH:D011078', (98, 124))	('testicular cancer', 'Disease', (245, 262))	('tobacco', 'Species', '4097', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))
17297	24204171	In non-seminomatous germ cell tumors chromosome Y deletions were associated with the presence of nodal metastasis in retroperitoneal lymph node dissections (RPLND).	('non-seminomatous germ cell tumors', 'Disease', 'MESH:C537844', (3, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('germ cell tumors', 'Phenotype', 'HP:0100728', (20, 36))	('nodal metastasis', 'CPA', (97, 113))	('chromosome Y', 'Gene', (37, 49))	('germ cell tumor', 'Phenotype', 'HP:0100728', (20, 35))	('associated', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('non-seminomatous germ cell tumors', 'Disease', (3, 36))	('deletions', 'Var', (50, 59))
17303	24204171	With regards to cardiovascular disease, a study of 990 men treated for testicular cancer with cisplatin, bleomycin, and etoposide (BEP) chemotherapy alone had a 5.7-fold higher risk (95% confidence interval [CI], 1.9-17.1-fold) of coronary artery disease compared with surgery alone, and a 3.1-fold higher risk (95% CI, 1.2-7.7-fold) of myocardial infarction compared with male controls.	('myocardial infarction', 'Disease', 'MESH:D009203', (337, 358))	('coronary artery disease', 'Disease', 'MESH:D003324', (231, 254))	('bleomycin', 'Chemical', 'MESH:D001761', (105, 114))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (16, 38))	('cardiovascular disease', 'Disease', 'MESH:D002318', (16, 38))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('coronary artery disease', 'Disease', (231, 254))	('cardiovascular disease', 'Disease', (16, 38))	('testicular cancer', 'Disease', 'MESH:D013736', (71, 88))	('BEP', 'Chemical', '-', (131, 134))	('cisplatin', 'Var', (94, 103))	('men', 'Species', '9606', (55, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('testicular cancer', 'Disease', (71, 88))	('testicular cancer', 'Phenotype', 'HP:0010788', (71, 88))	('myocardial infarction', 'Disease', (337, 358))	('etoposide', 'Chemical', 'MESH:D005047', (120, 129))	('bleomycin', 'Var', (105, 114))	('myocardial infarction', 'Phenotype', 'HP:0001658', (337, 358))
17368	32244483	These findings can be explained at least partially by the observation that known vascular risk factors (smoking, hypertension, ApoB, and low HDL cholesterol, all associated with SA in the multivariate analysis) and data related to lifestyle (adherence to Mediterranean diet, physical exercise) were more unfavorable in GCT survivors than in controls.	('GCT', 'Disease', (319, 322))	('hypertension', 'Disease', (113, 125))	('ApoB', 'Gene', '338', (127, 131))	('low HDL cholesterol', 'Phenotype', 'HP:0003233', (137, 156))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('ApoB', 'Gene', (127, 131))	('low', 'Var', (137, 140))	('SA', 'Chemical', '-', (178, 180))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))	('cholesterol', 'Chemical', 'MESH:D002784', (145, 156))
17441	31058267	Although advocated by many centers as a standard of care following chemotherapy, the indications for PC-RPLND are controversial in certain cases, in particular in cases with a complete response (CR), subcentimeter residual masses, or resistance to chemotherapy.	('complete', 'Disease', (176, 184))	('CR', 'Chemical', '-', (195, 197))	('subcentimeter', 'Var', (200, 213))
17479	31058267	On unadjusted univariate Cox regression analysis, patient age, higher comorbidity, minority race/ethnicity, non-private insurance coverage, lower median household income and education level, distance from hospital, clinical stage III (vs stage II), IGCCCG risk group other than good risk, and omission of PC-RPLND were significantly associated with higher risk of all-cause mortality.	('all-cause mortality', 'MPA', (364, 383))	('lower', 'NegReg', (140, 145))	('PC-RPLND', 'Gene', (305, 313))	('omission', 'Var', (293, 301))	('higher', 'PosReg', (63, 69))	('patient', 'Species', '9606', (50, 57))
17481	31058267	Of the 1230 patients who underwent PC-RPLND, pathologic nodal stage was not recorded for 360 patients (29.3%), with pN0 in 300 patients (24.4%), pN1 in 153 patients (12.4%), pN2 in 192 patients (15.6%), and pN3 in 215 patients (17.5%).	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (12, 20))	('pN2', 'Gene', '351', (174, 177))	('patients', 'Species', '9606', (218, 226))	('pN3', 'Gene', '6336', (207, 210))	('pN2', 'Gene', (174, 177))	('pN1', 'Gene', '5270', (145, 148))	('patients', 'Species', '9606', (127, 135))	('pN3', 'Gene', (207, 210))	('patients', 'Species', '9606', (185, 193))	('patients', 'Species', '9606', (93, 101))	('pN0', 'Var', (116, 119))	('pN1', 'Gene', (145, 148))
17500	31058267	Patients who underwent PC-RPLND were more likely to travel further to seek care, supporting centralization of TGCT management.	('Patients', 'Species', '9606', (0, 8))	('travel further', 'CPA', (52, 66))	('men', 'Species', '9606', (121, 124))	('PC-RPLND', 'Var', (23, 31))
17526	29843681	The prevalence of testicular microlithiasis or classic testicular microlithiasis was significantly higher in children with undescended testis compared to those without undescended testis (testicular microlithiasis; 43.8% versus 9.5% (p = 0.002), classic testicular microlithiasis; 37.5% versus 1.9% (p < 0.001).	('testicular microlithiasis', 'Disease', 'MESH:C566478', (18, 43))	('undescended', 'Var', (123, 134))	('higher', 'PosReg', (99, 105))	('testicular microlithiasis', 'Disease', (254, 279))	('testicular microlithiasis', 'Disease', (18, 43))	('testicular microlithiasis', 'Phenotype', 'HP:0012215', (188, 213))	('testicular microlithiasis', 'Disease', (55, 80))	('children', 'Species', '9606', (109, 117))	('undescended testis', 'Phenotype', 'HP:0000028', (123, 141))	('testicular microlithiasis', 'Phenotype', 'HP:0012215', (254, 279))	('testicular microlithiasis', 'Disease', 'MESH:C566478', (188, 213))	('testicular microlithiasis', 'Phenotype', 'HP:0012215', (55, 80))	('undescended testis', 'Phenotype', 'HP:0000028', (168, 186))	('testicular microlithiasis', 'Disease', 'MESH:C566478', (254, 279))	('testicular microlithiasis', 'Phenotype', 'HP:0012215', (18, 43))	('testicular microlithiasis', 'Disease', 'MESH:C566478', (55, 80))	('testicular microlithiasis', 'Disease', (188, 213))
17674	25095793	However, TGCT risk varies also by ethnicity (Caucasian men have a higher TGCT risk than men in Asian or African populations), and familial history of TGCT is also known to be associated with an increased TGCT risk, supporting a potential role of genetic factors.	('men', 'Species', '9606', (55, 58))	('TGCT', 'Disease', (73, 77))	('familial history', 'Var', (130, 146))	('men', 'Species', '9606', (88, 91))	('TGCT', 'Disease', (204, 208))
17724	25095793	Additionally, we identified 6 additional SNPs associated with organochlorine metabolism pathways and known to be able to modify the risk to develop a TGCT (2 loci: CYP1A1 and HSD17B4).	('TGCT', 'Disease', (150, 154))	('CYP1A1', 'Gene', '1543', (164, 170))	('organochlorine', 'Chemical', 'MESH:D006843', (62, 76))	('HSD17B4', 'Gene', '3295', (175, 182))	('organochlorine metabolism pathways', 'Pathway', (62, 96))	('HSD17B4', 'Gene', (175, 182))	('SNPs', 'Var', (41, 45))	('associated with', 'Reg', (46, 61))	('modify', 'Reg', (121, 127))	('CYP1A1', 'Gene', (164, 170))
17854	19852809	In contrast, a single Nme2b protein was found in medaka (Oryzias latipes), and fugu (Takifugu rubripes) while, the phylogentic tree clearly indicates a further duplication of the nme2b gene in zebrafish resulting in two distinct proteins termed Nme2b1 and Nme2b2.	('duplication', 'Var', (160, 171))	('medaka', 'Species', '8090', (49, 55))	('Nme2b1', 'Gene', '30083', (245, 251))	('Nme2b2', 'Gene', '30084', (256, 262))	('Nme2b1', 'Gene', (245, 251))	('zebrafish', 'Species', '7955', (193, 202))	('Takifugu rubripes', 'Species', '31033', (85, 102))	('Oryzias latipes', 'Species', '8090', (57, 72))	('nme2b', 'Gene', (179, 184))	('Nme2b2', 'Gene', (256, 262))
17865	19852809	Furthermore, for all studied teleosts displaying nme2a and nme2b, the two paralogous genes are always located on different chromosomes or scaffolds (Table 1).	('nme2a', 'Gene', (49, 54))	('nme2a', 'Gene', '335716', (49, 54))	('nme2b', 'Var', (59, 64))	('teleost', 'Species', '70862', (29, 36))
17866	19852809	Interestingly, the fugu nme2b gene is associated to a paralog of mbtd1 (data not shown), suggesting that the duplication event from which nme2a and nme2b arose in teleost is linked to the teleost-specific third round of whole genome duplication (3R).	('duplication', 'Var', (109, 120))	('teleost', 'Species', '70862', (163, 170))	('nme2b', 'Gene', (148, 153))	('teleost', 'Species', '70862', (188, 195))	('nme2a', 'Gene', (138, 143))	('nme2a', 'Gene', '335716', (138, 143))
17908	19852809	Nme3, as all the proteins of the Group I, displays a single NDPk_1 domain (Fig.	('NDPk', 'Gene', '129607', (60, 64))	('Nme3', 'Var', (0, 4))	('NDPk', 'Gene', (60, 64))
17929	19852809	It was previously shown that the presence of Serine129 residue has local structural effects that weaken subunit interactions and decreases hexamer stability.	('weaken', 'NegReg', (97, 103))	('Serine129', 'Chemical', '-', (45, 54))	('hexamer stability', 'MPA', (139, 156))	('subunit', 'Protein', (104, 111))	('decreases', 'NegReg', (129, 138))	('Serine129 residue', 'Var', (45, 62))
17942	19852809	In Xenopus laevis, Nme4 is predominantly expressed in the head region and an indirect regulation of retinal gliogenesis by Nme4 was demonstrated.	('rat', 'Species', '10116', (139, 142))	('retinal gliogenesis', 'CPA', (100, 119))	('Nme4', 'Gene', (19, 23))	('Nme4', 'Var', (123, 127))	('Xenopus laevis', 'Species', '8355', (3, 17))
17955	19852809	Functionally, murine Nme5 protein might be involved in late spermiogenesis by increasing the ability of late-stage spermatids to eliminate reactive oxygen species.	('murine', 'Species', '10090', (14, 20))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (139, 162))	('Nme5', 'Gene', (21, 25))	('late spermiogenesis', 'Phenotype', 'HP:0031040', (55, 74))	('increasing', 'PosReg', (78, 88))	('eliminate reactive oxygen species', 'MPA', (129, 162))	('murine', 'Var', (14, 20))	('protein', 'Protein', (26, 33))	('involved', 'Reg', (43, 51))
17969	19852809	The zebrafish Nme7, as human NME7, contains a DUF1126 domain, belonging to the DM10 family, and an NDPk_7A and an NDPk_7B domain (Fig.	('NME7', 'Gene', (29, 33))	('NDPk', 'Gene', (114, 118))	('zebrafish', 'Species', '7955', (4, 13))	('NDPk', 'Gene', (99, 103))	('NME7', 'Gene', '29922', (29, 33))	('NDPk', 'Gene', '129607', (114, 118))	('human', 'Species', '9606', (23, 28))	('NDPk', 'Gene', '129607', (99, 103))	('Nme7', 'Gene', (14, 18))	('DUF1126 domain', 'Var', (46, 60))
17998	19852809	In humans, mutation in the NME10 gene induce Retinitis Pigmentosa, the major form of heritable blindness.	('NME10', 'Gene', (27, 32))	('induce', 'Reg', (38, 44))	('Retinitis', 'Phenotype', 'HP:0032118', (45, 54))	('blindness', 'Phenotype', 'HP:0000618', (95, 104))	('NME10', 'Gene', '6102', (27, 32))	('Retinitis Pigmentosa', 'Phenotype', 'HP:0000510', (45, 65))	('Retinitis Pigmentosa', 'Disease', 'MESH:C538365', (45, 65))	('Retinitis Pigmentosa', 'Disease', (45, 65))	('humans', 'Species', '9606', (3, 9))	('blindness', 'Disease', (95, 104))	('blindness', 'Disease', 'MESH:D001766', (95, 104))	('mutation', 'Var', (11, 19))
17999	19852809	Interestingly, the partial NDPk domain of NME10 protein may have important function as most disease-related mutations of the NME10 gene concern this part of the protein.	('NME10', 'Gene', (42, 47))	('mutations', 'Var', (108, 117))	('NME10', 'Gene', (125, 130))	('NME10', 'Gene', '6102', (42, 47))	('NDPk', 'Gene', (27, 31))	('NME10', 'Gene', '6102', (125, 130))	('concern', 'Reg', (136, 143))	('NDPk', 'Gene', '129607', (27, 31))	('partial', 'Var', (19, 26))
18005	19852809	Nme1, Nme2, Nme3, and Nme4 belong to the Group I while vertebrate Nme5, Nme6, Nme7, Nme8, and Nme9 belong to the Group II.	('Nme7', 'Var', (78, 82))	('Nme6', 'Var', (72, 76))	('rat', 'Species', '10116', (61, 64))	('Nme4', 'Var', (22, 26))
18010	19852809	Our analyses also suggest that the Nme1 gene found in mammals, chicken and lizard results from the duplication of the Nme2 gene that occurred after amphibian radiation.	('lizard', 'Species', '8524', (75, 81))	('duplication', 'Var', (99, 110))	('results from', 'Reg', (82, 94))	('Nme2', 'Gene', (118, 122))	('Nme1', 'Gene', (35, 39))	('chicken', 'Species', '9031', (63, 70))
18234	17976178	In addition, as women further postpone childbearing they are increasingly relying on ART treatment and many may therefore wait too long for realising their fertility intentions.	('women', 'Species', '9606', (16, 21))	('men', 'Species', '9606', (18, 21))	('child', 'Species', '9606', (39, 44))	('men', 'Species', '9606', (94, 97))	('childbearing', 'CPA', (39, 51))	('man', 'Species', '9606', (103, 106))	('postpone', 'Var', (30, 38))
18249	17976178	However, poor semen quality may be caused by environmentally induced, but heritable, epigenetic changes.	('poor', 'NegReg', (9, 13))	('men', 'Species', '9606', (52, 55))	('epigenetic changes', 'Var', (85, 103))	('caused', 'Reg', (35, 41))	('men', 'Species', '9606', (16, 19))
18310	32093393	In most cases, the regimen of treatment received by children, adolescents, and young adults contains alkylating agents (e.g., chlorambucil, cyclophosphamide, cisplatin, busulphan), which are associated with a high risk of infertility.	('men', 'Species', '9606', (35, 38))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (140, 156))	('children', 'Species', '9606', (52, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))	('cisplatin', 'Var', (158, 167))	('men', 'Species', '9606', (23, 26))	('infertility', 'Disease', (222, 233))	('chlorambucil', 'Chemical', 'MESH:D002699', (126, 138))	('infertility', 'Phenotype', 'HP:0000789', (222, 233))	('infertility', 'Disease', 'MESH:D007247', (222, 233))	('busulphan', 'Chemical', 'MESH:D002066', (169, 178))
18352	32093393	Moreover, a long-term reduction of the SSC pool has been observed in prepubertal patients exposed to cancer treatment including alkylating agents, and the risk of infertility appears to increase with the proportion of altered SSCs.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('SSC pool', 'MPA', (39, 47))	('infertility', 'Disease', 'MESH:D007247', (163, 174))	('cancer', 'Disease', (101, 107))	('infertility', 'Phenotype', 'HP:0000789', (163, 174))	('reduction', 'NegReg', (22, 31))	('patients', 'Species', '9606', (81, 89))	('infertility', 'Disease', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('men', 'Species', '9606', (113, 116))	('altered', 'Var', (218, 225))
18362	32093393	Likewise, a short-term exposure to chemotherapeutic drugs such as bleomycin, etoposide, doxorubicin, cisplatin, and cyclophosphamide results in DNA damages (increased in gammaH2AX expression) in a C18-4 mouse spermatogonial cell line and in culture of mouse prepubertal testicular tissue after 48 h and 16 h, respectively.	('cyclophosphamide', 'Var', (116, 132))	('etoposide', 'Var', (77, 86))	('mouse', 'Species', '10090', (252, 257))	('mouse', 'Species', '10090', (203, 208))	('doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('bleomycin', 'Var', (66, 75))	('bleomycin', 'Chemical', 'MESH:D001761', (66, 75))	('DNA damages', 'CPA', (144, 155))	('expression', 'MPA', (180, 190))	('gammaH2AX', 'Gene', (170, 179))	('etoposide', 'Chemical', 'MESH:D005047', (77, 86))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (116, 132))	('increased', 'PosReg', (157, 166))	('doxorubicin', 'Var', (88, 99))	('cisplatin', 'Var', (101, 110))	('gammaH2AX', 'Gene', '15270', (170, 179))
18364	32093393	Because these structures are critical for genetic stability, their dysfunction might affect the most differentiated germ cell types and contribute to infertility.	('contribute', 'Reg', (136, 146))	('most differentiated germ cell types', 'CPA', (96, 131))	('infertility', 'Disease', 'MESH:D007247', (150, 161))	('affect', 'Reg', (85, 91))	('dysfunction', 'Var', (67, 78))	('infertility', 'Phenotype', 'HP:0000789', (150, 161))	('infertility', 'Disease', (150, 161))
18385	32093393	Disruption of germ cell telomeres leads to aberrant fertilization and abnormal cleavage of embryos, which might cause an increase of embryo losses or developmental abnormalities.	('increase', 'PosReg', (121, 129))	('developmental abnormalities', 'Disease', (150, 177))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (150, 177))	('developmental abnormalities', 'Disease', 'MESH:D006130', (150, 177))	('aberrant fertilization', 'CPA', (43, 65))	('embryo losses', 'CPA', (133, 146))	('abnormal cleavage', 'CPA', (70, 87))	('abnormal cleavage of embryos', 'Phenotype', 'HP:0012862', (70, 98))	('Disruption', 'Var', (0, 10))
18401	32093393	Moreover, it has been hypothesized that the alteration of the seminiferous epithelium might lead to a decrease of testicular volume and blood flow and, consequently, limited the testosterone level leaving the testis.	('alteration', 'Var', (44, 54))	('testosterone', 'Chemical', 'MESH:D013739', (178, 190))	('blood flow', 'CPA', (136, 146))	('testosterone level leaving', 'MPA', (178, 204))	('decrease', 'NegReg', (102, 110))	('testicular volume', 'CPA', (114, 131))	('limited', 'NegReg', (166, 173))	('decrease of testicular volume', 'Phenotype', 'HP:0008734', (102, 131))	('rat', 'Species', '10116', (48, 51))
18404	32093393	In the adult rat testis, it has been observed that bleomycin, etoposide, and cisplatin (BEP) chemotherapy induces an oxidative stress status, Leydig cell hyperplasia, and inhibition of the transcription of genes encoding steroidogenic enzymes.	('etoposide', 'Chemical', 'MESH:D005047', (62, 71))	('induces', 'Reg', (106, 113))	('Leydig cell hyperplasia', 'Phenotype', 'HP:0010791', (142, 165))	('transcription', 'MPA', (189, 202))	('etoposide', 'Var', (62, 71))	('cisplatin', 'Var', (77, 86))	('bleomycin', 'Var', (51, 60))	('chemotherapy', 'Var', (93, 105))	('inhibition', 'NegReg', (171, 181))	('Leydig cell hyperplasia', 'Disease', 'MESH:D007984', (142, 165))	('bleomycin', 'Chemical', 'MESH:D001761', (51, 60))	('rat', 'Species', '10116', (13, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (117, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('Leydig cell hyperplasia', 'Disease', (142, 165))	('BEP', 'Chemical', '-', (88, 91))	('oxidative stress status', 'MPA', (117, 140))
18422	32093393	Cyclophosphamide induces, for instance, apoptosis in spermatogonia and spermatocytes.	('Cyclophosphamide', 'Var', (0, 16))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (0, 16))	('induces', 'Reg', (17, 24))	('apoptosis', 'CPA', (40, 49))
18431	32093393	For instance, a return to normozoospermic levels was observed in 70% of men who received cumulative doses of cyclophosphamide under 7.5 g/m2, whereas only 10% recovered with higher doses after five years or even more.	('men', 'Species', '9606', (72, 75))	('under 7.5 g/m2', 'Var', (126, 140))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (109, 125))	('return', 'MPA', (16, 22))	('normozoospermic levels', 'MPA', (26, 48))
18449	32093393	Likewise, another study including five patients treated by BEP has shown an increase of the frequencies of disomy and diploidy for chromosome 16 and 18 during a recovery period from 6 to 18 months.	('diploidy', 'Var', (118, 126))	('disomy', 'Disease', (107, 113))	('disomy', 'Disease', 'MESH:D024182', (107, 113))	('patients', 'Species', '9606', (39, 47))	('BEP', 'Chemical', '-', (59, 62))
18450	32093393	In addition, a raised frequency of chromosome 13 and 21 nullisomy has been observed in testicular cancer patients and Hodgkin's lymphoma patients 18 to 24 months after the chemotherapy initiation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('raised frequency of chromosome 13', 'Phenotype', 'HP:0040012', (15, 48))	('patients', 'Species', '9606', (105, 113))	('testicular cancer', 'Disease', (87, 104))	('nullisomy', 'Var', (56, 65))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (118, 136))	('patients', 'Species', '9606', (137, 145))	('testicular cancer', 'Disease', 'MESH:D013736', (87, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('testicular cancer', 'Phenotype', 'HP:0010788', (87, 104))	('chromosome 13', 'Gene', (35, 48))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (118, 136))	("Hodgkin's lymphoma", 'Disease', (118, 136))
18458	32093393	It would appear that exposure of pachytene spermatocytes to etoposide led to the increased frequencies of chromosome numerical and structural abnormalities (duplications and deletions) in mice spermatozoa, whereas SSCs exposure only lead to sperm chromosome structural abnormalities.	('mice', 'Species', '10090', (188, 192))	('structural abnormalities', 'Disease', (258, 282))	('structural abnormalities', 'Disease', (131, 155))	('etoposide', 'Gene', (60, 69))	('deletions', 'Var', (174, 183))	('structural abnormalities', 'Disease', 'MESH:C566527', (258, 282))	('etoposide', 'Chemical', 'MESH:D005047', (60, 69))	('structural abnormalities', 'Disease', 'MESH:C566527', (131, 155))
18469	32093393	Hypomethylation of H19, a paternally imprinted gene, has been observed almost a year after the first day of initial treatment in one patient diagnosed for anaplastic oligodendroglioma.	('men', 'Species', '9606', (121, 124))	('anaplastic oligodendroglioma', 'Disease', 'MESH:D009837', (155, 183))	('patient', 'Species', '9606', (133, 140))	('Hypomethylation', 'Var', (0, 15))	('H19', 'Gene', '283120', (19, 22))	('anaplastic oligodendroglioma', 'Disease', (155, 183))	('H19', 'Gene', (19, 22))	('observed', 'Reg', (62, 70))
18483	32093393	This disruption of zygotic gene expression disturbs the kinetics of embryonic development and could explain the losses of early embryos fathered by males treated by alkylating agents.	('kinetics of embryonic development', 'CPA', (56, 89))	('men', 'Species', '9606', (85, 88))	('disruption', 'Var', (5, 15))	('disturbs', 'NegReg', (43, 51))
18522	32093393	MOPP Mechloretamine, Vincristine, Procarbazine, and Prednisone  ABVD Adriamycin, Bleomycin, Vinblastine, and Dacarbazine  CHOP Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone  DNA DeoxyriboNucleic Acid  SSCs Spermatogonial Stem Cells  FSH Follicle Stimulating Hormone  ABP Androgen Binding Protein  LH Luteinizing Hormone  gammaH2AX gamma Histone 2AX  dpp day post-partum  CED Cyclophosphamide Equivalent Dose  BEP Bleomycin, Etoposide, and cisPlatin  CYP19A1 Cytochrome P450 Family 19 Subfamily A Member 1  AMH Anti-Mullerian Hormone  CDKN1a Cyclin-Dependent Kinase Inhibitor 1a  ROS Reactive Oxygen Species  FISH Fluorescence In Situ Hybridization  ABV Adriamycin, Bleomycin, and Vinblastine   MOPP-ABV Mechlorethamine, Vincristine, Procarbazine, Prednisone-Doxorubicin, Bleomycin, Vinblastine  TUNEL TdT-Mediated dUTP Nickend Labelling Assay  BRDT Testis-Specific Bromodomain-Protein  H3K9me Histone H3 Monomethylated On Lysine 9  H2B Histone 2B  H3 Histone 3  H4 Histone 4  H19D Histone 19  ICSI Intracytoplasmic Sperm Injection	('Etoposide', 'Chemical', 'MESH:D005047', (439, 448))	('CYP19A1', 'Gene', '1588', (465, 472))	('MOPP', 'Chemical', 'MESH:C014553', (0, 4))	('ABP', 'Gene', (282, 285))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (390, 406))	('MOPP-ABV', 'Chemical', 'MESH:C056641', (709, 717))	('ABP', 'Gene', '6462', (282, 285))	('Cyclophosphamide', 'Chemical', 'MESH:D003520', (127, 143))	('Androgen Binding Protein', 'Gene', '6462', (286, 310))	('LH', 'Chemical', 'MESH:D007986', (312, 314))	('CYP19A1', 'Gene', (465, 472))	('gammaH2AX', 'Gene', (336, 345))	('BEP', 'Chemical', '-', (424, 427))	('H19D', 'SUBSTITUTION', 'None', (991, 995))	('H19D', 'Var', (991, 995))	('ABVD', 'Chemical', 'MESH:C034632', (64, 68))	('BRDT', 'Gene', '676', (859, 863))	('ROS', 'Chemical', 'MESH:D017382', (594, 597))	('AMH', 'Gene', (521, 524))	('BRDT', 'Gene', (859, 863))	('CDKN1a', 'Gene', '114851', (549, 555))	('CDKN1a', 'Gene', (549, 555))	('Androgen Binding Protein', 'Gene', (286, 310))	('MOPP', 'Chemical', 'MESH:C014553', (709, 713))	('gammaH2AX', 'Gene', '15270', (336, 345))	('AMH', 'Gene', '268', (521, 524))
18553	27527410	Seminoma histology was determined using International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes 9061 and 9062 for seminoma and anaplastic seminoma, respectively.	('seminoma', 'Disease', 'MESH:D018239', (143, 151))	('Seminoma', 'Disease', 'MESH:D018239', (0, 8))	('seminoma', 'Disease', (143, 151))	('seminoma', 'Disease', (167, 175))	('Seminoma', 'Disease', (0, 8))	('Oncology', 'Phenotype', 'HP:0002664', (85, 93))	('seminoma', 'Disease', 'MESH:D018239', (167, 175))	('9062', 'Var', (134, 138))
18634	28003740	The weights of body, testis, epididymis, prostate, seminal vesicle, and kidney; sperm count; sperm motility; steroidogenic acute regulatory protein level; and epididymal sperm count were significantly lower in the CIS-treated groups than in the control group.	('epididymis', 'Disease', (29, 39))	('CIS-treated', 'Var', (214, 225))	('sperm count', 'CPA', (80, 91))	('steroidogenic acute regulatory protein', 'Gene', (109, 147))	('steroidogenic acute regulatory protein', 'Gene', '25557', (109, 147))	('epididymis', 'Disease', 'MESH:D004823', (29, 39))	('sperm motility', 'CPA', (93, 107))	('lower', 'NegReg', (201, 206))	('epididymal sperm count', 'CPA', (159, 181))
18666	28003740	The amount of kidney tubular damage was scored according to the percentage of cortical tubules with epithelial necrosis: 0, normal; 1, <=10%, 2, 10%-25%, 3, 26%-75%, and 4, >=75%.	('necrosis', 'Disease', (111, 119))	('necrosis', 'Disease', 'MESH:D009336', (111, 119))	('<=10%', 'Var', (135, 140))	('kidney tubular damage', 'Disease', (14, 35))	('kidney tubular damage', 'Disease', 'MESH:D007674', (14, 35))
18677	28003740	The weights of the body, testis, epididymis, seminal vesicle, prostate, and kidney were significantly less in CIS-treated groups than in the control group.	('epididymis', 'Disease', (33, 43))	('seminal vesicle', 'CPA', (45, 60))	('less', 'NegReg', (102, 106))	('prostate', 'CPA', (62, 70))	('CIS-treated', 'Var', (110, 121))	('epididymis', 'Disease', 'MESH:D004823', (33, 43))
18679	28003740	The plasma MDA level was also significantly higher in the CIS-6, CIS-8, and CIS-10 groups than in the control group (Table 3).	('CIS-10', 'Gene', (76, 82))	('higher', 'PosReg', (44, 50))	('CIS-6', 'Var', (58, 63))	('CIS-10', 'Gene', '83681', (76, 82))	('CIS-8', 'Var', (65, 70))	('plasma MDA level', 'MPA', (4, 20))	('MDA', 'Chemical', 'MESH:D008315', (11, 14))
18680	28003740	The RBC count and Hb level were significantly higher in the CIS-6, CIS-8, and CIS-10 groups than in the control group.	('CIS-6', 'Var', (60, 65))	('CIS-10', 'Gene', '83681', (78, 84))	('CIS-8', 'Var', (67, 72))	('higher', 'PosReg', (46, 52))	('RBC count', 'CPA', (4, 13))	('CIS-10', 'Gene', (78, 84))	('Hb level', 'MPA', (18, 26))
18683	28003740	The concentration of StAR protein in the testis tissue was also significantly lower in the CIS-treated groups than in the control group (Figure 1B and C).	('CIS-treated', 'Var', (91, 102))	('StAR', 'Gene', (21, 25))	('rat', 'Species', '10116', (11, 14))	('StAR', 'Gene', '25557', (21, 25))	('lower', 'NegReg', (78, 83))
18684	28003740	Epididymal sperm CatSper was significantly lower in the CIS-6, CIS-8, and CIS-10 groups than in the control group (Figure 2A and B).	('CatSper', 'Gene', (17, 24))	('CIS-10', 'Gene', '83681', (74, 80))	('CatSper', 'Gene', '225865', (17, 24))	('CIS-6', 'Var', (56, 61))	('CIS-10', 'Gene', (74, 80))	('CIS-8', 'Var', (63, 68))	('lower', 'NegReg', (43, 48))
18685	28003740	The ER stress markers GRP-78 (Figure 3A and E), ATF (Figure 3B and F), pIRE (Figure 3C and G), and pPERK (Figure 3D and H) were significantly higher in the CIS-6, CIS-8, and CIS-10 groups than in the control group.	('ATF', 'Gene', (48, 51))	('ATF', 'Gene', '25453', (48, 51))	('CIS-8', 'Var', (163, 168))	('GRP-78', 'Gene', '25617', (22, 28))	('CIS-10', 'Gene', '83681', (174, 180))	('GRP-78', 'Gene', (22, 28))	('pPERK', 'MPA', (99, 104))	('ER stress', 'MPA', (4, 13))	('pIRE', 'MPA', (71, 75))	('CIS-10', 'Gene', (174, 180))	('higher', 'PosReg', (142, 148))	('CIS-6', 'Var', (156, 161))
18686	28003740	Plasma BUN level was also significantly higher in the CIS-4, CIS-6, CIS-8, and CIS-10 groups than in the control group (Table 5).	('CIS-10', 'Gene', (79, 85))	('higher', 'PosReg', (40, 46))	('Plasma BUN level', 'MPA', (0, 16))	('CIS-8', 'Var', (68, 73))	('CIS-10', 'Gene', '83681', (79, 85))	('CIS-4', 'Var', (54, 59))	('CIS-6', 'Var', (61, 66))
18687	28003740	The tubular necrosis score was also significantly higher in the CIS-treated groups than in the control group (Table 5).	('higher', 'PosReg', (50, 56))	('tubular necrosis', 'Disease', 'MESH:D009956', (4, 20))	('CIS-treated', 'Var', (64, 75))	('tubular necrosis', 'Disease', (4, 20))	('tubular necrosis', 'Phenotype', 'HP:0008682', (4, 20))
18688	28003740	The spermatogenic cell density and Johnson's score were significantly lower in the CIS-4, CIS-6, CIS-8, and CIS-10 groups than in the control group (Table 6).	("Johnson's score", 'CPA', (35, 50))	('CIS-10', 'Gene', (108, 114))	('CIS-4', 'Var', (83, 88))	('lower', 'NegReg', (70, 75))	('spermatogenic cell density', 'CPA', (4, 30))	('CIS-6', 'Var', (90, 95))	('CIS-10', 'Gene', '83681', (108, 114))
18689	28003740	The rats treated with CIS exhibited significantly lower body weight and reproductive organ weight than the untreated control animals.	('reproductive organ weight', 'CPA', (72, 97))	('lower', 'NegReg', (50, 55))	('CIS', 'Var', (22, 25))	('rats', 'Species', '10116', (4, 8))	('lower body weight and reproductive organ', 'Phenotype', 'HP:0003241', (50, 90))	('body weight', 'CPA', (56, 67))	('lower body weight', 'Phenotype', 'HP:0004325', (50, 67))
18690	28003740	CIS is a potent anticancer drug that has been shown to induce testicular disintegration, sperm dysfunction, germ cell apoptosis, and abnormalities in the Leydig cells, as well as toxicity due to membrane rigidification, lipid peroxidation, and oxidative damage in rats and a reduction in antioxidants.	('lipid', 'Chemical', 'MESH:D008055', (220, 225))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('abnormalities', 'CPA', (133, 146))	('reduction', 'NegReg', (275, 284))	('membrane rigidification', 'CPA', (195, 218))	('CIS', 'Var', (0, 3))	('oxidative', 'CPA', (244, 253))	('rats', 'Species', '10116', (264, 268))	('induce', 'Reg', (55, 61))	('antioxidants', 'MPA', (288, 300))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('abnormalities in the Leydig cells', 'Phenotype', 'HP:0010789', (133, 166))	('cancer', 'Disease', (20, 26))	('germ cell apoptosis', 'CPA', (108, 127))	('lipid peroxidation', 'CPA', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('sperm dysfunction', 'CPA', (89, 106))	('rat', 'Species', '10116', (81, 84))	('toxicity', 'Disease', (179, 187))	('testicular disintegration', 'CPA', (62, 87))	('rat', 'Species', '10116', (264, 267))
18692	28003740	CIS also increases lipid peroxidation by markedly increasing the MDA level in a dose-dependent manner.	('MDA', 'Chemical', 'MESH:D008315', (65, 68))	('MDA level', 'MPA', (65, 74))	('increasing', 'PosReg', (50, 60))	('lipid peroxidation', 'MPA', (19, 37))	('CIS', 'Var', (0, 3))	('increases', 'PosReg', (9, 18))	('lipid', 'Chemical', 'MESH:D008055', (19, 24))
18694	28003740	StAR protein was significantly lower in the CIS-treated groups than in the control group, thus interfering with testosterone production.	('testosterone', 'Chemical', 'MESH:D013739', (112, 124))	('CIS-treated', 'Var', (44, 55))	('StAR', 'Gene', (0, 4))	('lower', 'NegReg', (31, 36))	('interfering', 'NegReg', (95, 106))	('StAR', 'Gene', '25557', (0, 4))	('testosterone production', 'MPA', (112, 135))
18695	28003740	The total testosterone level decreased significantly in the CIS-treated rats compared with the control rats as a result of damage caused to the Leydig cells.	('CIS-treated', 'Var', (60, 71))	('rats', 'Species', '10116', (103, 107))	('testosterone', 'Chemical', 'MESH:D013739', (10, 22))	('rats', 'Species', '10116', (72, 76))	('testosterone level decreased', 'Phenotype', 'HP:0040171', (10, 38))	('decreased', 'NegReg', (29, 38))
18696	28003740	CatSper channels (or Ca2+ ion channels) were significantly lower in the sperm cells of CIS-treated rats.	('rats', 'Species', '10116', (99, 103))	('Ca2+', 'Chemical', 'MESH:D000069285', (21, 25))	('CatSper', 'Gene', (0, 7))	('lower', 'NegReg', (59, 64))	('CatSper', 'Gene', '225865', (0, 7))	('CIS-treated', 'Var', (87, 98))
18699	28003740	By contrast, the renal index, BUN, and tubular necrosis were higher in CIS-treated rats than in untreated control animals.	('tubular necrosis', 'Disease', (39, 55))	('CIS-treated', 'Var', (71, 82))	('higher', 'PosReg', (61, 67))	('rats', 'Species', '10116', (83, 87))	('tubular necrosis', 'Phenotype', 'HP:0008682', (39, 55))	('BUN', 'CPA', (30, 33))	('tubular necrosis', 'Disease', 'MESH:D009956', (39, 55))	('renal', 'MPA', (17, 22))
18701	28003740	Furthermore, the spermatogenic cell density and Johnsen's score were lower in CIS-treated rats, and testicular disintegration and germ cell apoptosis were observed.	("Johnsen's score", 'CPA', (48, 63))	('testicular disintegration', 'CPA', (100, 125))	('CIS-treated', 'Var', (78, 89))	('germ cell apoptosis', 'CPA', (130, 149))	('lower', 'NegReg', (69, 74))	('rat', 'Species', '10116', (119, 122))	('rats', 'Species', '10116', (90, 94))	('spermatogenic cell density', 'CPA', (17, 43))	('rat', 'Species', '10116', (90, 93))
18713	28003740	Therefore, it is likely that CIS-induced infertility results from a lower number of Ca2+ ion channels.	('infertility', 'Disease', 'MESH:D007247', (41, 52))	('lower', 'NegReg', (68, 73))	('infertility', 'Phenotype', 'HP:0000789', (41, 52))	('CIS-induced', 'Var', (29, 40))	('infertility', 'Disease', (41, 52))	('Ca2+ ion channels', 'MPA', (84, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (84, 88))
18717	28003740	Treatment with CIS was shown to increase the levels of ER stress markers and reduce the numbers of CatSper in the sperm, which are required for hyperactivated sperm motility.	('reduce', 'NegReg', (77, 83))	('CatSper', 'Gene', '225865', (99, 106))	('increase', 'PosReg', (32, 40))	('CIS', 'Var', (15, 18))	('hyperactivated sperm motility', 'Disease', 'MESH:D015835', (144, 173))	('hyperactivated sperm motility', 'Disease', (144, 173))	('CatSper', 'Gene', (99, 106))	('levels of ER stress markers', 'MPA', (45, 72))
18762	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
18776	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
18784	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
18794	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('hallmark characteristics', 'MPA', (70, 94))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('TRIM44', 'Gene', '54765', (18, 24))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
18796	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
18798	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
18799	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin', 'Gene', (125, 131))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', (111, 117))
18801	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('TRIM44', 'Gene', '54765', (14, 20))	('p27', 'Gene', '10671', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
18802	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('p21', 'Gene', (22, 25))	('glioma', 'Disease', (112, 118))	('activated', 'PosReg', (99, 108))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
18803	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
18804	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
18815	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('NUPR1', 'Gene', (89, 94))	('knockdown', 'Var', (39, 48))	('CADM1', 'Gene', (103, 108))	('DDIT4', 'Gene', (130, 135))	('TRIM44', 'Gene', '54765', (32, 38))	('CADM1', 'Gene', '23705', (103, 108))	('TNFSF10', 'Gene', '8743', (117, 124))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('CDK19', 'Gene', '23097', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
18824	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('c-IAP2', 'Gene', (84, 90))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
18831	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
18847	31083486	We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions.	('associations', 'Interaction', (265, 277))	('nephrotoxicity', 'Disease', (328, 342))	('rs11615', 'Var', (165, 172))	('nephrotoxicity', 'Disease', 'MESH:D007674', (92, 106))	('rs316019', 'Var', (149, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (318, 327))	('rs1799793', 'Mutation', 'rs1799793', (194, 203))	('rs3212986', 'Var', (177, 186))	('rs1799793', 'Var', (194, 203))	('ERCC1', 'Gene', '2067', (159, 164))	('nephrotoxicity', 'Disease', 'MESH:D007674', (328, 342))	('rs11615', 'Mutation', 'rs11615', (165, 172))	('rs13181', 'Mutation', 'rs13181', (208, 215))	('rs316019', 'Mutation', 'rs316019', (149, 157))	('rs3212986', 'Mutation', 'rs3212986', (177, 186))	('ERCC1', 'Gene', (159, 164))	('rs13181', 'Var', (208, 215))	('SLC22A2', 'Gene', '6582', (141, 148))	('ERCC2', 'Gene', (188, 193))	('associated', 'Reg', (58, 68))	('nephrotoxicity', 'Disease', (92, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('SLC22A2', 'Gene', (141, 148))	('ERCC2', 'Gene', '2068', (188, 193))
18850	31083486	Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08-0.70; p = 0.009) compared to genotype CC.	('rs3212986', 'Mutation', 'rs3212986', (105, 114))	('ERCC1', 'Gene', '2067', (99, 104))	('nephrotoxicity', 'Disease', 'MESH:D007674', (163, 177))	('nephrotoxicity', 'Disease', (163, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('rs3212986', 'Var', (105, 114))	('decreased', 'NegReg', (135, 144))	('ERCC1', 'Gene', (99, 104))
18851	31083486	In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96-9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69-15.16; p = 0.004) compared to genotype CC.	('SLC22A2', 'Gene', (37, 44))	('SLC22A2', 'Gene', '6582', (37, 44))	('rs316019', 'Var', (45, 53))	('rs316019', 'Mutation', 'rs316019', (45, 53))	('nephrotoxicity', 'Disease', (199, 213))	('cisplatin', 'MPA', (189, 198))	('nephrotoxicity', 'Disease', 'MESH:D007674', (199, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
18864	31083486	Cisplatin may induce vascular injury as well, which accelerates tubular cell death.	('tubular cell death', 'CPA', (64, 82))	('vascular injury', 'Disease', 'MESH:D057772', (21, 36))	('induce', 'Reg', (14, 20))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin', 'Var', (0, 9))	('accelerates', 'PosReg', (52, 63))	('vascular injury', 'Disease', (21, 36))
18866	31083486	This loss of function manifests itself in multiple ways: acute kidney injury (as measured by decreased glomerular filtration rate (GFR)), decreased magnesium and potassium levels and increased serum creatinine (SCr) are paramount but cisplatin may also cause hypocalcaemia, renal salt wasting and even chronic kidney disease.	('hypocalcaemia', 'Phenotype', 'HP:0002901', (259, 272))	('magnesium', 'Chemical', 'MESH:D008274', (148, 157))	('chronic kidney disease', 'Disease', (302, 324))	('acute kidney injury', 'Disease', (57, 76))	('cause', 'Reg', (253, 258))	('increased serum creatinine', 'Phenotype', 'HP:0003259', (183, 209))	('acute kidney injury', 'Disease', 'MESH:D058186', (57, 76))	('potassium', 'Chemical', 'MESH:D011188', (162, 171))	('acute kidney', 'Phenotype', 'HP:0001919', (57, 69))	('chronic kidney disease', 'Disease', 'MESH:D051436', (302, 324))	('decreased', 'NegReg', (93, 102))	('cisplatin', 'Var', (234, 243))	('renal salt wasting', 'Phenotype', 'HP:0000127', (274, 292))	('glomerular filtration rate', 'MPA', (103, 129))	('hypocalcaemia, renal salt wasting', 'Disease', 'MESH:D007674', (259, 292))	('creatinine', 'Chemical', 'MESH:D003404', (199, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (302, 324))	('decreased', 'NegReg', (138, 147))	('increased', 'PosReg', (183, 192))	('decreased glomerular filtration', 'Phenotype', 'HP:0012213', (93, 124))	('serum creatinine', 'MPA', (193, 209))	('decreased magnesium', 'Phenotype', 'HP:0002917', (138, 157))	('kidney disease', 'Phenotype', 'HP:0000112', (310, 324))
18868	31083486	In addition, previous studies also suggest that variations in genes involved in cisplatin pharmacodynamics and pharmacokinetics contribute to cisplatin nephrotoxicity.	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('variations', 'Var', (48, 58))	('nephrotoxicity', 'Disease', (152, 166))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('nephrotoxicity', 'Disease', 'MESH:D007674', (152, 166))	('contribute', 'Reg', (128, 138))
18869	31083486	Genetic variations have been reported to play a role both as protective and as risk factors for cisplatin nephrotoxicity.	('Genetic variations', 'Var', (0, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('nephrotoxicity', 'Disease', (106, 120))	('nephrotoxicity', 'Disease', 'MESH:D007674', (106, 120))
18870	31083486	In a recent systematic review we reported that variants in ERCC1, ERCC2 and SLC22A2 genes were associated with cisplatin nephrotoxicity and replicated in at least one other study.	('ERCC1', 'Gene', (59, 64))	('nephrotoxicity', 'Disease', (121, 135))	('variants', 'Var', (47, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('nephrotoxicity', 'Disease', 'MESH:D007674', (121, 135))	('ERCC1', 'Gene', '2067', (59, 64))	('ERCC2', 'Gene', (66, 71))	('SLC22A2', 'Gene', '6582', (76, 83))	('associated', 'Reg', (95, 105))	('SLC22A2', 'Gene', (76, 83))	('ERCC2', 'Gene', '2068', (66, 71))
18871	31083486	ERCC1 and ERCC2 polymorphisms have been associated with alterations of DNA repair process in cells including possibly the nephron following cisplatin exposure.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('ERCC2', 'Gene', (10, 15))	('DNA repair process', 'MPA', (71, 89))	('polymorphisms', 'Var', (16, 29))	('alterations', 'Reg', (56, 67))	('nephron', 'Disease', (122, 129))	('nephron', 'Disease', 'MESH:D007683', (122, 129))	('ERCC2', 'Gene', '2068', (10, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('associated', 'Reg', (40, 50))
18872	31083486	In addition, ERCC1 polymorphisms may alter cell sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('alter', 'Reg', (37, 42))	('polymorphisms', 'Var', (19, 32))	('ERCC1', 'Gene', (13, 18))	('cell sensitivity to cisplatin', 'MPA', (43, 72))	('ERCC1', 'Gene', '2067', (13, 18))
18873	31083486	Polymorphisms in SLC22A2, a gene which product is the organic cation transporter OCT2 responsible for cellular cisplatin uptake in renal proximal tubule cells, affects the severity of tubular injury process due to cisplatin accumulation.	('affects', 'Reg', (160, 167))	('OCT2', 'Gene', '6582', (81, 85))	('SLC22A2', 'Gene', '6582', (17, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('SLC22A2', 'Gene', (17, 24))	('severity', 'MPA', (172, 180))	('Polymorphisms', 'Var', (0, 13))	('OCT2', 'Gene', (81, 85))	('tubular injury', 'Disease', 'MESH:D005198', (184, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('tubular injury', 'Disease', (184, 198))
18876	31083486	Our aim is to validate the use of already associated genetic variants to predict cisplatin nephrotoxicity and to determine if different cisplatin nephrotoxicity definitions contributed to the variability in effect size and direction of already published associations between these genetic polymorphisms and cisplatin nephrotoxicity.	('nephrotoxicity', 'Disease', 'MESH:D007674', (317, 331))	('associations', 'Interaction', (254, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (307, 316))	('nephrotoxicity', 'Disease', (146, 160))	('nephrotoxicity', 'Disease', 'MESH:D007674', (146, 160))	('nephrotoxicity', 'Disease', 'MESH:D007674', (91, 105))	('nephrotoxicity', 'Disease', (91, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('variants', 'Var', (61, 69))	('nephrotoxicity', 'Disease', (317, 331))
18898	31083486	Hyperhydration during administration may cause a hypervolemic state which may provoke hyponatremia.	('hyponatremia', 'Disease', 'MESH:D007010', (86, 98))	('hypervolemic state', 'Phenotype', 'HP:0011105', (49, 67))	('hyponatremia', 'Disease', (86, 98))	('hypervolemic state', 'Disease', (49, 67))	('provoke', 'Reg', (78, 85))	('cause', 'Reg', (41, 46))	('Hyperhydration', 'Var', (0, 14))	('hyponatremia', 'Phenotype', 'HP:0002902', (86, 98))
18907	31083486	The following five single nucleotide polymorphisms (SNPs) meeting these criteria were included in this study: ERCC1 rs11615 (chr19:45420395; A>G; a synonymous variant) and rs3212986 (chr19:45409478; C>A/C>G/C>T; non-coding transcript variant), ERCC2 rs13181 (chr19:45351661; T>A/T>G; stop gained) and rs1799793 (chr19:45364001; C>A/C>T; a missense variant)) and SLC22A2 rs316019 (chr6:160249250; A>C; a missense variant).	('rs1799793', 'Mutation', 'rs1799793', (301, 310))	('rs11615', 'Var', (116, 123))	('ERCC2', 'Gene', (244, 249))	('rs316019', 'Mutation', 'rs316019', (370, 378))	('rs3212986', 'Mutation', 'rs3212986', (172, 181))	('ERCC1', 'Gene', '2067', (110, 115))	('ERCC1', 'Gene', (110, 115))	('ERCC2', 'Gene', '2068', (244, 249))	('SLC22A2', 'Gene', (362, 369))	('rs11615', 'Mutation', 'rs11615', (116, 123))	('SLC22A2', 'Gene', '6582', (362, 369))	('C>A/C>G/C>T', 'Var', (199, 210))	('rs13181', 'Mutation', 'rs13181', (250, 257))	('chr6:160249250', 'Var', (380, 394))
18908	31083486	Genomic DNA samples for all patients were genotyped for 7907 variants located within absorption, distribution, metabolism, excretion (ADME) gene regions using the Illumina Infinium Panel (Illumina, San Diego, CA, USA), according to the manufacturer's instructions at the Canadian Pharmacogenomics Network for Drug Safety at the University of British Columbia.	('British Columbia', 'Disease', 'OMIM:176500', (342, 358))	('patients', 'Species', '9606', (28, 36))	('variants', 'Var', (61, 69))	('British Columbia', 'Disease', (342, 358))
18924	31083486	The lowest SNP call rate was 97.5% for SLC22A2 rs316019 (Table S2).	('SLC22A2', 'Gene', (39, 46))	('rs316019', 'Var', (47, 55))	('rs316019', 'Mutation', 'rs316019', (47, 55))	('SNP call rate', 'CPA', (11, 24))	('SLC22A2', 'Gene', '6582', (39, 46))
18925	31083486	HWE was fulfilled in the control group of all evaluated SNPs for adjusted-AKI outcome (p > 0.05) but not in the control group of ERCC1 rs1799793 for the CTCAE-AKI outcome (p = 0.013) (Tables S1 and S2).	('ERCC1', 'Gene', '2067', (129, 134))	('rs1799793', 'Mutation', 'rs1799793', (135, 144))	('ERCC1', 'Gene', (129, 134))	('rs1799793', 'Var', (135, 144))
18930	31083486	None of the genetic variants were found to be significantly associated with the risk of nephrotoxicity using this definition (Table 5 and Table 6).	('nephrotoxicity', 'Disease', (88, 102))	('variants', 'Var', (20, 28))	('nephrotoxicity', 'Disease', 'MESH:D007674', (88, 102))	('associated', 'Reg', (60, 70))
18933	31083486	When corrected for age, ancestry from four PCs, chemotherapy protocol, cumulative dosage, hydration and PPI usage, patients carrying ERCC1 rs3212986 heterozygous genotypes were found to have fewer nephrotoxicity events when compared with patients carrying the homozygous wildtype (ORadj = 0.24, CI = 0.08-0.70, p = 0.009).	('patients', 'Species', '9606', (115, 123))	('rs3212986', 'Var', (139, 148))	('nephrotoxicity', 'Disease', (197, 211))	('nephrotoxicity', 'Disease', 'MESH:D007674', (197, 211))	('fewer', 'NegReg', (191, 196))	('rs3212986', 'Mutation', 'rs3212986', (139, 148))	('ERCC1', 'Gene', '2067', (133, 138))	('ERCC1', 'Gene', (133, 138))	('patients', 'Species', '9606', (238, 246))
18934	31083486	Patients carrying SLC22A2 rs316019 heterozygous genotypes were found to have a greater number of nephrotoxicity events than patients who carrying the wildtype (normal) genotype before and after adjusting for the same covariates (ORadj = 5.06, CI = 1.69-15.16, p = 0.004).	('rs316019', 'Mutation', 'rs316019', (26, 34))	('nephrotoxicity', 'Disease', (97, 111))	('nephrotoxicity', 'Disease', 'MESH:D007674', (97, 111))	('Patients', 'Species', '9606', (0, 8))	('SLC22A2', 'Gene', '6582', (18, 25))	('SLC22A2', 'Gene', (18, 25))	('patients', 'Species', '9606', (124, 132))	('rs316019', 'Var', (26, 34))
18935	31083486	Besides this, the SLC22A2 rs316109 homozygous variant carriers had more nephrotoxicity events than patients carrying the wildtype genotype, however after Bonferroni correction this was no longer statistically significant (ORadj = 38.12, CI = 1.89-767.51, p = 0.017).	('nephrotoxicity', 'Disease', 'MESH:D007674', (72, 86))	('rs316109', 'Mutation', 'rs316109', (26, 34))	('rs316109', 'Var', (26, 34))	('patients', 'Species', '9606', (99, 107))	('SLC22A2', 'Gene', '6582', (18, 25))	('SLC22A2', 'Gene', (18, 25))	('nephrotoxicity', 'Disease', (72, 86))
18936	31083486	Additive effect of risk allele was found significant only on SLC22A2 rs316109.	('SLC22A2', 'Gene', '6582', (61, 68))	('rs316109', 'Mutation', 'rs316109', (69, 77))	('SLC22A2', 'Gene', (61, 68))	('rs316109', 'Var', (69, 77))
18937	31083486	In contrast, addition of minor allele on ERCC1 rs3212986 produce protective effect although the result was not significant (ORadj = 0.52, CI = 0.26-1.07, p = 0.076).	('protective effect', 'CPA', (65, 82))	('rs3212986', 'Mutation', 'rs3212986', (47, 56))	('rs3212986', 'Var', (47, 56))	('ERCC1', 'Gene', '2067', (41, 46))	('ERCC1', 'Gene', (41, 46))
18938	31083486	The additive effect of minor allele was confirmed by Cochran-Armitage trend test but only for SLC22A2 rs316019 and ERCC2 rs13181 (Table 8).	('rs316019', 'Var', (102, 110))	('ERCC2', 'Gene', '2068', (115, 120))	('rs316019', 'Mutation', 'rs316019', (102, 110))	('rs13181', 'Var', (121, 128))	('ERCC2', 'Gene', (115, 120))	('SLC22A2', 'Gene', '6582', (94, 101))	('rs13181', 'Mutation', 'rs13181', (121, 128))	('SLC22A2', 'Gene', (94, 101))
18939	31083486	However, there was a very slight trend for the ERCC1 rs3212986 variant to be protective and the SLC22A2 rs316019 homozygous variant to be a risk factor, based on box-plots (Figures S1 and S2).	('ERCC1', 'Gene', '2067', (47, 52))	('SLC22A2', 'Gene', (96, 103))	('rs3212986', 'Var', (53, 62))	('rs316019', 'Var', (104, 112))	('SLC22A2', 'Gene', '6582', (96, 103))	('rs316019', 'Mutation', 'rs316019', (104, 112))	('ERCC1', 'Gene', (47, 52))	('rs3212986', 'Mutation', 'rs3212986', (53, 62))
18940	31083486	Previous studies assessing the associations between ERCC1 rs3212986 and SLC22A2 rs316019 genotypes and cisplatin-induced nephrotoxicity have reported conflicting results.	('associations', 'Interaction', (31, 43))	('nephrotoxicity', 'Disease', (121, 135))	('nephrotoxicity', 'Disease', 'MESH:D007674', (121, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('SLC22A2', 'Gene', '6582', (72, 79))	('ERCC1', 'Gene', '2067', (52, 57))	('ERCC1', 'Gene', (52, 57))	('SLC22A2', 'Gene', (72, 79))	('rs3212986', 'Mutation', 'rs3212986', (58, 67))	('rs316019', 'Var', (80, 88))	('rs3212986', 'Var', (58, 67))	('rs316019', 'Mutation', 'rs316019', (80, 88))
18941	31083486	In this study, associations between genetic variants and multiple definitions of cisplatin-induced nephrotoxicity were analysed in the same dataset and demonstrated that different definitions of cisplatin nephrotoxicity contributed to variability of results.	('nephrotoxicity', 'Disease', (205, 219))	('nephrotoxicity', 'Disease', 'MESH:D007674', (205, 219))	('associations', 'Interaction', (15, 27))	('nephrotoxicity', 'Disease', 'MESH:D007674', (99, 113))	('nephrotoxicity', 'Disease', (99, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('variants', 'Var', (44, 52))
18942	31083486	In contrast, when using the CTCAE-AKI outcome in the same patient sample, the ERCC1 rs3212986 heterozygous genotype was reno-protective whilst the SLC22A2 rs316019 homozygous genotype was a risk factor for cisplatin-induced nephrotoxicity.	('reno-protective', 'CPA', (120, 135))	('nephrotoxicity', 'Disease', (224, 238))	('rs3212986', 'Var', (84, 93))	('SLC22A2', 'Gene', (147, 154))	('rs316019', 'Var', (155, 163))	('nephrotoxicity', 'Disease', 'MESH:D007674', (224, 238))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('SLC22A2', 'Gene', '6582', (147, 154))	('patient', 'Species', '9606', (58, 65))	('rs316019', 'Mutation', 'rs316019', (155, 163))	('ERCC1', 'Gene', '2067', (78, 83))	('ERCC1', 'Gene', (78, 83))	('rs3212986', 'Mutation', 'rs3212986', (84, 93))
18943	31083486	We also found that additive effect of risk allele was found significant only on SLC22A2 rs316109.	('SLC22A2', 'Gene', (80, 87))	('rs316109', 'Var', (88, 96))	('rs316109', 'Mutation', 'rs316109', (88, 96))	('SLC22A2', 'Gene', '6582', (80, 87))
18944	31083486	Several published studies could not detect any significant associations between the CTCAE-AKI outcome definition of cisplatin-induced nephrotoxicity and ERCC1 rs3212986; the reasons for this lack of association include lack of study power, population stratification or phenotypic heterogeneity.	('rs3212986', 'Var', (159, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('nephrotoxicity', 'Disease', 'MESH:D007674', (134, 148))	('ERCC1', 'Gene', '2067', (153, 158))	('ERCC1', 'Gene', (153, 158))	('nephrotoxicity', 'Disease', (134, 148))	('rs3212986', 'Mutation', 'rs3212986', (159, 168))
18945	31083486	did reveal associations between ERCC1 rs3212986 genotypes and cisplatin-induced nephrotoxicity.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('nephrotoxicity', 'Disease', (80, 94))	('rs3212986', 'Mutation', 'rs3212986', (38, 47))	('associations', 'Interaction', (11, 23))	('nephrotoxicity', 'Disease', 'MESH:D007674', (80, 94))	('rs3212986', 'Var', (38, 47))	('ERCC1', 'Gene', (32, 37))	('ERCC1', 'Gene', '2067', (32, 37))
18947	31083486	Furthermore, we found that variant genotypes were protective against cisplatin nephrotoxicity when applying the CTCAE-AKI definition of nephrotoxicity: heterozygous carriers of the ERCC1 rs3212986 had an ORadj of 0.24 (95% CI: 0.08-0.70) while the homozygous variant had an ORadj of 0.43 (95% CI: 0.07-2.47; p = 0.341).	('ERCC1', 'Gene', (181, 186))	('rs3212986', 'Var', (187, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('ERCC1', 'Gene', '2067', (181, 186))	('nephrotoxicity', 'Disease', (136, 150))	('nephrotoxicity', 'Disease', 'MESH:D007674', (136, 150))	('nephrotoxicity', 'Disease', (79, 93))	('rs3212986', 'Mutation', 'rs3212986', (187, 196))	('nephrotoxicity', 'Disease', 'MESH:D007674', (79, 93))
18949	31083486	The relationship between SLC22A2 rs316019 genotypes and cisplatin-induced nephrotoxicity has been assessed in multiple studies.	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('SLC22A2', 'Gene', '6582', (25, 32))	('SLC22A2', 'Gene', (25, 32))	('nephrotoxicity', 'Disease', 'MESH:D007674', (74, 88))	('nephrotoxicity', 'Disease', (74, 88))	('rs316019', 'Var', (33, 41))	('rs316019', 'Mutation', 'rs316019', (33, 41))
18952	31083486	observed a higher increase of cystatin C in homozygous wildtype patients compared to heterozygous and homozygous variant patients (0.043 +- 0.107 vs. -0.013 +- 0.120 mmol/L, p = 0.009, respectively).	('cystatin C', 'Gene', '1471', (30, 40))	('increase', 'PosReg', (18, 26))	('cystatin C', 'Gene', (30, 40))	('patients', 'Species', '9606', (64, 72))	('variant', 'Var', (113, 120))	('patients', 'Species', '9606', (121, 129))
18954	31083486	In contrast, our results suggest that both homozygous and heterozygous variant carriers have an increased risk of cisplatin-induced nephrotoxicity when using the CTCAE-AKI definition.	('nephrotoxicity', 'Disease', (132, 146))	('nephrotoxicity', 'Disease', 'MESH:D007674', (132, 146))	('variant', 'Var', (71, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))
18955	31083486	This finding also supported by significant additive effect of risk allele on SLC22A2 rs316109 when applying additive genetic model.	('rs316109', 'Var', (85, 93))	('SLC22A2', 'Gene', '6582', (77, 84))	('rs316109', 'Mutation', 'rs316109', (85, 93))	('SLC22A2', 'Gene', (77, 84))
18956	31083486	However, our study identified a possible greater risk of nephrotoxicity as defined by  SCr in patients carrying the homozygous variant (Figure S1); these data are consistent with Zhang et al.	('nephrotoxicity', 'Disease', (57, 71))	('variant', 'Var', (127, 134))	('patients', 'Species', '9606', (94, 102))	('nephrotoxicity', 'Disease', 'MESH:D007674', (57, 71))
18959	31083486	This may explain the elevated SCr levels in the wildtype homozygous group of SLC22A2 rs316019 found by Iwata et al.	('SCr levels', 'MPA', (30, 40))	('rs316019', 'Var', (85, 93))	('rs316019', 'Mutation', 'rs316019', (85, 93))	('elevated', 'PosReg', (21, 29))	('SLC22A2', 'Gene', '6582', (77, 84))	('SLC22A2', 'Gene', (77, 84))
18963	31083486	Acute kidney injury caused by cisplatin mainly manifests itself as renal tubular injury and is therefore characterized earlier by electrolyte abnormalities (phosphate, magnesium, potassium and sodium).	('sodium', 'Chemical', 'MESH:D012964', (193, 199))	('Acute kidney injury', 'Disease', (0, 19))	('Acute kidney injury', 'Disease', 'MESH:D058186', (0, 19))	('magnesium', 'MPA', (168, 177))	('cisplatin', 'Var', (30, 39))	('renal tubular injury', 'Disease', (67, 87))	('electrolyte abnormalities', 'Phenotype', 'HP:0003111', (130, 155))	('phosphate', 'Chemical', 'MESH:D010710', (157, 166))	('potassium', 'Chemical', 'MESH:D011188', (179, 188))	('Acute kidney', 'Phenotype', 'HP:0001919', (0, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('renal tubular injury', 'Disease', 'MESH:D007674', (67, 87))	('magnesium', 'Chemical', 'MESH:D008274', (168, 177))
18965	31083486	ERCC1 rs3212986, located at the 3' UTR (non-coding region) was not associated with changes in protein and mRNA expression.	('ERCC1', 'Gene', '2067', (0, 5))	('ERCC1', 'Gene', (0, 5))	('rs3212986', 'Mutation', 'rs3212986', (6, 15))	('mRNA expression', 'MPA', (106, 121))	('rs3212986', 'Var', (6, 15))	('protein', 'MPA', (94, 101))
18966	31083486	However, the tissue expression quantitative trait loci (eQTL) analysis from the Genotype-Tissue Expression (GTEx) Project reported a significant association between rs3212986 and gene expression in various tissues.	('rs3212986', 'Mutation', 'rs3212986', (165, 174))	('rs3212986', 'Var', (165, 174))	('gene expression', 'MPA', (179, 194))
18967	31083486	Unfortunately, no association has been found between rs3212986 and ERCC1 expression in kidney cortex tissue.	('ERCC1', 'Gene', '2067', (67, 72))	('rs3212986', 'Var', (53, 62))	('ERCC1', 'Gene', (67, 72))	('rs3212986', 'Mutation', 'rs3212986', (53, 62))
18968	31083486	SLC22A2 rs316019, a nonsynonymous missense mutation (p.270Ala>Ser), is the only common coding polymorphism of SLCC2A2 with an allele frequency ranging from 9-16% and is reported to cause changes in transporter function.	('p.270Ala>Ser', 'Mutation', 'rs316019', (53, 65))	('SLC22A2', 'Gene', '6582', (0, 7))	('SLC22A2', 'Gene', (0, 7))	('rs316019', 'Var', (8, 16))	('SLCC2A2', 'Gene', (110, 117))	('transporter function', 'MPA', (198, 218))	('rs316019', 'Mutation', 'rs316019', (8, 16))	('changes', 'Reg', (187, 194))
18970	31083486	Specific functional validation of ERCC1 rs3212986 and SLC22A2 rs316019 in kidney tubular tissue is needed to elucidate their role in cisplatin nephrotoxicity and how they affect protein expression involved in cisplatin nephrotoxicity pathway (e.g., OCT2).	('protein', 'Protein', (178, 185))	('ERCC1', 'Gene', (34, 39))	('OCT2', 'Gene', (249, 253))	('ERCC1', 'Gene', '2067', (34, 39))	('rs316019', 'Var', (62, 70))	('rs3212986', 'Var', (40, 49))	('rs316019', 'Mutation', 'rs316019', (62, 70))	('OCT2', 'Gene', '6582', (249, 253))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('nephrotoxicity', 'Disease', 'MESH:D007674', (143, 157))	('affect', 'Reg', (171, 177))	('SLC22A2', 'Gene', (54, 61))	('SLC22A2', 'Gene', '6582', (54, 61))	('nephrotoxicity', 'Disease', 'MESH:D007674', (219, 233))	('nephrotoxicity', 'Disease', (143, 157))	('nephrotoxicity', 'Disease', (219, 233))	('rs3212986', 'Mutation', 'rs3212986', (40, 49))
18976	31083486	Furthermore, this study provides more evidence for associations between genetic variants and cisplatin-induced nephrotoxicity by using serum creatinine-based grading.	('nephrotoxicity', 'Disease', 'MESH:D007674', (111, 125))	('associations', 'Interaction', (51, 63))	('nephrotoxicity', 'Disease', (111, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('creatinine', 'Chemical', 'MESH:D003404', (141, 151))	('genetic variants', 'Var', (72, 88))
19009	29130004	B-HCG was elevated to 1468 mIU/mL (normal 0-4 mIU/mL), LDH was 367 IU/L (normal 140-271 IU/L), and alpha fetoprotein (AFP) was normal (0.9 ng/mL).	('alpha fetoprotein', 'Gene', (99, 116))	('LDH', 'MPA', (55, 58))	('AFP', 'Gene', '174', (118, 121))	('B-HCG', 'MPA', (0, 5))	('alpha fetoprotein', 'Gene', '174', (99, 116))	('elevated', 'PosReg', (10, 18))	('367 IU/L', 'Var', (63, 71))	('AFP', 'Gene', (118, 121))
19015	29130004	He was staged as Stage IIIA, pT1N3M1aS1 given the metastases to the retroperitoneum and lungs.	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('pT1N3M1aS1', 'Var', (29, 39))	('metastases', 'Disease', (50, 60))
19105	33906548	SET-binding factor 2 (SBF2) antisense RNA1 (lncRNA-SBF2-AS1) is a promising long non-coding RNA.	('SBF2-AS1', 'Gene', '283104;81846;5729', (51, 59))	('SET-binding factor 2', 'Gene', '81846', (0, 20))	('SBF2', 'Gene', '81846', (22, 26))	('SET-binding factor 2', 'Gene', (0, 20))	('SBF2', 'Gene', (22, 26))	('antisense', 'Var', (28, 37))	('SBF2', 'Gene', '81846', (51, 55))	('SBF2-AS1', 'Gene', (51, 59))	('SBF2', 'Gene', (51, 55))
19110	33906548	The combined results revealed that high expression of SBF2-AS1 was significantly associated with unfavorable overall survival (OS) (HR = 1.48, 95% CI: 1.34-1.62, P < 0.00001) in a variety of cancers.	('SBF2-AS1', 'Gene', '283104;81846;5729', (54, 62))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('SBF2-AS1', 'Gene', (54, 62))	('overall survival', 'MPA', (109, 125))	('high expression', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('associated', 'Reg', (81, 91))
19114	33906548	Our results of this meta-analysis demonstrate that high SBF2-AS1 expression may become a potential target for predicting the prognosis of human cancers.	('SBF2-AS1', 'Gene', (56, 64))	('human', 'Species', '9606', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('high', 'Var', (51, 55))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('SBF2-AS1', 'Gene', '283104;81846;5729', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
19124	33906548	Accumulating studies in the field of oncology have indicated that the aberrant expression of lncRNA is associated with tumorigenesis, metastasis, and prognosis in cancers.	('oncology', 'Phenotype', 'HP:0002664', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('tumor', 'Disease', (119, 124))	('cancers', 'Disease', (163, 170))	('associated', 'Reg', (103, 113))	('aberrant expression', 'Var', (70, 89))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('metastasis', 'CPA', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lncRNA', 'Protein', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
19128	33906548	In non-small-cell lung cancer, the study conducted by Chen et al revealed that the high expression of SBF2-AS1 is a significant risk factor correlated to poor overall survival and advanced clinical stage.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('overall survival', 'CPA', (159, 175))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('SBF2-AS1', 'Gene', '283104;81846;5729', (102, 110))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('poor', 'NegReg', (154, 158))	('high', 'Var', (83, 87))	('SBF2-AS1', 'Gene', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('expression', 'MPA', (88, 98))
19150	33906548	The subgroup for the different of cancer types indicated that the high SBF2-AS1 expression was strongly correlated to poor OS in both subgroups (digestive system tumors: pooled HR = 1.65 95%CI: 1.32-2.07, I2 = 56%, P < 0.00001; non-digestive system tumors: pooled HR = 1.70 95%CI: 1.20-2.41, I2 = 39%, P = 0.003) (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('expression', 'MPA', (80, 90))	('digestive system tumors', 'Phenotype', 'HP:0007378', (145, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('digestive system tumors', 'Phenotype', 'HP:0007378', (232, 255))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('SBF2-AS1', 'Gene', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('SBF2-AS1', 'Gene', '283104;81846;5729', (71, 79))	('cancer', 'Disease', (34, 40))	('poor OS', 'Disease', (118, 125))	('tumors', 'Disease', (162, 168))	('high', 'Var', (66, 70))	('non-digestive system tumors', 'Phenotype', 'HP:0006719', (228, 255))	('tumors', 'Disease', (249, 255))
19152	33906548	Furthermore, the investigators performed a subgroup meta-analysis stratified by the analysis method and sample size, and this suggested that the high SBF2-AS1expression is obviously correlated with poor OS (Figure 3).	('SBF2-AS1', 'Gene', '283104;81846;5729', (150, 158))	('poor OS', 'Disease', (198, 205))	('SBF2-AS1', 'Gene', (150, 158))	('correlated', 'Reg', (182, 192))	('high', 'Var', (145, 149))
19162	33906548	It is noteworthy that an abnormal lncRNA expression may be involved in various biological processes of tumorigenesis and have an effect on its progression.	('lncRNA expression', 'Protein', (34, 51))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('abnormal', 'Var', (25, 33))	('tumor', 'Disease', (103, 108))	('involved', 'Reg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('effect', 'Reg', (129, 135))
19168	33906548	Meanwhile, Yang's study revealed that SBF2-AS1 was described as a key regulator in the proliferation and migration of clear cell renal cell carcinoma cells via sponging miR-338-3p and suppressing E26 transformation specific-1 (ETS1).	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 149))	('E26 transformation specific-1', 'Gene', '2113', (196, 225))	('clear cell renal cell carcinoma', 'Disease', (118, 149))	('ETS1', 'Gene', '2113', (227, 231))	('ETS1', 'Gene', (227, 231))	('sponging', 'Var', (160, 168))	('SBF2-AS1', 'Gene', '283104;81846;5729', (38, 46))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (118, 149))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('migration', 'CPA', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('E26 transformation specific-1', 'Gene', (196, 225))	('SBF2-AS1', 'Gene', (38, 46))	('suppressing', 'NegReg', (184, 195))
19170	33906548	Another research demonstrated that the high SBF2-AS1 expression could downregulate the miR-122-5p expression and then promoted the X-linked inhibitor of apoptosis protein (XIAP) expression, which in turn, led to the proliferation of pancreatic cancer cells.	('high', 'Var', (39, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('XIAP', 'Gene', (172, 176))	('pancreatic cancer', 'Disease', (233, 250))	('XIAP', 'Gene', '331', (172, 176))	('expression', 'MPA', (178, 188))	('SBF2-AS1', 'Gene', (44, 52))	('miR-122-5p', 'Gene', (87, 97))	('X-linked inhibitor of apoptosis protein', 'Gene', (131, 170))	('led to', 'Reg', (205, 211))	('X-linked inhibitor of apoptosis protein', 'Gene', '331', (131, 170))	('SBF2-AS1', 'Gene', '283104;81846;5729', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('downregulate', 'NegReg', (70, 82))	('miR-122-5p', 'Gene', '100188847', (87, 97))	('promoted', 'PosReg', (118, 126))	('proliferation', 'CPA', (216, 229))
19171	33906548	The majority of other mechanism studies demonstrated that SBF2-AS1may be functioned as a ceRNA to modulate target genes through the miRNA sponge, and regulate specific classical signaling pathways in different cancers, including miR-338-3p availability in glioblastoma, miR-361-5o in cervical cancer, miR-30a in osteosarcoma.	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('regulate', 'Reg', (150, 158))	('SBF2-AS1', 'Gene', (58, 66))	('miR-30a', 'Gene', '407029', (301, 308))	('modulate', 'Reg', (98, 106))	('SBF2-AS1', 'Gene', '283104;81846;5729', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('osteosarcoma', 'Disease', (312, 324))	('cancer', 'Disease', (293, 299))	('osteosarcoma', 'Disease', 'MESH:D012516', (312, 324))	('glioblastoma', 'Disease', 'MESH:D005909', (256, 268))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('miR-361', 'Gene', '494323', (270, 277))	('miR-30a', 'Gene', (301, 308))	('miR-338-3p availability', 'Var', (229, 252))	('classical signaling pathways', 'Pathway', (168, 196))	('glioblastoma', 'Disease', (256, 268))	('miR-361', 'Gene', (270, 277))	('glioblastoma', 'Phenotype', 'HP:0012174', (256, 268))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))	('osteosarcoma', 'Phenotype', 'HP:0002669', (312, 324))
19177	33906548	In the present study, the combined results revealed that the hoisted SBF2-AS1 expression can be regarded as a sign of poor OS in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('expression', 'MPA', (78, 88))	('cancer', 'Disease', (129, 135))	('hoisted', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('patients', 'Species', '9606', (136, 144))	('SBF2-AS1', 'Gene', '283104;81846;5729', (69, 77))	('SBF2-AS1', 'Gene', (69, 77))
19178	33906548	The present analysis demonstrated that the high expression of SBF2-AS1 might be an essential predictive factor for OS in various cancers.	('SBF2-AS1', 'Gene', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('high', 'Var', (43, 47))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('SBF2-AS1', 'Gene', '283104;81846;5729', (62, 70))
19212	30542293	In brush cells, TAS2Rs are instrumental for inducing a breath-hold, mediated by acetylcholine (Ach) as well as in chemosensory cells expressing TAS2Rs that enhance the responsiveness of the trigeminal nerve leading to apnea in mice (Tizzano et al.,; Krasteva et al.,).	('apnea', 'Phenotype', 'HP:0002104', (218, 223))	('acetylcholine', 'Chemical', 'MESH:D000109', (80, 93))	('mice', 'Species', '10090', (227, 231))	('TAS2Rs', 'Var', (144, 150))	('enhance', 'PosReg', (156, 163))	('Ach', 'Chemical', 'MESH:D000109', (95, 98))	('apnea', 'Disease', 'MESH:D001049', (218, 223))	('responsiveness of the trigeminal nerve', 'MPA', (168, 206))	('apnea', 'Disease', (218, 223))
19219	30542293	In addition, one single nucleotide polymorphism discovered in the TAS2R9 haplotype has been shown to alter glucose metabolism and insulin homeostasis, potentially contributing to the metabolic diseases (Dotson et al.,).	('glucose metabolism and insulin homeostasis', 'Disease', 'MESH:D044882', (107, 149))	('TAS2R9', 'Gene', (66, 72))	('single nucleotide polymorphism', 'Var', (17, 47))	('metabolic diseases', 'Disease', (183, 201))	('alter', 'Reg', (101, 106))	('contributing to', 'Reg', (163, 178))	('TAS2R9', 'Gene', '50835', (66, 72))	('metabolic diseases', 'Disease', 'MESH:D008659', (183, 201))
19220	30542293	It has been shown that activation of the TAS2R108 receptor increases fat loss, increases glucose tolerance and insulin sensitivity, as well as normalizes plasma lipids in diet-induced obese mice (Kok et al.,).	('activation', 'Var', (23, 33))	('obese', 'Disease', (184, 189))	('increases glucose tolerance', 'Disease', 'MESH:D018149', (79, 106))	('normalizes', 'NegReg', (143, 153))	('insulin', 'Gene', '3630', (111, 118))	('TAS2R108', 'Gene', '57253', (41, 49))	('obese', 'Disease', 'MESH:D009765', (184, 189))	('lipids', 'Chemical', 'MESH:D008055', (161, 167))	('mice', 'Species', '10090', (190, 194))	('increases glucose tolerance', 'Phenotype', 'HP:0040270', (79, 106))	('fat', 'CPA', (69, 72))	('insulin', 'Gene', (111, 118))	('plasma lipids', 'MPA', (154, 167))	('increases glucose tolerance', 'Disease', (79, 106))	('TAS2R108', 'Gene', (41, 49))	('increases', 'PosReg', (59, 68))
19257	30542293	Tastants, specifically L-alanine and L-serine, increase chemotactic migration of neutrophils as well as reduce the production of TNF-alpha induced by lipopolysaccharide (Lee et al.,).	('increase', 'PosReg', (47, 55))	('rat', 'Species', '10116', (71, 74))	('Tastants', 'Chemical', '-', (0, 8))	('L-alanine', 'Var', (23, 32))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (150, 168))	('lipopolysaccharide', 'MPA', (150, 168))	('TNF-alpha', 'Gene', '7124', (129, 138))	('L-alanine', 'Chemical', 'MESH:D000409', (23, 32))	('chemotactic migration of neutrophils', 'CPA', (56, 92))	('reduce', 'NegReg', (104, 110))	('TNF-alpha', 'Gene', (129, 138))	('L-serine', 'Var', (37, 45))	('L-serine', 'Chemical', 'MESH:D012694', (37, 45))
19261	30542293	The specific structure of each opsin determines the wavelength that the chromophore will absorb; therefore small changes near the chromophore binding site result in a variety of opsins that react to different wavelengths (Shichida and Matsuyama,).	('result in', 'Reg', (155, 164))	('react', 'MPA', (190, 195))	('changes', 'Var', (113, 120))	('opsin', 'Gene', '368725', (178, 183))	('opsin', 'Gene', '368725', (31, 36))	('opsin', 'Gene', (178, 183))	('opsin', 'Gene', (31, 36))
19300	30542293	In that study the authors showed that photorelaxation was blue-wavelength-specific and that both pharmacologic inhibition and genetic knockdown of melanopsin (Opn4) ablated the response in the mouse aorta.	('ablated', 'NegReg', (165, 172))	('Opn4', 'Gene', (159, 163))	('response', 'MPA', (177, 185))	('knockdown', 'Var', (134, 143))	('mouse', 'Species', '10090', (193, 198))	('Opn4', 'Gene', '30044', (159, 163))
19313	30542293	In a variety of species, the expression of several opsins has been confirmed, including pinopsin (460-470 nm), vertebrate ancient opsin (460-490 nm), exorhodopsin (498 nm), parapinopsin (370 and 515 nm bi-stable), teleost multiple tissue opsin, and parietopsin (520 nm) (Peirson et al.,; Hankins et al.,).	('opsin', 'Gene', '368725', (130, 135))	('opsin', 'Gene', (91, 96))	('opsin', 'Gene', (130, 135))	('460-490 nm', 'Var', (137, 147))	('opsin', 'Gene', '368725', (51, 56))	('expression', 'Species', '29278', (29, 39))	('opsin', 'Gene', (51, 56))	('teleost', 'Species', '70862', (214, 221))	('opsin', 'Gene', '368725', (255, 260))	('opsin', 'Gene', (255, 260))	('opsin', 'Gene', '368725', (238, 243))	('opsin', 'Gene', (238, 243))	('opsin', 'Gene', '368725', (157, 162))	('rat', 'Species', '10116', (117, 120))	('opsin', 'Gene', (157, 162))	('opsin', 'Gene', '368725', (180, 185))	('370', 'Var', (187, 190))	('520 nm', 'Var', (262, 268))	('498 nm', 'Var', (164, 170))	('opsin', 'Gene', (180, 185))	('460-470 nm', 'Var', (98, 108))	('opsin', 'Gene', '368725', (91, 96))
19360	30542293	That study demonstrated that ligands for OR51E2 modulated proliferation and cytoskeletal remodeling and that these effects were dependent on OR51E2 expression.	('rat', 'Species', '10116', (18, 21))	('OR51E2', 'Var', (41, 47))	('proliferation', 'CPA', (58, 71))	('expression', 'Species', '29278', (148, 158))	('cytoskeletal remodeling', 'CPA', (76, 99))	('modulated', 'Reg', (48, 57))	('rat', 'Species', '10116', (65, 68))
19398	30542293	In 2009, it was shown that a soluble ligand for MOR23 is secreted by muscle cells and that loss of MOR23 leads to increased myofiber branching (Griffin et al.,).	('MOR23', 'Gene', (48, 53))	('MOR23', 'Gene', '18313', (99, 104))	('increased', 'PosReg', (114, 123))	('MOR23', 'Gene', '18313', (48, 53))	('MOR23', 'Gene', (99, 104))	('increased myofiber', 'Phenotype', 'HP:0003712', (114, 132))	('loss', 'Var', (91, 95))	('myofiber branching', 'CPA', (124, 142))
19409	30542293	Patients with chronic rhinosinusitis who have gene allelic frequencies favoring dysfunctional TAS2R38 are at higher risk for sinus surgery than those who are homozygous for functional TAS2R38 alleles (Lee and Cohen,; Adappa et al.,).	('chronic rhinosinusitis', 'Disease', (14, 36))	('sinus surgery', 'Disease', (125, 138))	('Patients', 'Species', '9606', (0, 8))	('TAS2R38', 'Gene', (94, 101))	('dysfunctional', 'Var', (80, 93))	('chronic rhinosinusitis', 'Disease', 'MESH:D006505', (14, 36))
19410	30542293	Activation of enteroendocrine cells via TAS2Rs results in increased ghrelin levels, acutely increasing food intake; however, it also leads to decreased gastric emptying, which, in mice, decreases food intake in the long term (Janssen et al.,).	('increased', 'PosReg', (58, 67))	('increasing', 'PosReg', (92, 102))	('decreases food intake', 'Disease', (186, 207))	('decreased gastric emptying', 'Phenotype', 'HP:0002578', (142, 168))	('decreased', 'NegReg', (142, 151))	('TAS2Rs', 'Var', (40, 46))	('food intake', 'MPA', (103, 114))	('decreases food intake', 'Disease', 'MESH:D000080146', (186, 207))	('gastric emptying', 'MPA', (152, 168))	('mice', 'Species', '10090', (180, 184))	('ghrelin', 'Gene', '58991', (68, 75))	('ghrelin', 'Gene', (68, 75))
19413	30542293	Activation of TAS2Rs leads to smooth muscle relaxation in many different tissue types, providing therapeutic targets to treat diseases like pulmonary hypertension, reactive airway disease (including asthma), and bladder spasms.	('leads to', 'Reg', (21, 29))	('bladder spasms', 'Disease', 'MESH:D013035', (212, 226))	('asthma', 'Phenotype', 'HP:0002099', (199, 205))	('bladder spasms', 'Disease', (212, 226))	('reactive airway disease', 'Phenotype', 'HP:0002099', (164, 187))	('hypertension', 'Phenotype', 'HP:0000822', (150, 162))	('smooth muscle relaxation', 'MPA', (30, 54))	('pulmonary hypertension', 'Disease', (140, 162))	('Activation', 'Var', (0, 10))	('pulmonary hypertension', 'Disease', 'MESH:D006976', (140, 162))	('reactive airway disease', 'Disease', (164, 187))	('TAS2Rs', 'Gene', (14, 20))
19436	30542293	Whereas blue light, the wavelength that activates the OPN3 and 4 receptors, has very limited tissue penetrance, NIR light has the potential for deep tissue penetration, including bone.	('deep tissue penetration', 'CPA', (144, 167))	('bone', 'CPA', (179, 183))	('NIR light', 'Var', (112, 121))	('rat', 'Species', '10116', (161, 164))	('OPN3', 'Protein', (54, 58))
19447	30542293	OR51E2 has been shown to modulate proliferation and cytoskeletal remodeling in ASM from both asthmatics and non-asthmatics, implying that modulation of OR51E2 signaling may be beneficial in asthma (Aisenberg et al.,).	('proliferation', 'CPA', (34, 47))	('asthma', 'Phenotype', 'HP:0002099', (112, 118))	('beneficial', 'PosReg', (176, 186))	('OR51E2', 'Var', (0, 6))	('modulation', 'Var', (138, 148))	('asthma', 'Disease', (190, 196))	('asthma', 'Phenotype', 'HP:0002099', (93, 99))	('modulate', 'Reg', (25, 33))	('cytoskeletal remodeling', 'CPA', (52, 75))	('rat', 'Species', '10116', (41, 44))	('OR51E2', 'Var', (152, 158))	('asthma', 'Phenotype', 'HP:0002099', (190, 196))
19449	30542293	Hence, modulating OR signaling might offer the possibility to inhibit cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('OR', 'Gene', '170639', (18, 20))	('inhibit', 'NegReg', (62, 69))	('modulating', 'Var', (7, 17))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
19450	30542293	OR51E2/PSGR has been shown to inhibit the growth of prostate cancer cells (Neuhaus et al.,; Spehr et al.,; Wiese et al.,).	('OR51E2/PSGR', 'Var', (0, 11))	('growth', 'CPA', (42, 48))	('inhibit', 'NegReg', (30, 37))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Disease', (52, 67))
19452	30542293	Thus, the utility of modulating OR51E2/PSGR in cancer is currently unclear.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('modulating', 'Var', (21, 31))	('OR51E2/PSGR', 'Gene', (32, 43))
19458	30542293	The suggestion that bourgeonal may act through an OR to help direct the sperm in the direction of the egg to aid in fertilization (Spehr et al.,) implies that modulation of this pathway may be efficacious in infertility.	('aid', 'Gene', (109, 112))	('infertility', 'Phenotype', 'HP:0000789', (208, 219))	('modulation', 'Var', (159, 169))	('fertilization', 'CPA', (116, 129))	('infertility', 'Disease', 'MESH:D007247', (208, 219))	('aid', 'Gene', '57379', (109, 112))	('infertility', 'Disease', (208, 219))	('OR', 'Gene', '170639', (50, 52))
19459	30542293	Olfr78 increases renin secretion by the kidney and also plays a role in modulating vascular tone (Pluznick et al.,), implying that modulation of this receptor could be efficacious in hypertension.	('increases', 'PosReg', (7, 16))	('hypertension', 'Disease', (183, 195))	('renin', 'Gene', (17, 22))	('modulation', 'Var', (131, 141))	('modulating', 'Reg', (72, 82))	('hypertension', 'Disease', 'MESH:D006973', (183, 195))	('renin', 'Gene', '5972', (17, 22))	('Olfr78', 'Gene', (0, 6))	('vascular tone', 'MPA', (83, 96))	('increases renin', 'Phenotype', 'HP:0000848', (7, 22))	('hypertension', 'Phenotype', 'HP:0000822', (183, 195))	('Olfr78', 'Gene', '170639', (0, 6))
19461	30542293	Activation of OR2AT4 has been shown to promote cell proliferation and migration in keratinocytes (Busse et al.,), implying that it may play a role in wound healing.	('play', 'Reg', (135, 139))	('promote', 'PosReg', (39, 46))	('rat', 'Species', '10116', (85, 88))	('migration in keratinocytes', 'CPA', (70, 96))	('Activation', 'Var', (0, 10))	('rat', 'Species', '10116', (59, 62))	('OR2AT4', 'Gene', (14, 20))	('OR2AT4', 'Gene', '341152', (14, 20))	('rat', 'Species', '10116', (73, 76))	('cell proliferation', 'CPA', (47, 65))
19462	30542293	When transgenic mice for MOR23 were crossed with dystrophic mice, mechanical stress caused less damage to the muscles from dystrophic mice with elevated MOR23 than to muscles from dystrophic mice with normal MOR23 levels (Pichavant et al.,).	('dystrophic', 'Disease', (123, 133))	('MOR23', 'Gene', '18313', (208, 213))	('mice', 'Species', '10090', (134, 138))	('dystrophic', 'Disease', 'MESH:D020388', (49, 59))	('MOR23', 'Gene', (25, 30))	('dystrophic', 'Disease', 'MESH:D020388', (180, 190))	('dystrophic', 'Disease', (49, 59))	('MOR23', 'Gene', (153, 158))	('dystrophic', 'Disease', (180, 190))	('dystrophic', 'Disease', 'MESH:D020388', (123, 133))	('MOR23', 'Gene', (208, 213))	('transgenic mice', 'Species', '10090', (5, 20))	('mice', 'Species', '10090', (191, 195))	('MOR23', 'Gene', '18313', (25, 30))	('mice', 'Species', '10090', (60, 64))	('mice', 'Species', '10090', (16, 20))	('elevated', 'Var', (144, 152))	('MOR23', 'Gene', '18313', (153, 158))
19512	24559313	A Y-chromosome deletion (gr/gr) has been identified as conferring 2- and 3-fold increases in risk of sporadic and familial testicular cancers, respectively, in a small percentage of men, and reports have identified germline variants in PDE11A and DND1 as candidate modifiers of familial testicular cancer risk .	('sporadic', 'Disease', (101, 109))	('PDE11A', 'Gene', (236, 242))	('familial testicular cancer', 'Disease', 'MESH:D013736', (114, 140))	('familial testicular cancers', 'Disease', (114, 141))	('familial testicular cancer', 'Disease', (278, 304))	('deletion', 'Var', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('familial testicular cancer', 'Disease', 'MESH:D013736', (278, 304))	('testicular cancer', 'Phenotype', 'HP:0010788', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('men', 'Species', '9606', (182, 185))	('DND1', 'Gene', '373863', (247, 251))	('testicular cancer', 'Phenotype', 'HP:0010788', (287, 304))	('increases', 'PosReg', (80, 89))	('testicular cancers', 'Phenotype', 'HP:0010788', (123, 141))	('familial testicular cancers', 'Disease', 'MESH:D013736', (114, 141))	('PDE11A', 'Gene', '50940', (236, 242))	('DND1', 'Gene', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
19513	24559313	Three genomewide association studies (GWAS) of unselected testicular cancer patients have identified single nucleotide polymorphisms that are strongly associated with TGCT risk .	('patients', 'Species', '9606', (76, 84))	('TGCT', 'Disease', (167, 171))	('associated', 'Reg', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('single nucleotide polymorphisms', 'Var', (101, 132))	('testicular cancer', 'Phenotype', 'HP:0010788', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
19514	24559313	Kratz et al., confirmed findings of BAK1, DMRT1, TERT-CLPTM1L, and KITLG variants in familial and bilateral cases of TGCT .	('DMRT1', 'Gene', (42, 47))	('BAK1', 'Gene', (36, 40))	('CLPTM1L', 'Gene', (54, 61))	('KITLG', 'Gene', '4254', (67, 72))	('KITLG', 'Gene', (67, 72))	('variants', 'Var', (73, 81))	('TGCT', 'Disease', (117, 121))	('TERT', 'Gene', (49, 53))	('BAK1', 'Gene', '578', (36, 40))	('DMRT1', 'Gene', '1761', (42, 47))	('TERT', 'Gene', '7015', (49, 53))	('CLPTM1L', 'Gene', '81037', (54, 61))
19549	24559313	The prevalence of congenital inguinal hernia was similar in FTGCT males vs. unaffected family members (18.4% vs. 19%), statistically significantly higher than the occurrence in the general population, 5% .	('FTGCT', 'Var', (60, 65))	('congenital inguinal hernia', 'Disease', (18, 44))	('hernia', 'Phenotype', 'HP:0100790', (38, 44))	('inguinal hernia', 'Phenotype', 'HP:0000023', (29, 44))	('higher', 'PosReg', (147, 153))	('congenital inguinal hernia', 'Disease', 'MESH:D006552', (18, 44))
19556	24559313	Compared with the normal population, FTGCT men were more likely to have tall stature, macrocephaly, and retro- and/or micro-gnathia.	('macrocephaly', 'Phenotype', 'HP:0000256', (86, 98))	('retro- and/or micro-gnathia', 'Disease', (104, 131))	('tall stature', 'Disease', (72, 84))	('men', 'Species', '9606', (43, 46))	('macrocephaly', 'Disease', 'MESH:D058627', (86, 98))	('- and/or micro-gnathia', 'Phenotype', 'HP:0000308', (109, 131))	('tall stature', 'Phenotype', 'HP:0000098', (72, 84))	('FTGCT', 'Var', (37, 42))	('macrocephaly', 'Disease', (86, 98))
19580	24559313	This work was supported by funding from the National Cancer Institute Intramural Research Program and by support services contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat Inc., Rockville MD.	('NO2-CP-11019-50', 'Var', (132, 147))	('Cancer', 'Disease', (53, 59))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NO2-CP', 'Chemical', '-', (132, 138))	('NO2-CP', 'Chemical', '-', (152, 158))	('NO2-CP-65504-50', 'Var', (152, 167))
19582	21975279	Given positive associations between chlordane isomers and testicular germ cell tumors, it is reasonable to assume that chlordanes might also be associated with other testicular dysgenesis syndrome disorders, namely cryptorchidism and hypospadias.	('testicular dysgenesis syndrome disorders', 'Disease', (166, 206))	('cryptorchidism', 'Phenotype', 'HP:0000028', (215, 229))	('associated', 'Reg', (144, 154))	('chlordane', 'Chemical', 'MESH:D002706', (119, 128))	('germ cell tumors', 'Phenotype', 'HP:0100728', (69, 85))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (166, 187))	('chlordanes', 'Chemical', 'MESH:D002706', (119, 129))	('associations', 'Interaction', (15, 27))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('testicular dysgenesis syndrome disorders', 'Disease', 'MESH:D013733', (166, 206))	('cryptorchidism and hypospadias', 'Disease', 'MESH:D003456', (215, 245))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('chlordanes', 'Var', (119, 129))	('hypospadias', 'Phenotype', 'HP:0000047', (234, 245))	('chlordane', 'Chemical', 'MESH:D002706', (36, 45))
19586	21975279	Results: The quartile-specific ORs for cryptorchidism or hypospadias show no notable associations with trans-nonachlor or oxychlordane.	('hypospadias', 'Phenotype', 'HP:0000047', (57, 68))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (103, 118))	('cryptorchidism or hypospadias', 'Disease', (39, 68))	('oxychlordane', 'Chemical', 'MESH:C008743', (122, 134))	('trans-nonachlor', 'Var', (103, 118))	('cryptorchidism', 'Phenotype', 'HP:0000028', (39, 53))	('cryptorchidism or hypospadias', 'Disease', 'MESH:D003456', (39, 68))	('associations', 'Interaction', (85, 97))
19591	21975279	Chlordane consists of > 140 isomers; the most abundant include trans-chlordane, cis-chlordane, trans-nonachlor, beta-chlordane, and heptachlor.	('cis-chlordane', 'Var', (80, 93))	('trans-nonachlor', 'Var', (95, 110))	('trans-chlordane', 'Chemical', '-', (63, 78))	('beta-chlordane', 'Var', (112, 126))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (95, 110))	('Chlordane', 'Chemical', 'MESH:D002706', (0, 9))	('heptachlor', 'Chemical', 'MESH:D006533', (132, 142))	('trans-chlordane', 'Var', (63, 78))	('cis-chlordane', 'Chemical', '-', (80, 93))	('beta-chlordane', 'Chemical', '-', (112, 126))
19597	21975279	Given the associations between chlordane isomers and TGCT, it is reasonable to assume that chlordane levels might also be associated with other testicular dysgenesis syndrome disorders, namely cryptorchidism (failure of one or both testicles to descend into the scrotum) and hypospadias (urethral opening on the ventral side of the penis or on the perineum).	('associated', 'Reg', (122, 132))	('penis', 'Disease', (332, 337))	('hypospadias', 'Disease', 'MESH:D007021', (275, 286))	('chlordane', 'Chemical', 'MESH:D002706', (91, 100))	('hypospadias', 'Disease', (275, 286))	('chlordane', 'Var', (91, 100))	('testicular dysgenesis syndrome disorders', 'Disease', 'MESH:D013733', (144, 184))	('chlordane', 'Chemical', 'MESH:D002706', (31, 40))	('cryptorchidism', 'Phenotype', 'HP:0000028', (193, 207))	('testicular dysgenesis syndrome disorders', 'Disease', (144, 184))	('cryptorchidism', 'Disease', (193, 207))	('penis', 'Disease', 'MESH:D010409', (332, 337))	('TGCT', 'Gene', (53, 57))	('one or both testicles', 'Phenotype', 'HP:0010470', (220, 241))	('hypospadias', 'Phenotype', 'HP:0000047', (275, 286))	('urethral opening', 'Disease', 'MESH:D014526', (288, 304))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (144, 165))	('urethral opening', 'Disease', (288, 304))
19636	21975279	A total of 971 (217 cryptorchid, 197 hypospadias, 557 controls) subjects were included in the analysis of trans-nonachlor, and a total of 919 (206 cryptorchid, 181 hypospadias, 532 controls) were included in the analysis of oxychlordane.	('hypospadias', 'Disease', (164, 175))	('hypospadias', 'Phenotype', 'HP:0000047', (37, 48))	('trans-nonachlor', 'Var', (106, 121))	('hypospadias', 'Phenotype', 'HP:0000047', (164, 175))	('oxychlordane', 'Chemical', 'MESH:C008743', (224, 236))	('hypospadias', 'Disease', 'MESH:D007021', (37, 48))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (106, 121))	('hypospadias', 'Disease', 'MESH:D007021', (164, 175))	('hypospadias', 'Disease', (37, 48))
19644	21975279	If, on deletion, the OR for the contrast of the highest-to-lowest chlordane strata or the OR from the trend test changed by >= 15%, the factor was considered a confounder and was included in the adjusted analyses.	('chlordane', 'Chemical', 'MESH:D002706', (66, 75))	('deletion', 'Var', (7, 15))	('changed', 'Reg', (113, 120))
19652	21975279	All of the exposures evaluated were positively correlated, with the strongest correlation between trans-nonachlor and oxychlordane (r = 0.78), as expected.	('correlation', 'Interaction', (78, 89))	('trans-nonachlor', 'Var', (98, 113))	('oxychlordane', 'MPA', (118, 130))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (98, 113))	('oxychlordane', 'Chemical', 'MESH:C008743', (118, 130))
19653	21975279	trans-Nonachlor was moderately associated with DDE (r = 0.52), while the remaining compounds were less correlated (r = 0.08-0.46).	('DDE', 'Disease', (47, 50))	('DDE', 'Chemical', 'MESH:D003633', (47, 50))	('trans-Nonachlor', 'Chemical', 'MESH:C001870', (0, 15))	('trans-Nonachlor', 'Var', (0, 15))	('associated', 'Interaction', (31, 41))
19670	21975279	Maternal milk levels of trans-chlordane were slightly higher in mothers of cryptorchid boys than mothers of healthy boys; however, the overall exposure was very low (0.04 ng/g lipid in controls).	('boys', 'Species', '9606', (87, 91))	('higher', 'PosReg', (54, 60))	('trans-chlordane', 'Chemical', '-', (24, 39))	('lipid', 'Chemical', 'MESH:D008055', (176, 181))	('boys', 'Species', '9606', (116, 120))	('cryptorchid', 'Var', (75, 86))	('cryptorchid boys', 'Phenotype', 'HP:0000028', (75, 91))
19674	21975279	We did not evaluate trans- or cis-chlordane; however, we report no association between trans-nonachlor, another chlordane derivative, and cryptorchidism.	('chlordane', 'Chemical', 'MESH:D002706', (112, 121))	('cryptorchidism', 'Disease', (138, 152))	('chlordane', 'Chemical', 'MESH:D002706', (34, 43))	('trans- or cis-chlordane', 'Chemical', '-', (20, 43))	('cryptorchidism', 'Phenotype', 'HP:0000028', (138, 152))	('trans-nonachlor', 'Var', (87, 102))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (87, 102))
19676	21975279	However, chlordane exposures has been shown to affect reproduction in test animals, delaying puberty, disrupting estrous cycling in females, and reducing fertility by as much as 50%.	('reducing fertility', 'Phenotype', 'HP:0000144', (145, 163))	('disrupting', 'NegReg', (102, 112))	('chlordane exposures', 'Var', (9, 28))	('reproduction', 'CPA', (54, 66))	('exposures', 'Var', (19, 28))	('fertility', 'CPA', (154, 163))	('delaying puberty', 'Phenotype', 'HP:0000823', (84, 100))	('affect', 'Reg', (47, 53))	('estrous cycling', 'CPA', (113, 128))	('reducing', 'NegReg', (145, 153))	('puberty', 'CPA', (93, 100))	('chlordane', 'Chemical', 'MESH:D002706', (9, 18))	('delaying', 'NegReg', (84, 92))
19677	21975279	Furthermore, chlordane is classified as potentially carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC 2001) and has been associated with risk of TGCT.	('Cancer', 'Disease', (130, 136))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('chlordane', 'Chemical', 'MESH:D002706', (13, 22))	('chlordane', 'Var', (13, 22))	('associated', 'Reg', (162, 172))	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('TGCT', 'Disease', (186, 190))	('carcinogenic', 'Disease', (52, 64))	('humans', 'Species', '9606', (68, 74))
19713	27279862	For research reasons and for the benefit of future studies on UDT, as well as to allow the possibility to compare results of treatment studies, more precise classification of testis maldescent regarding testis position is suggested:  A brief review of testis formation is essential to understand how disorders of this process could lead to seemingly diverse abnormalities, such as cryptorchidism, abnormal spermatogenesis, tumors of the testis or male excurrent duct system, or aplasia of male genitalia.	('tumors of the testis', 'Disease', 'MESH:D013736', (423, 443))	('tumors of the testis', 'Phenotype', 'HP:0010788', (423, 443))	('UDT', 'Phenotype', 'HP:0000028', (62, 65))	('aplasia of male genitalia', 'Phenotype', 'HP:0000050', (478, 503))	('disorders', 'Var', (300, 309))	('lead to', 'Reg', (332, 339))	('abnormal spermatogenesis', 'CPA', (397, 421))	('abnormal spermatogenesis', 'Phenotype', 'HP:0008669', (397, 421))	('tumors', 'Phenotype', 'HP:0002664', (423, 429))	('cryptorchidism', 'Phenotype', 'HP:0000028', (381, 395))	('aplasia of male genitalia', 'Disease', (478, 503))	('aplasia of male genitalia', 'Disease', 'MESH:D012734', (478, 503))	('men', 'Species', '9606', (130, 133))	('tumors of the testis', 'Disease', (423, 443))	('cryptorchidism', 'Disease', (381, 395))
19715	27279862	SRY is an intronless sex-determining gene on the Y chromosome in the therians (placental mammals and marsupials), and mutations in this gene lead to a range of sex-related disorders with varying effects on an individual's phenotype, e.g.	('SRY', 'Gene', '6736', (0, 3))	('marsupials', 'Species', '9263', (101, 111))	('SRY', 'Gene', (0, 3))	('mutations', 'Var', (118, 127))	('sex-related disorders', 'Disease', (160, 181))	('lead to', 'Reg', (141, 148))	('placental mammals', 'Species', '9347', (79, 96))
19723	27279862	However, in cryptorchid boys mutations of the INSL3 gene are uncommon, probably because in the trans-abdominal phase the testis stays attached by the gubernacula to the inguinal region and its descent is rather feigned.	('boys', 'Species', '9606', (24, 28))	('cryptorchid boys', 'Phenotype', 'HP:0000028', (12, 28))	('mutations', 'Var', (29, 38))	('INSL3', 'Gene', (46, 51))
19725	27279862	In the persistent Mullerian duct syndrome, which is caused by genetic abnormality of AMH or its receptor, the testes are very mobile and may be located in an ovarian position, in an inguinal hernia together with a Fallopian tube and the uterus.	('inguinal hernia', 'Disease', 'MESH:D006552', (182, 197))	('inguinal hernia', 'Phenotype', 'HP:0000023', (182, 197))	('ovarian position', 'Disease', (158, 174))	('AMH', 'Gene', (85, 88))	('ovarian position', 'Disease', 'MESH:D010051', (158, 174))	('Mullerian duct syndrome', 'Disease', (18, 41))	('AMH', 'Gene', '268', (85, 88))	('hernia', 'Phenotype', 'HP:0100790', (191, 197))	('caused by', 'Reg', (52, 61))	('Mullerian duct syndrome', 'Disease', 'MESH:C537371', (18, 41))	('genetic abnormality', 'Var', (62, 81))	('inguinal hernia', 'Disease', (182, 197))
19736	27279862	Risk factors of UDT:  The environmental factors such as persistent organochlorine compounds, mono-esters of the phthalates, maternal smoking and maternal diabetes mellitus also increase the risk of cryptorchidism.	('maternal diabetes mellitus', 'Disease', 'MESH:D003920', (145, 171))	('cryptorchidism', 'Phenotype', 'HP:0000028', (198, 212))	('mono-esters', 'Chemical', '-', (93, 104))	('cryptorchidism', 'Disease', (198, 212))	('increase', 'PosReg', (177, 185))	('maternal diabetes mellitus', 'Disease', (145, 171))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (154, 171))	('organochlorine compounds', 'Chemical', 'MESH:D006843', (67, 91))	('men', 'Species', '9606', (33, 36))	('mono-esters', 'Var', (93, 104))	('UDT', 'Phenotype', 'HP:0000028', (16, 19))	('maternal diabetes', 'Phenotype', 'HP:0009800', (145, 162))
19738	27279862	anomalies of the testis, epididymis and vas deferens, improper attachment of the gubernaculum, patent processus vaginalis and inguinal hernia (hernias are found in 90% of UDT), anomalies of the inguinal canal.	('inguinal hernia', 'Phenotype', 'HP:0000023', (126, 141))	('hernias', 'Disease', (143, 150))	('hernias', 'Phenotype', 'HP:0100790', (143, 150))	('men', 'Species', '9606', (69, 72))	('inguinal hernia', 'Disease', (126, 141))	('hernias', 'Disease', 'MESH:D006547', (143, 150))	('inguinal hernia', 'Disease', 'MESH:D006552', (126, 141))	('UDT', 'Phenotype', 'HP:0000028', (171, 174))	('hernia', 'Phenotype', 'HP:0100790', (143, 149))	('improper', 'Var', (54, 62))	('hernia', 'Phenotype', 'HP:0100790', (135, 141))	('anomalies of the testis', 'Phenotype', 'HP:0000035', (0, 23))	('anomalies of the testis, epididymis', 'Disease', 'MESH:D013736', (0, 35))
19739	27279862	anatomical:  deficient GnRH (gonadotropin releasing hormone) and/or gonadotropin production or insensitivity of GnRH or LH receptors, deficient androgen production or insensitivity of androgen receptor, deficient AMH production or insensitivity of AMH receptor, deficient INSL3 production or insensitivity of INSL3 receptor, deficient CGRP production (disorder of genito-femoral nerves) or insensitivity of CGRP receptor.	('GnRH', 'Gene', (23, 27))	('GnRH', 'Gene', '2796', (112, 116))	('deficient', 'Var', (134, 143))	('androgen', 'CPA', (144, 152))	('INSL3', 'Protein', (272, 277))	('AMH', 'Gene', (213, 216))	('CGRP', 'Gene', '796', (407, 411))	('GnRH (gonadotropin releasing hormone', 'Gene', '2796', (23, 59))	('AMH', 'Gene', '268', (248, 251))	('GnRH', 'Gene', '2796', (23, 27))	('CGRP', 'Gene', '796', (335, 339))	('CGRP', 'Gene', (407, 411))	('deficient androgen', 'Phenotype', 'HP:0008226', (134, 152))	('deficient', 'Var', (13, 22))	('deficient', 'Var', (203, 212))	('CGRP', 'Gene', (335, 339))	('AMH', 'Gene', '268', (213, 216))	('insensitivity', 'MPA', (390, 403))	('deficient', 'NegReg', (262, 271))	('GnRH', 'Gene', (112, 116))	('deficient', 'NegReg', (325, 334))	('insensitivity', 'NegReg', (292, 305))	('androgen receptor', 'Gene', (184, 201))	('INSL3 receptor', 'Protein', (309, 323))	('androgen receptor', 'Gene', '367', (184, 201))	('AMH', 'Gene', (248, 251))
19740	27279862	hormonal:  androgen receptor gene mutations (chromosome X), i.e.	('mutations', 'Var', (34, 43))	('androgen receptor', 'Gene', '367', (11, 28))	('androgen receptor', 'Gene', (11, 28))
19762	27279862	One hypothesis is that abnormally high temperature in which UDT develops impairs both transformation of the neonatal gonocytes into the Ad spermatogonia and apoptosis of remaining gonocytes, allowing some to persist to become a possible source of CIS and malignancy after puberty.	('UDT', 'Phenotype', 'HP:0000028', (60, 63))	('apoptosis', 'CPA', (157, 166))	('transformation', 'CPA', (86, 100))	('malignancy', 'Disease', 'MESH:D009369', (255, 265))	('malignancy', 'Disease', (255, 265))	('impairs', 'NegReg', (73, 80))	('abnormally', 'Var', (23, 33))
19778	27279862	Cryptorchidism and testicular dysgenesis or presence of streak gonads may also be seen in chromosome 9p deletion, campomelic dysplasia (SOX9 mutation) and mutations in the WT-1 or SRY gene.	('dysplasia', 'Disease', (125, 134))	('mutations', 'Var', (155, 164))	('SOX9', 'Gene', '6662', (136, 140))	('dysplasia', 'Disease', 'MESH:D004476', (125, 134))	('Cryptorchidism and testicular dysgenesis', 'Disease', 'MESH:D003456', (0, 40))	('SRY', 'Gene', '6736', (180, 183))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (19, 40))	('WT-1', 'Gene', (172, 176))	('SRY', 'Gene', (180, 183))	('Cryptorchidism', 'Phenotype', 'HP:0000028', (0, 14))	('WT-1', 'Gene', '7490', (172, 176))	('SOX9', 'Gene', (136, 140))
19909	29311615	HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans.	('inhibit', 'NegReg', (79, 86))	('hTERT', 'Gene', '7015', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('promotes', 'PosReg', (171, 179))	('miR-615', 'Gene', (10, 17))	('hTERT', 'Gene', (69, 74))	('repression', 'Var', (105, 115))	('tumor', 'Disease', (87, 92))	('telomerase', 'Gene', (119, 129))	('humans', 'Species', '9606', (290, 296))	('replicative aging', 'CPA', (180, 197))	('HoxC5', 'Gene', '3222', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('miR-615', 'Gene', '693200', (10, 17))	('HoxC5', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
19910	29311615	Here we describe how miR-615-3p represses hTERT expression.	('miR-615-3p', 'Var', (21, 31))	('represses', 'NegReg', (32, 41))	('hTERT', 'Gene', (42, 47))	('hTERT', 'Gene', '7015', (42, 47))
19913	29311615	Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation.	('hTERT', 'Gene', (171, 176))	('hTERT', 'Gene', '7015', (171, 176))	('mir-615-3p', 'Var', (5, 15))
19914	29311615	Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.	('Deregulation', 'Var', (0, 12))	('human', 'Species', '9606', (93, 98))	('hTERT', 'Gene', '7015', (84, 89))	('mir-615-3p', 'Var', (26, 36))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('hTERT', 'Gene', (84, 89))	('activation', 'PosReg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
19916	29311615	Here, the authors show HoxC5 and miR-615-3p can negatively regulate hTERT to impede tumorigenesis by targeting the newly evolved cis-regulatory genomic elements of hTERT.	('negatively', 'NegReg', (48, 58))	('hTERT', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('hTERT', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-615-3p', 'Var', (33, 43))	('impede', 'NegReg', (77, 83))	('tumor', 'Disease', (84, 89))	('hTERT', 'Gene', '7015', (68, 73))	('hTERT', 'Gene', '7015', (164, 169))
19923	29311615	Genetic mutations in telomere- and telomerase-associated genes can lead to various diseases, termed telomere syndromes or telomeropathies, which are characterized by accelerated telomere shortening, premature aging and increase risk for cancer.	('telomeropathies', 'Disease', (122, 137))	('accelerated', 'PosReg', (166, 177))	('lead to', 'Reg', (67, 74))	('telomeropathies', 'Disease', 'None', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('telomere shortening', 'Phenotype', 'HP:0031413', (178, 197))	('telomere syndromes', 'Disease', (100, 118))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('telomere-', 'Gene', (21, 30))	('rat', 'Species', '10116', (172, 175))	('Genetic mutations', 'Var', (0, 17))	('cancer', 'Disease', (237, 243))
19932	29311615	Recent studies have shown that mutations in hTERT promoter are the most frequent non-coding mutations in specific subsets of human cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('human', 'Species', '9606', (125, 130))	('hTERT', 'Gene', '7015', (44, 49))	('hTERT', 'Gene', (44, 49))
19933	29311615	These mutations not only increase hTERT mRNA expression in cancer cells, but also abolish hTERT silencing during stem cells differentiation.	('hTERT', 'Gene', (34, 39))	('hTERT', 'Gene', '7015', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('hTERT', 'Gene', (90, 95))	('increase', 'PosReg', (25, 33))	('hTERT', 'Gene', '7015', (34, 39))	('abolish', 'NegReg', (82, 89))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (6, 15))
19935	29311615	Here we have identified roles for HoxC5 and miR-615-3p in the negative regulation of hTERT in cancer cells and during differentiation of pluripotent stem cells.	('hTERT', 'Gene', (85, 90))	('negative', 'NegReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hTERT', 'Gene', '7015', (85, 90))	('miR-615-3p', 'Var', (44, 54))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
19936	29311615	Our data suggest that HoxC5 and miR-615-3p repress hTERT via an upstream enhancer region and 3'UTR, respectively.	('hTERT', 'Gene', '7015', (51, 56))	('hTERT', 'Gene', (51, 56))	('miR-615-3p', 'Var', (32, 42))	('repress', 'NegReg', (43, 50))	('TR', 'Gene', '7012', (96, 98))
19939	29311615	In addition, overexpression of HOXC5 and miR-615-3p in human cancer cells significantly inhibits hTERT expression and suppresses cancer cell growth both in vitro and in vivo.	('suppresses', 'NegReg', (118, 128))	('miR-615-3p', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('hTERT', 'Gene', '7015', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('hTERT', 'Gene', (97, 102))	('overexpression', 'PosReg', (13, 27))	('inhibits', 'NegReg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
19958	29311615	In addition, two of the miRNA hairpin inhibitors, targeting miR-483-3p and miR-615-3p, also dramatically increased endogenous hTERT mRNA levels and telomerase activity in HeLa cells (Fig.	('hTERT', 'Gene', (126, 131))	('miR-483-3p', 'Var', (60, 70))	('telomerase activity', 'MPA', (148, 167))	('HeLa', 'CellLine', 'CVCL:0030', (171, 175))	('miR-615-3p', 'Var', (75, 85))	('increased', 'PosReg', (105, 114))	('hTERT', 'Gene', '7015', (126, 131))
19964	29311615	We then mutated the predicted seed region (M1) as well as both seed region and an additional conserved site (M2) in the psiCHECK2-5' + 3'UTR (hTERT) reporter construct (Fig.	('mutated', 'Var', (8, 15))	('hTERT', 'Gene', (142, 147))	('hTERT', 'Gene', '7015', (142, 147))	('TR', 'Gene', '7012', (138, 140))
19966	29311615	Elimination of both the miRNA binding seed sequence and the additional conserved site (psiCHECK2-5' + 3'UTR-M2) further increased the Renilla/Firefly luciferase luminescence ratio (Fig.	('Renilla/Firefly luciferase luminescence ratio', 'MPA', (134, 179))	('Elimination', 'Var', (0, 11))	('rat', 'Species', '10116', (174, 177))	('TR', 'Gene', '7012', (105, 107))	('increased', 'PosReg', (120, 129))
19967	29311615	Consistent with these results, overexpression of miR-615-3p further decreased Renilla/Firefly luciferase luminescence ratio in HeLa cells transfected with psiCHECK2-5' + 3'UTR, but not psiCHECK2-5' + 3'UTR-M2 (Supplementary Fig.	('decreased', 'NegReg', (68, 77))	('Renilla/Firefly luciferase luminescence ratio', 'MPA', (78, 123))	('rat', 'Species', '10116', (118, 121))	('miR-615-3p', 'Var', (49, 59))	('TR', 'Gene', '7012', (173, 175))	('HeLa', 'CellLine', 'CVCL:0030', (127, 131))	('TR', 'Gene', '7012', (203, 205))	('overexpression', 'PosReg', (31, 45))
19968	29311615	These results suggest that miR-615-3p negatively regulates hTERT by targeting this region within the 3'UTR.	('miR-615-3p', 'Var', (27, 37))	('TR', 'Gene', '7012', (104, 106))	('hTERT', 'Gene', (59, 64))	('hTERT', 'Gene', '7015', (59, 64))	('regulates', 'Reg', (49, 58))	('negatively', 'NegReg', (38, 48))
19969	29311615	To further investigate the function of miR615-3p in regulating endogenous hTERT expression, we compared the expression profile of hTERT mRNA and miR-615-3p in NCI-60 cell lines.	('NCI-60', 'CellLine', 'CVCL:A592', (159, 165))	('miR-615-3p', 'Var', (145, 155))	('hTERT', 'Gene', '7015', (74, 79))	('miR615', 'Gene', '693200', (39, 45))	('hTERT', 'Gene', '7015', (130, 135))	('hTERT', 'Gene', (74, 79))	('hTERT', 'Gene', (130, 135))	('miR615', 'Gene', (39, 45))
19971	29311615	Further, transient transfection of the miR-615-3p hairpin inhibitor into these two cell lines led to a significant increase in hTERT mRNA expression and a corresponding increase in telomerase activity (Fig.	('hTERT', 'Gene', (127, 132))	('increase', 'PosReg', (115, 123))	('increase', 'PosReg', (169, 177))	('miR-615-3p', 'Var', (39, 49))	('hTERT', 'Gene', '7015', (127, 132))	('telomerase activity', 'MPA', (181, 200))
19973	29311615	We observed a significant reduction of hTERT mRNA levels and telomerase activity when miR-615-3p was overexpressed in these cell lines (Fig.	('miR-615-3p', 'Var', (86, 96))	('hTERT', 'Gene', '7015', (39, 44))	('activity', 'MPA', (72, 80))	('telomerase', 'Enzyme', (61, 71))	('overexpressed', 'PosReg', (101, 114))	('reduction', 'NegReg', (26, 35))	('hTERT', 'Gene', (39, 44))
19974	29311615	Thus, miR-615-3p represses endogenous hTERT expression in various cancer cell lines.	('expression', 'MPA', (44, 54))	('miR-615-3p', 'Var', (6, 16))	('represses', 'NegReg', (17, 26))	('endogenous', 'MPA', (27, 37))	('hTERT', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('hTERT', 'Gene', '7015', (38, 43))	('cancer', 'Disease', (66, 72))
19975	29311615	To further confirm the function of miR-615-3p in the regulation of hTERT expression, we utilized the CRISPR/Cas9 system to introduce small deletion in the region of the mir-615 hairpin that is crucial for its maturation.	('deletion', 'Var', (139, 147))	('mir-615', 'Gene', (169, 176))	('hTERT', 'Gene', '7015', (67, 72))	('rat', 'Species', '10116', (213, 216))	('hTERT', 'Gene', (67, 72))
19980	29311615	We also observed an increase in telomere length in RKO-KO-1 and RKO-KO-2 compared to parental RKO cells (Fig.	('telomere', 'MPA', (32, 40))	('RKO-KO-2', 'Var', (64, 72))	('RKO', 'CellLine', 'CVCL:0504', (64, 67))	('RKO', 'CellLine', 'CVCL:0504', (51, 54))	('RKO-KO-1', 'Var', (51, 59))	('RKO', 'CellLine', 'CVCL:0504', (94, 97))	('increase', 'PosReg', (20, 28))
19981	29311615	We further utilized the CRISPR/Cas9 system to introduce small deletions or mutations into the endogenous hTERT 3'UTR.	('TR', 'Gene', '7012', (114, 116))	('hTERT', 'Gene', (105, 110))	('mutations', 'Var', (75, 84))	('hTERT', 'Gene', '7015', (105, 110))
19982	29311615	5a and 5b, clonal-derived RKO cells harboring biallelic deletions or mutations in the miR-615-3p-binding site displayed increased hTERT mRNA levels, but not in the cells harboring deletions outside the miR-615-3p-binding site.	('mutations', 'Var', (69, 78))	('RKO', 'CellLine', 'CVCL:0504', (26, 29))	('biallelic', 'Var', (46, 55))	('hTERT', 'Gene', '7015', (130, 135))	('increased', 'PosReg', (120, 129))	('miR-615-3p-binding', 'Gene', (86, 104))	('hTERT', 'Gene', (130, 135))
19983	29311615	Taken together, these data suggest that miR-615-3p suppresses endogenous hTERT expression by targeting the 3'UTR of hTERT.	('hTERT', 'Gene', (116, 121))	('hTERT', 'Gene', '7015', (73, 78))	('TR', 'Gene', '7012', (110, 112))	('miR-615-3p', 'Var', (40, 50))	('hTERT', 'Gene', (73, 78))	('hTERT', 'Gene', '7015', (116, 121))	('suppresses', 'NegReg', (51, 61))	('targeting', 'Reg', (93, 102))
19988	29311615	Together, our data suggest that miR-615-3p and HoxC5 form a feed-forward loop to negatively regulate hTERT mRNA expression, telomerase activity and telomere elongation.	('telomerase', 'Enzyme', (124, 134))	('hTERT', 'Gene', '7015', (101, 106))	('regulate', 'Reg', (92, 100))	('activity', 'MPA', (135, 143))	('telomere elongation', 'CPA', (148, 167))	('miR-615-3p', 'Var', (32, 42))	('hTERT', 'Gene', (101, 106))	('negatively', 'NegReg', (81, 91))
19999	29311615	To investigate whether these motifs are required for HoxC5-mediated repression of hTERT, we engineered HoxC5 mutants with disruptions of either the HX or HD motifs (Fig.	('HD', 'Disease', 'MESH:D006816', (154, 156))	('disruptions', 'Var', (122, 133))	('hTERT', 'Gene', '7015', (82, 87))	('mutants', 'Var', (109, 116))	('hTERT', 'Gene', (82, 87))	('HoxC5', 'Gene', (103, 108))
20000	29311615	We found that mutation of the HD domain, but not the HX domain, abrogated HoxC5-mediated repression of hTERT and telomerase activity in both HeLa cells (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (141, 145))	('HoxC5-mediated repression', 'MPA', (74, 99))	('activity', 'MPA', (124, 132))	('hTERT', 'Gene', (103, 108))	('HD', 'Disease', 'MESH:D006816', (30, 32))	('telomerase', 'Enzyme', (113, 123))	('mutation', 'Var', (14, 22))	('abrogated', 'NegReg', (64, 73))	('hTERT', 'Gene', '7015', (103, 108))
20001	29311615	The mutations in the HX or HD motifs did not affect the expression of HoxC5 in HeLa (Fig.	('mutations', 'Var', (4, 13))	('expression', 'MPA', (56, 66))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('HD', 'Disease', 'MESH:D006816', (27, 29))
20006	29311615	Consistent with these results, immunoprecipitation of Flag-tagged Pbx4, but not of Flag-tagged Pbx1, 2 or 3, resulted in efficient co-immunoprecipitation of V5-tagged HoxC5 (Supplementary Fig.	('Pbx4', 'Gene', (66, 70))	('Pbx4', 'Gene', '80714', (66, 70))	('Pbx1, 2 or 3', 'Gene', '5087;5089;5090', (95, 107))	('co-immunoprecipitation', 'MPA', (131, 153))	('V5-tagged HoxC5', 'MPA', (157, 172))	('Flag-tagged', 'Var', (54, 65))
20008	29311615	We found that immunoprecipitation of Flag-tagged HoxC5 resulted in specific co-immunoprecipitation of V5-tagged Meis3, but not Meis1 and 2 (Fig.	('V5-tagged', 'Var', (102, 111))	('Meis3', 'Gene', '56917', (112, 117))	('co-immunoprecipitation', 'MPA', (76, 98))	('Meis1 and 2', 'Gene', '150365', (127, 138))	('Meis3', 'Gene', (112, 117))
20009	29311615	Consistent with these data, immunoprecipitation of V5-tagged Meis3, but not V5-tagged Meis1 and 2, resulted in efficient co-immunoprecipitation of Flag-tagged HoxC5 (Supplementary Fig.	('co-immunoprecipitation', 'MPA', (121, 143))	('Meis3', 'Gene', '56917', (61, 66))	('V5-tagged', 'Var', (51, 60))	('Meis3', 'Gene', (61, 66))	('Flag-tagged HoxC5', 'MPA', (147, 164))	('Meis1 and 2', 'Gene', '150365', (86, 97))
20018	29311615	To probe the interaction of HoxC5 and Pbx4 with class I HDACs, we transiently co-expressed V5-tagged HOXC5 or V5-tagged PBX4 with Flag-tagged HDAC1, HDAC2 or HDAC3 in HeLa cells (Supplementary Fig.	('HDAC3', 'Gene', (158, 163))	('HDAC3', 'Gene', '8841', (158, 163))	('HDAC1', 'Gene', '3065', (142, 147))	('HD', 'Disease', 'MESH:D006816', (149, 151))	('Pbx4', 'Gene', '80714', (38, 42))	('V5-tagged', 'Var', (91, 100))	('HD', 'Disease', 'MESH:D006816', (142, 144))	('PBX4', 'Gene', '80714', (120, 124))	('PBX4', 'Gene', (120, 124))	('HeLa', 'CellLine', 'CVCL:0030', (167, 171))	('HD', 'Disease', 'MESH:D006816', (158, 160))	('HDAC1', 'Gene', (142, 147))	('HD', 'Disease', 'MESH:D006816', (56, 58))	('HDAC2', 'Gene', (149, 154))	('HDAC2', 'Gene', '3066', (149, 154))	('Pbx4', 'Gene', (38, 42))
20027	29311615	This region is marked by H3K27ac and H3K4me1 in human ES cells and PC-3 cells, indicative of an active enhancer region, which is consistent with permissive expression of hTERT in these cell types.	('ES', 'Chemical', '-', (54, 56))	('H3K27ac', 'Var', (25, 32))	('human', 'Species', '9606', (48, 53))	('hTERT', 'Gene', '7015', (170, 175))	('hTERT', 'Gene', (170, 175))	('H3K4me1', 'Var', (37, 44))
20028	29311615	In contrast, IMR90 cells show depletion of H3K27ac at this region, and enrichment of H3K27me3 spanning the hTERT genomic locus, consistent with the silencing of hTERT in primary fibroblasts.	('hTERT', 'Gene', '7015', (107, 112))	('IMR90', 'CellLine', 'CVCL:0347', (13, 18))	('H3K27ac', 'Protein', (43, 50))	('hTERT', 'Gene', (107, 112))	('H3K27me3', 'Var', (85, 93))	('depletion', 'MPA', (30, 39))	('hTERT', 'Gene', '7015', (161, 166))	('hTERT', 'Gene', (161, 166))
20031	29311615	In addition, overexpression of HoxC5 in PC-3 and A375 cells resulted in a corresponding depletion of RNA Pol II as well as histone marks associated with active gene transcription such as H3K4me1 and H3K27ac (Fig.	('H3K27ac', 'Var', (199, 206))	('A375', 'CellLine', 'CVCL:0132', (49, 53))	('depletion', 'MPA', (88, 97))	('H3K4me1', 'Var', (187, 194))	('overexpression', 'PosReg', (13, 27))	('histone marks', 'MPA', (123, 136))	('RNA Pol', 'Protein', (101, 108))
20036	29311615	6e) as well as depletion of RNA Pol II, H3K4me1 and H3K27ac at hTERT promoter and enhancer, but not at hTERT -10 kb region (Supplementary Fig.	('hTERT', 'Gene', (63, 68))	('depletion', 'MPA', (15, 24))	('hTERT', 'Gene', (103, 108))	('H3K27ac', 'Var', (52, 59))	('H3K4me1', 'Var', (40, 47))	('RNA Pol', 'Protein', (28, 35))	('hTERT', 'Gene', '7015', (63, 68))	('hTERT', 'Gene', '7015', (103, 108))
20037	29311615	The depletion of RNA Pol II, H3K4me1, and H3K27ac from hTERT promoter is likely due to the disruption of long-range interaction between hTERT promoter and the upstream enhancer by HoxC5, leading to the suppression of hTERT expression.	('hTERT', 'Gene', '7015', (55, 60))	('hTERT', 'Gene', (136, 141))	('H3K27ac', 'Var', (42, 49))	('hTERT', 'Gene', (217, 222))	('disruption', 'NegReg', (91, 101))	('hTERT', 'Gene', (55, 60))	('hTERT', 'Gene', '7015', (217, 222))	('long-range interaction', 'Interaction', (105, 127))	('depletion', 'MPA', (4, 13))	('hTERT', 'Gene', '7015', (136, 141))	('suppression', 'NegReg', (202, 213))
20046	29311615	In addition, telomerase is often aberrantly activated in cancer, and inhibition of hTERT expression suppresses cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('telomerase', 'Protein', (13, 23))	('cancer', 'Disease', (57, 63))	('hTERT', 'Gene', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('activated', 'PosReg', (44, 53))	('rat', 'Species', '10116', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('suppresses', 'NegReg', (100, 110))	('cancer', 'Disease', (111, 117))	('inhibition', 'Var', (69, 79))	('hTERT', 'Gene', '7015', (83, 88))
20047	29311615	To study the potential role of miR-615-3p and HoxC5 in cancer cell proliferation, we transduced PC-3 cells with lentivirus expressing GFP, HOXC5, or mir-615-3p alone, or HOXC5 and mir-615-3p in combination.	('mir-615-3p', 'Var', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rat', 'Species', '10116', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
20048	29311615	Consistent with our previous results, real-time RT-PCR revealed that overexpression of mir-615-3p alone moderately reduced hTERT mRNA levels, overexpression of HOXC5 alone resulted in >50% reduction in hTERT mRNA levels, and co-expression of HOXC5 and mir-615-3p resulted in further repression of hTERT mRNA levels (Supplementary Fig.	('hTERT', 'Gene', '7015', (202, 207))	('rat', 'Species', '10116', (108, 111))	('mir-615-3p', 'Var', (87, 97))	('repression', 'NegReg', (283, 293))	('hTERT', 'Gene', (123, 128))	('hTERT', 'Gene', (202, 207))	('reduced', 'NegReg', (115, 122))	('mir-615-3p', 'Var', (252, 262))	('hTERT', 'Gene', '7015', (297, 302))	('hTERT', 'Gene', '7015', (123, 128))	('reduction', 'NegReg', (189, 198))	('hTERT', 'Gene', (297, 302))
20050	29311615	We established xenograft models to further validate the effects of miR-615-3p and HoxC5 on cancer cell growth in vivo.	('miR-615-3p', 'Var', (67, 77))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
20051	29311615	We injected PC-3 cells expressing GFP, HOXC5, or mir-615-3p alone, or co-expressing HOXC5 and mir-615-3p, subcutaneously into immunocompromised NSG mice and followed the tumor growth for 5 weeks (Fig.	('mir-615-3p', 'Var', (49, 59))	('mir-615-3p', 'Var', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mice', 'Species', '10090', (148, 152))
20055	29311615	Although hTERT promoter mutations and genomic rearrangements have been shown to activate telomerase expression in a subset of human cancers, alternative mechanisms remain to be explored to understand the activation of telomerase in a vast majority of human cancers without known hTERT promoter mutations or genomic rearrangements.	('cancers', 'Disease', (132, 139))	('human', 'Species', '9606', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('hTERT', 'Gene', '7015', (279, 284))	('hTERT', 'Gene', '7015', (9, 14))	('telomerase', 'Protein', (89, 99))	('human', 'Species', '9606', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('hTERT', 'Gene', (279, 284))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (100, 110))	('hTERT', 'Gene', (9, 14))	('activate', 'PosReg', (80, 88))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('mutations', 'Var', (24, 33))	('cancers', 'Disease', (257, 264))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
20057	29311615	Failure to suppress the expression of hTERT during cellular differentiation in these tissues due to genetic alterations may be hijacked by cancer cells to activate telomerase.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('alterations', 'Var', (108, 119))	('hTERT', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('activate', 'PosReg', (155, 163))	('rat', 'Species', '10116', (112, 115))	('telomerase', 'Enzyme', (164, 174))	('hTERT', 'Gene', '7015', (38, 43))	('cancer', 'Disease', (139, 145))
20068	29311615	However, we did not observe significant negative correlation between the expression of miR-615-3p and hTERT (Fig.	('miR-615-3p', 'Var', (87, 97))	('hTERT', 'Gene', (102, 107))	('hTERT', 'Gene', '7015', (102, 107))
20069	29311615	These results suggest that miR-615-3p only plays a fine-tuning role in modulation of hTERT expression, while HoxC5 plays the key role in hTERT suppression.	('miR-615-3p', 'Var', (27, 37))	('hTERT', 'Gene', (85, 90))	('hTERT', 'Gene', (137, 142))	('hTERT', 'Gene', '7015', (85, 90))	('hTERT', 'Gene', '7015', (137, 142))	('modulation', 'MPA', (71, 81))
20073	29311615	Here we show that the induction of HOXC5 and miR-615-3p during stem cell differentiation represses hTERT via transcriptional and post-transcriptional pathways, respectively.	('hTERT', 'Gene', (99, 104))	('miR-615-3p', 'Var', (45, 55))	('hTERT', 'Gene', '7015', (99, 104))	('transcriptional', 'Pathway', (109, 124))	('post-transcriptional pathways', 'Pathway', (129, 158))	('represses', 'NegReg', (89, 98))
20078	29311615	Our data indicated that miR-615-3p negatively regulates hTERT expression by targeting hTERT 3'UTR.	('miR-615-3p', 'Var', (24, 34))	('hTERT', 'Gene', '7015', (86, 91))	('hTERT', 'Gene', '7015', (56, 61))	('negatively', 'NegReg', (35, 45))	('hTERT', 'Gene', (86, 91))	('hTERT', 'Gene', (56, 61))	('TR', 'Gene', '7012', (95, 97))	('targeting', 'Reg', (76, 85))	('regulates', 'Reg', (46, 55))
20079	29311615	The expression of mir-615-3p likely functions as a micro-switch to further repress the expression of hTERT.	('mir-615-3p', 'Var', (18, 28))	('hTERT', 'Gene', '7015', (101, 106))	('expression', 'MPA', (87, 97))	('hTERT', 'Gene', (101, 106))	('repress', 'NegReg', (75, 82))
20092	29311615	Deregulation of HOX and TALE genes have been implicated in many human diseases, including cancer.	('human', 'Species', '9606', (64, 69))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HOX', 'Gene', (16, 19))	('implicated', 'Reg', (45, 55))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
20095	29311615	Further, overexpression of miR-615-3p and HoxC5 suppress cancer cell growth both in vitro and in vivo in mouse xenograft model.	('miR-615-3p', 'Var', (27, 37))	('suppress', 'NegReg', (48, 56))	('overexpression', 'PosReg', (9, 23))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mouse', 'Species', '10090', (105, 110))
20098	29311615	These results provide a novel mechanism for the activation of telomerase in human cancers in addition to known hTERT promoter mutations and translocations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hTERT', 'Gene', '7015', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('hTERT', 'Gene', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('activation', 'PosReg', (48, 58))	('mutations', 'Var', (126, 135))	('telomerase', 'Enzyme', (62, 72))
20124	29311615	For quantification of hTERT expression, the Taqman probe against TERT (Hs00972656_m1 FAM, Applied Biosystems) and GAPDH (Hs02758991_g1 FAM, Applied Biosystems) were used for real-time RT-PCR.	('Hs02758991_g1', 'Var', (121, 134))	('GAPDH', 'Gene', '2597', (114, 119))	('hTERT', 'Gene', '7015', (22, 27))	('GAPDH', 'Gene', (114, 119))	('hTERT', 'Gene', (22, 27))
20131	29311615	CRISPR sgRNA used for engineer of hTERT 3'UTR truncation and knockin mutants is 5'-TGCCGTCTTCACTTCCCCACAGG-3'.	('mutants', 'Var', (69, 76))	('TR', 'Gene', '7012', (43, 45))	('hTERT', 'Gene', (34, 39))	('hTERT', 'Gene', '7015', (34, 39))
20132	29311615	The single-stranded oligo (5'-CGGCTGAAGGCTGAGTGTCCGGCTGAGGCCTGAGCGAGTGTCCAGCCAAGGGCTGAGTGTCCAGCACACCTGCCGTCTTCACTTCCCCACTCCGTGGCCGAGCCCTCCACCCCAGGGCCAGCTTTTCCTCACCAGGAGCCCGGCTTCCACTCCCCACATAGGAATAGTCCATCCCCAGATTCGCCATTGTTCACC-3') is used as template for knockin mutation of miR-615-3p binding site in the hTERT 3'UTR.	('TR', 'Gene', '7012', (314, 316))	('miR-615-3p', 'Gene', (274, 284))	('mutation', 'Var', (262, 270))	('hTERT', 'Gene', '7015', (305, 310))	('hTERT', 'Gene', (305, 310))
20143	29311615	Mapped reads of PC-3 histone profiles (ENCFF537RRY, ENCFF297RXW, ENCFF122EOV, ENCFF945UYG) were downloaded from encodeproject.org.	('ENCFF537RRY', 'Var', (39, 50))	('ENCFF122', 'CellLine', 'CVCL:0242', (65, 73))	('ENCFF297', 'CellLine', 'CVCL:D764', (52, 60))	('ENCFF122EOV', 'Var', (65, 76))	('ENCFF297RXW', 'Var', (52, 63))	('ENCFF945', 'CellLine', 'CVCL:X078', (78, 86))
20163	29311615	T.Y., A.C., D.M., G.M.S., C.X., M.X., L.P., J.W., Y.P.L., J.H.J.H., J.J.Q.N.	('C.X.', 'Var', (26, 30))	('Y.P.L.', 'Var', (50, 56))	('J.H.J.H.', 'Var', (58, 66))	('J.H.J.H', 'CellLine', 'CVCL:M891', (58, 65))	('M.X.', 'Var', (32, 36))
20164	28203648	Gene regulatory effects of disease-associated variation in the NRF2 network Reactive oxygen species (ROS), which are both a natural byproduct of oxidative metabolism and an undesirable byproduct of many environmental stressors, can damage all classes of cellular macromolecules and promote diseases from cancer to neurodegeneration.	('neurodegeneration', 'Phenotype', 'HP:0002180', (314, 331))	('NRF2', 'Gene', (63, 67))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (76, 99))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('diseases', 'Disease', (290, 298))	('neurodegeneration', 'Disease', (314, 331))	('cancer', 'Disease', (304, 310))	('neurodegeneration', 'Disease', 'MESH:D019636', (314, 331))	('variation', 'Var', (46, 55))	('classes of cellular macromolecules', 'MPA', (243, 277))	('damage', 'Reg', (232, 238))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('promote', 'PosReg', (282, 289))	('NRF2', 'Gene', '4780', (63, 67))
20167	28203648	NRF2 hyperactivating mutations are associated with tumorigenesis.	('NRF2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', (51, 56))	('hyperactivating mutations', 'Var', (5, 30))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
20168	28203648	On the subtler end of the spectrum, single nucleotide variants (SNVs) that alter individual ARE sequences have been linked to neurodegenerative disorders including progressive supranuclear palsy and Parkinson's disease, as well as other diseases.	("Parkinson's disease", 'Disease', (199, 218))	('supranuclear palsy', 'Disease', (176, 194))	('supranuclear palsy', 'Disease', 'MESH:D013494', (176, 194))	('single nucleotide variants', 'Var', (36, 62))	('linked', 'Reg', (116, 122))	("Parkinson's disease", 'Disease', 'MESH:D010300', (199, 218))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (126, 153))	('neurodegenerative disorders', 'Disease', (126, 153))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (126, 153))
20171	28203648	ROS have the potential to damage macromolecules including proteins, lipids, and DNA.	('ROS', 'Var', (0, 3))	('DNA', 'MPA', (80, 83))	('proteins', 'Protein', (58, 66))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('lipids', 'MPA', (68, 74))	('macromolecules', 'MPA', (33, 47))	('damage', 'Reg', (26, 32))	('lipids', 'Chemical', 'MESH:D008055', (68, 74))
20172	28203648	The latter effect is especially harmful because it can cause DNA mutations with long-term consequences, but significant oxidative stress can also lead to apoptotic or necrotic cell death.	('necrotic cell death', 'Disease', (167, 186))	('cause', 'Reg', (55, 60))	('necrotic cell death', 'Disease', 'MESH:D003643', (167, 186))	('oxidative stress', 'Phenotype', 'HP:0025464', (120, 136))	('apoptotic', 'CPA', (154, 163))	('DNA', 'Disease', (61, 64))	('lead to', 'Reg', (146, 153))	('mutations', 'Var', (65, 74))
20178	28203648	However, ROS modify KEAP1 and impair its ability to target NRF2 for degradation.	('impair', 'NegReg', (30, 36))	('NRF2', 'Gene', (59, 63))	('modify', 'Reg', (13, 19))	('ability', 'MPA', (41, 48))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('degradation', 'MPA', (68, 79))	('ROS', 'Var', (9, 12))
20185	28203648	Loss of NRF2 is associated with genomic instability and tumorigenesis, whereas activation of NRF2 is chemopreventive and promotes longevity.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('genomic instability', 'CPA', (32, 51))	('promotes', 'PosReg', (121, 129))	('NRF2', 'Gene', (8, 12))	('associated', 'Reg', (16, 26))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('longevity', 'CPA', (130, 139))
20186	28203648	Yet NRF2 activation beyond a certain threshold can be detrimental: somatic mutations that disrupt NRF2-KEAP1 interaction promote cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('NRF2-KEAP1', 'Gene', (98, 108))	('mutations', 'Var', (75, 84))	('promote', 'PosReg', (121, 128))	('interaction', 'Interaction', (109, 120))
20187	28203648	Mutations altering either the NRF2 binding domain of KEAP1 or the KEAP1 binding domain of NRF2 were first observed in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('binding', 'Interaction', (35, 42))	('NRF2', 'Gene', (90, 94))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Disease', (118, 129))	('observed', 'Reg', (106, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))
20188	28203648	Lung tissue is particularly prone to NRF2 hyperactivating mutations, but such mutations are also found in head and neck squamous cell carcinomas, endometrial cancer, and many other solid tumor types.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (115, 144))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('neck squamous cell carcinomas', 'Disease', (115, 144))	('endometrial cancer', 'Disease', (146, 164))	('tumor', 'Disease', (187, 192))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (120, 144))	('endometrial cancer', 'Phenotype', 'HP:0012114', (146, 164))	('NRF2', 'Gene', (37, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('endometrial cancer', 'Disease', 'MESH:D016889', (146, 164))	('hyperactivating mutations', 'Var', (42, 67))
20189	28203648	In addition to somatic mutation, DNA hypermethylation at the KEAP1 locus is also associated with KEAP1 repression, increased NRF2 activity, and tumorigenesis.	('KEAP1', 'Gene', (61, 66))	('tumor', 'Disease', (144, 149))	('DNA hypermethylation', 'Var', (33, 53))	('increased', 'PosReg', (115, 124))	('NRF2', 'Protein', (125, 129))	('KEAP1', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('repression', 'NegReg', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('activity', 'MPA', (130, 138))
20190	28203648	Importantly, data from The Cancer Genome Atlas (TCGA) indicate that mutations altering the KEAP1 binding domain of NRF2 are associated with similar patterns of gene upregulation across diverse tumor types (Table 1).	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('NRF2', 'Gene', (115, 119))	('Cancer Genome Atlas', 'Disease', (27, 46))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (27, 46))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', (193, 198))	('upregulation', 'PosReg', (165, 177))
20191	28203648	Because these gene expression changes are a result of genetic variation at an unlinked locus (the NFE2L2 gene), they represent the trans-effects of mutations at NFE2L2.	('mutations', 'Var', (148, 157))	('NFE2L2', 'Gene', '4780', (98, 104))	('NFE2L2', 'Gene', '4780', (161, 167))	('NFE2L2', 'Gene', (98, 104))	('NFE2L2', 'Gene', (161, 167))	('gene expression', 'MPA', (14, 29))
20204	28203648	Approximately 7.5% (2689 out of 35,659) of the AREs consistently bound by NRF2 and/or sMAFs contain a potential ARE-altering single nucleotide variant (SNV), and 14 of the variable AREs are in linkage disequilibrium (i.e., co-inherited) with disease-associated variants identified by GWAS.	('MAF', 'Gene', (87, 90))	('bound', 'Reg', (65, 70))	('single', 'Var', (125, 131))	('MAF', 'Gene', '4094', (87, 90))	('ARE-altering', 'Disease', (112, 124))	('NRF2', 'Gene', (74, 78))
20206	28203648	However variant AREs are also linked to disease beyond cancer.	('variant', 'Var', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('disease', 'Disease', (40, 47))	('linked', 'Reg', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
20208	28203648	One ARE-altering SNV, rs242561, falls within an NRF2-bound ARE at the MAPT locus.	('MAPT', 'Gene', (70, 74))	('rs242561', 'Var', (22, 30))	('rs242561', 'Mutation', 'rs242561', (22, 30))	('fall', 'Phenotype', 'HP:0002527', (32, 36))	('falls', 'Phenotype', 'HP:0002527', (32, 37))	('MAPT', 'Gene', '4137', (70, 74))
20209	28203648	The major allele of rs242561 creates a mismatch ARE (CGCTGAGTCAC - variant sequence is underlined) and the minor allele creates a perfect ARE (TGCTGAGTCAC).	('rs242561', 'Mutation', 'rs242561', (20, 28))	('rs242561', 'Var', (20, 28))	('mismatch', 'MPA', (39, 47))
20210	28203648	Thus, most people carry one or two copies of a mismatch NRF2-targeted ARE in a MAPT enhancer region.	('MAPT', 'Gene', (79, 83))	('people', 'Species', '9606', (11, 17))	('mismatch', 'Var', (47, 55))	('NRF2-targeted', 'Gene', (56, 69))	('MAPT', 'Gene', '4137', (79, 83))
20212	28203648	MAPT encodes the protein tau, which plays a central role in multiple neurodegenerative diseases, and rs242561 is in linkage disequilibrium with variants associated PSP, PD, and corticobasal degeneration.	('variants', 'Var', (144, 152))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (69, 94))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (69, 95))	('multiple neurodegenerative diseases', 'Disease', 'MESH:D019636', (60, 95))	('PSP', 'Disease', (164, 167))	('rs242561', 'Mutation', 'rs242561', (101, 109))	('PSP', 'Disease', 'MESH:D013494', (164, 167))	('multiple neurodegenerative diseases', 'Disease', (60, 95))	('associated', 'Reg', (153, 163))	('corticobasal degeneration', 'Disease', (177, 202))	('MAPT', 'Gene', '4137', (0, 4))	('PD', 'Disease', 'MESH:D010300', (169, 171))	('MAPT', 'Gene', (0, 4))
20213	28203648	Importantly, the minor allele of rs242561 (perfect-match ARE) is associated with decreased risk of all three aforementioned neurodegenerative disorders, acts as a hypermorphic ARE in reporter assays, and is associated with increased expression of a protective isoform of MAPT.	('decreased', 'NegReg', (81, 90))	('increased', 'PosReg', (223, 232))	('MAPT', 'Gene', (271, 275))	('expression', 'MPA', (233, 243))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (124, 151))	('rs242561', 'Var', (33, 41))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (124, 151))	('neurodegenerative disorders', 'Disease', (124, 151))	('MAPT', 'Gene', '4137', (271, 275))	('rs242561', 'Mutation', 'rs242561', (33, 41))
20214	28203648	Although it is possible that additional non-coding variants affect MAPT expression and neurodegenerative disease risk, these data suggest that the ARE impacted by rs242561 plays a significant functional role at this locus.	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (87, 112))	('rs242561', 'Var', (163, 171))	('MAPT', 'Gene', '4137', (67, 71))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (87, 112))	('rs242561', 'Mutation', 'rs242561', (163, 171))	('expression', 'MPA', (72, 82))	('MAPT', 'Gene', (67, 71))	('neurodegenerative disease', 'Disease', (87, 112))	('affect', 'Reg', (60, 66))
20215	28203648	Cancer genome sequencing data from TCGA indicate that somatic variants disrupting ARE-like sequences are under positive selection in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('variants', 'Var', (62, 70))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (133, 139))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
20217	28203648	Thus, ARE mutations and aberrant expression of select NRF2 target genes are also likely to play an important functional role in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('NRF2', 'Gene', (54, 58))	('aberrant', 'Var', (24, 32))	('play', 'Reg', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('expression', 'MPA', (33, 43))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (128, 134))
20218	28203648	In addition, there are many variant AREs associated with gene expression changes that have not yet been linked to a disease phenotype (SL and MS, not shown).	('gene expression changes', 'MPA', (57, 80))	('variant', 'Var', (28, 35))	('SL', 'Disease', 'MESH:C564794', (135, 137))
20219	28203648	This explanation holds for rs242561, as oxidative stress plays a significant role in the pathology of neurodegenerative diseases such as PD and PSP.	('rs242561', 'Mutation', 'rs242561', (27, 35))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (102, 128))	('PD', 'Disease', 'MESH:D010300', (137, 139))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (102, 127))	('PSP', 'Disease', (144, 147))	('rs242561', 'Var', (27, 35))	('neurodegenerative diseases', 'Disease', (102, 128))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (102, 128))	('oxidative stress', 'Phenotype', 'HP:0025464', (40, 56))	('PSP', 'Disease', 'MESH:D013494', (144, 147))
20248	24691397	Further, both are predisposed by mutations in the Kitl or Dmrt1 genes, and both appear to involve epigenetic changes in their etiology.	('Dmrt1', 'Gene', (58, 63))	('predisposed by', 'Reg', (18, 32))	('Kitl', 'Gene', (50, 54))	('mutations', 'Var', (33, 42))	('Dmrt1', 'Gene', '50796', (58, 63))	('Kitl', 'Gene', '17311', (50, 54))
20301	24691397	There was only a marginally significant difference (P = 0.04) with higher incidence of TGCTs in CP-treated 129S5 mice than in CP-treated 129S1/SvImJ mice.	('TGCTs', 'Protein', (87, 92))	('higher', 'PosReg', (67, 73))	('mice', 'Species', '10090', (149, 153))	('mice', 'Species', '10090', (113, 117))	('CP-treated', 'Var', (96, 106))
20316	24691397	The time points for exposure to potential carcinogenic agents for induction of TGCTs were initially chosen at E10.5 and E11.5 since those are the earliest days just after the PGCs colonize the fetal gonad and are undergoing extensive epigenetic changes.	('carcinogenic', 'Disease', (42, 54))	('carcinogenic', 'Disease', 'MESH:D063646', (42, 54))	('E11.5', 'Var', (120, 125))
20360	22140272	To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health.	('patients', 'Species', '9606', (176, 184))	('variants', 'Var', (20, 28))	('Human', 'Species', '9606', (142, 147))	('TDS', 'Disease', (202, 205))
20363	22140272	Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer.	('KITLG', 'Gene', '4254', (39, 44))	('associations', 'Interaction', (69, 81))	('KITLG', 'Gene', (39, 44))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('testicular cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('testicular cancer', 'Phenotype', 'HP:0010788', (97, 114))	('testicular cancer', 'Disease', 'MESH:D013736', (97, 114))
20364	22140272	The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor beta signalling pathway, suggests a role for this pathway in the pathogenesis of TDS.	('TDS', 'Disease', (209, 212))	('TGFBR3', 'Gene', (58, 64))	('association', 'Interaction', (4, 15))	('BMP7', 'Gene', (69, 73))	('single-nucleotide polymorphisms', 'Var', (19, 50))	('BMP7', 'Gene', '655', (69, 73))	('role', 'Reg', (164, 168))
20365	22140272	Infertility, cryptorchidism, small testis size with poor semen quality, and hypospadias are relatively common among men in Western countries and are all risk factors for testicular germ cell cancer (TGCC),  which has been increasing in incidence and is the most common malignancy of young men in many countries.	('Infertility', 'Disease', (0, 11))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('hypospadias', 'Disease', 'MESH:D007021', (76, 87))	('cryptorchidism', 'Phenotype', 'HP:0000028', (13, 27))	('malignancy', 'Disease', 'MESH:D009369', (269, 279))	('small testis', 'Phenotype', 'HP:0008734', (29, 41))	('hypospadias', 'Disease', (76, 87))	('men', 'Species', '9606', (289, 292))	('malignancy', 'Disease', (269, 279))	('small', 'Var', (29, 34))	('Infertility', 'Phenotype', 'HP:0000789', (0, 11))	('hypospadias', 'Phenotype', 'HP:0000047', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cryptorchidism', 'Disease', (13, 27))	('men', 'Species', '9606', (116, 119))	('germ cell cancer', 'Phenotype', 'HP:0100728', (181, 197))	('men', 'Species', '9606', (59, 62))
20374	22140272	The variants with highest effect size were found at 12q21, implicating KITLG/KIT signalling as a pathway involved in TGCC susceptibility.	('TGCC', 'Disease', (117, 121))	('KITLG', 'Gene', '4254', (71, 76))	('KITLG', 'Gene', (71, 76))	('variants', 'Var', (4, 12))
20382	22140272	With the above approaches we were able to: (1) identify pleiotropic risk variants for TDS:that is, variants associated with all of the phenotypic subtypes; (2) confirm the risk factors in the KITLG gene found by two recent GWASs on TGCC; and (3) identify genes and protein complexes through integrative systems biology approaches that would not be found by single-marker association.	('variants', 'Var', (73, 81))	('KITLG', 'Gene', '4254', (192, 197))	('TDS', 'Disease', (86, 89))	('associated', 'Reg', (108, 118))	('KITLG', 'Gene', (192, 197))
20414	22140272	We identified a strong association with all phenotypes of TDS (p<10-6) for nine markers, within the same linkage disequilibrium block, at 2q31.1, with the strongest association for rs17198432 (figure 1).	('rs17198432', 'Var', (181, 191))	('rs17198432', 'Mutation', 'rs17198432', (181, 191))	('TDS', 'Disease', (58, 61))
20417	22140272	Thus all human genes were ranked on the basis of a combination of microarray gene expression time-series studies of the developing fetal testis in mouse and human, protein-protein interaction data, targeted mice knockouts resulting in developmental defects of the testis (MGI), and gene scores based on the single-marker analysis of this GWAS (figure 2; see Materials and methods for details).	('mouse', 'Species', '10090', (147, 152))	('defects of the testis', 'Phenotype', 'HP:0000035', (249, 270))	('developmental defects of the testis', 'Disease', 'MESH:D013736', (235, 270))	('human', 'Species', '9606', (9, 14))	('mice', 'Species', '10090', (207, 211))	('developmental defects of the testis', 'Disease', (235, 270))	('knockouts', 'Var', (212, 221))	('human', 'Species', '9606', (157, 162))	('resulting in', 'Reg', (222, 234))
20429	22140272	Here, we identified, using a combination of GWAS and systems biology approaches, genomic variants in TGFBR3 and BMP7 between several TDS phenotypes, most notably cryptorchidism and testicular cancer.	('cryptorchidism', 'Disease', (162, 176))	('testicular cancer', 'Disease', (181, 198))	('variants', 'Var', (89, 97))	('BMP7', 'Gene', '655', (112, 116))	('cryptorchidism', 'Phenotype', 'HP:0000028', (162, 176))	('testicular cancer', 'Disease', 'MESH:D013736', (181, 198))	('testicular cancer', 'Phenotype', 'HP:0010788', (181, 198))	('TGFBR3', 'Gene', (101, 107))	('BMP7', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
20431	22140272	In the single-marker approach, we also found evidence in the discovery cohort for a possible association for rs17198432 and other markers in the HOXD gene cluster.	('HOXD', 'Gene', '3230', (145, 149))	('rs17198432', 'Mutation', 'rs17198432', (109, 119))	('rs17198432', 'Var', (109, 119))	('HOXD', 'Gene', (145, 149))
20437	22140272	This expression pattern supports the idea that TGFBR3 is essential for embryonic development of the reproductive system, as silencing of the murine Tgfbr3 gene resulted in impaired function of fetal Leydig cells and testicular dysgenesis.	('Tgfbr3', 'Gene', '21814', (148, 154))	('function', 'CPA', (181, 189))	('silencing', 'Var', (124, 133))	('Tgfbr3', 'Gene', (148, 154))	('men', 'Species', '9606', (88, 91))	('testicular dysgenesis', 'Disease', 'MESH:D013733', (216, 237))	('murine', 'Species', '10090', (141, 147))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (216, 237))	('development of the reproductive system', 'Phenotype', 'HP:0000078', (81, 119))	('impaired', 'NegReg', (172, 180))	('testicular dysgenesis', 'Disease', (216, 237))
20442	22140272	However, it has been suggested that SNPs in the KIT and KITLG genes may also be involved in infertility, but we did not detect an association for other subtypes of TDS.	('infertility', 'Disease', (92, 103))	('SNPs', 'Var', (36, 40))	('KIT', 'Gene', (48, 51))	('infertility', 'Disease', 'MESH:D007247', (92, 103))	('KITLG', 'Gene', '4254', (56, 61))	('involved', 'Reg', (80, 88))	('infertility', 'Phenotype', 'HP:0000789', (92, 103))	('KITLG', 'Gene', (56, 61))
20443	22140272	Thus, the KITLG region should be further studied to pinpoint causative variants within KITLG or its regulatory regions.	('variants', 'Var', (71, 79))	('KITLG', 'Gene', (87, 92))	('KITLG', 'Gene', '4254', (10, 15))	('KITLG', 'Gene', '4254', (87, 92))	('KITLG', 'Gene', (10, 15))
20444	22140272	In the single-marker approach, we also found evidence for a possible association for rs17198432 and other markers in the HOXD gene cluster (supplementary table 10 online).	('rs17198432', 'Var', (85, 95))	('HOXD', 'Gene', '3230', (121, 125))	('men', 'Species', '9606', (146, 149))	('rs17198432', 'Mutation', 'rs17198432', (85, 95))	('association', 'Interaction', (69, 80))	('HOXD', 'Gene', (121, 125))
20467	21892262	Testicular maldescent is a recognized aetiological factor with a relative risk (RR) of 4.8, familial testicular cancer constitutes a RR of 3-10 and ipsilateral testicular germ cell cancer results in a 25-fold increased risk of developing a second GCT in the contralateral testis.	('familial testicular cancer', 'Disease', 'MESH:D013736', (92, 118))	('GCT', 'Phenotype', 'HP:0100728', (247, 250))	('Testicular maldescent', 'Phenotype', 'HP:0008715', (0, 21))	('CT', 'Chemical', 'MESH:D002251', (248, 250))	('testicular cancer', 'Phenotype', 'HP:0010788', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('ipsilateral', 'Var', (148, 159))	('familial testicular cancer', 'Disease', (92, 118))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('germ cell cancer', 'Phenotype', 'HP:0100728', (171, 187))	('Testicular maldescent', 'Disease', (0, 21))
20483	21892262	The beta-hCG was elevated in one patient (11150 U/L), and the alphaFP elevated in two patients (115 and 387 kU/L).	('patient', 'Species', '9606', (33, 40))	('beta-hCG', 'Protein', (4, 12))	('alphaFP', 'Gene', '174', (62, 69))	('patient', 'Species', '9606', (86, 93))	('alphaFP', 'Gene', (62, 69))	('elevated', 'PosReg', (17, 25))	('11150 U/L', 'Var', (42, 51))	('patients', 'Species', '9606', (86, 94))
20521	21892262	In a multivariate analysis, positive tumour markers at initial presentation and the presence of TD in post-chemotherapy surgical specimens were predictive of late recurrence.	('tumour', 'Disease', (37, 43))	('presence', 'Var', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('men', 'Species', '9606', (134, 137))
20557	25791729	Since 2009, several genome wide association studies (GWAS) have been published, reporting on single-nucleotide polymorphisms (SNPs) with significant associations in or near the genes KITLG, SPRY4, BAK1, DMRT1, TERT, ATF7IP, HPGDS, MAD1L1, RFWD3, TEX14, and PPM1E, likely to be related to TGCT development.	('TEX14', 'Gene', (246, 251))	('KITLG', 'Gene', '4254', (183, 188))	('RFWD3', 'Gene', (239, 244))	('BAK1', 'Gene', (197, 201))	('GCT', 'Phenotype', 'HP:0100728', (289, 292))	('related', 'Reg', (277, 284))	('RFWD3', 'Gene', '55159', (239, 244))	('MAD1L1', 'Gene', (231, 237))	('TGCT', 'Disease', (288, 292))	('DMRT1', 'Gene', (203, 208))	('TEX14', 'Gene', '56155', (246, 251))	('SPRY4', 'Gene', '81848', (190, 195))	('PPM1E', 'Gene', (257, 262))	('TERT', 'Gene', (210, 214))	('TERT', 'Gene', '7015', (210, 214))	('ATF7IP', 'Gene', (216, 222))	('HPGDS', 'Gene', (224, 229))	('MAD1L1', 'Gene', '8379', (231, 237))	('single-nucleotide', 'Var', (93, 110))	('PPM1E', 'Gene', '22843', (257, 262))	('KITLG', 'Gene', (183, 188))	('men', 'Species', '9606', (300, 303))	('associations', 'Interaction', (149, 161))	('SPRY4', 'Gene', (190, 195))	('ATF7IP', 'Gene', '55729', (216, 222))	('DMRT1', 'Gene', '1761', (203, 208))	('BAK1', 'Gene', '578', (197, 201))
20584	25791729	In addition, men surviving TGCT can present long-term side effects of systemic cancer treatment, such as chronic fatigue, cardiovascular disease, metabolic syndrome, infertility, and even second cancers.	('GCT', 'Phenotype', 'HP:0100728', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('TGCT', 'Var', (27, 31))	('infertility', 'Disease', (166, 177))	('systemic cancer', 'Disease', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('infertility', 'Disease', 'MESH:D007247', (166, 177))	('men', 'Species', '9606', (13, 16))	('fatigue', 'Phenotype', 'HP:0012378', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('chronic fatigue', 'Disease', (105, 120))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (122, 144))	('systemic cancer', 'Disease', 'MESH:D009369', (70, 85))	('metabolic syndrome', 'Disease', 'MESH:D008659', (146, 164))	('cardiovascular disease', 'Disease', 'MESH:D002318', (122, 144))	('metabolic syndrome', 'Disease', (146, 164))	('men', 'Species', '9606', (91, 94))	('chronic fatigue', 'Phenotype', 'HP:0012432', (105, 120))	('infertility', 'Phenotype', 'HP:0000789', (166, 177))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('chronic fatigue', 'Disease', 'MESH:D015673', (105, 120))	('cardiovascular disease', 'Disease', (122, 144))	('cancers', 'Disease', (195, 202))
20637	25791729	Single-nucleotide polymorphisms at 12q22 likely related to KITLG have the strongest association with the development of TGCT, with a risk greater than 2.5-fold of TGCT per major allele.	('association', 'Interaction', (84, 95))	('men', 'Species', '9606', (112, 115))	('TGCT', 'Disease', (120, 124))	('GCT', 'Phenotype', 'HP:0100728', (121, 124))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('KITLG', 'Gene', '4254', (59, 64))	('KITLG', 'Gene', (59, 64))	('GCT', 'Phenotype', 'HP:0100728', (164, 167))
20644	25791729	The link between cancer and infertility can, therefore, further be investigated in studies of KITLG variation in men with a history of infertility with and without TGCT.	('KITLG', 'Gene', '4254', (94, 99))	('infertility', 'Disease', 'MESH:D007247', (28, 39))	('KITLG', 'Gene', (94, 99))	('GCT', 'Phenotype', 'HP:0100728', (165, 168))	('infertility', 'Phenotype', 'HP:0000789', (28, 39))	('infertility', 'Disease', 'MESH:D007247', (135, 146))	('infertility', 'Disease', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('variation', 'Var', (100, 109))	('infertility', 'Phenotype', 'HP:0000789', (135, 146))	('cancer', 'Disease', (17, 23))	('men', 'Species', '9606', (113, 116))	('infertility', 'Disease', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
20660	25791729	This is also confirmed by the fact that SNP identified at this locus were more strongly associated with seminomas than nonseminomas.	('associated', 'Reg', (88, 98))	('SNP identified', 'Var', (40, 54))	('seminomas than nonseminomas', 'Disease', (104, 131))	('seminomas than nonseminomas', 'Disease', 'MESH:D018239', (104, 131))
20662	25791729	Knock down of ATF7IP results in a significant decrease in TERT and TERC expression and also in telomerase activity.	('TERC', 'Gene', (67, 71))	('ATF7IP', 'Gene', (14, 20))	('TERC', 'Gene', '7012', (67, 71))	('telomerase activity', 'MPA', (95, 114))	('TERT', 'Gene', (58, 62))	('ATF7IP', 'Gene', '55729', (14, 20))	('TERT', 'Gene', '7015', (58, 62))	('Knock down', 'Var', (0, 10))	('decrease', 'NegReg', (46, 54))
20665	25791729	Disruption of HPGDS leads to modification of the phenotype of apcMin/+ mice.	('mice', 'Species', '10090', (71, 75))	('phenotype', 'MPA', (49, 58))	('HPGDS', 'Gene', (14, 19))	('Disruption', 'Var', (0, 10))	('modification', 'Reg', (29, 41))
20722	25791729	It is found that aberrations in regulation of expression of miRNAs can be involved in the development of cancers, so they can act as both oncogenes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancers', 'Disease', (105, 112))	('regulation', 'MPA', (32, 42))	('men', 'Species', '9606', (97, 100))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('miRNAs', 'Gene', (60, 66))	('tumor', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (46, 56))	('aberrations', 'Var', (17, 28))	('involved', 'Reg', (74, 82))
20748	25791729	A promising noninvasive method for CIS screening seems to be the detection of specific TGCT miRNAs in semen, because there was demonstrated that miRNAs of the miR-371~373 and miR-302/367 clusters are highly overexpressed in serum in all TGCT and specific miRNA associated to infertility has already been found in semen.	('miR-302/367 clusters', 'Var', (175, 195))	('infertility', 'Disease', 'MESH:D007247', (275, 286))	('infertility', 'Phenotype', 'HP:0000789', (275, 286))	('men', 'Species', '9606', (104, 107))	('infertility', 'Disease', (275, 286))	('GCT', 'Phenotype', 'HP:0100728', (238, 241))	('overexpressed', 'PosReg', (207, 220))	('miR-371', 'Gene', (159, 166))	('GCT', 'Phenotype', 'HP:0100728', (88, 91))	('men', 'Species', '9606', (315, 318))	('miR-371', 'Gene', '442916', (159, 166))	('CIS', 'Phenotype', 'HP:0030075', (35, 38))
20839	24672311	Paternal exposure to heavy metals such as lead, arsenic, and mercury has been associated with decreased fertility and pregnancy delay.	('pregnancy delay', 'CPA', (118, 133))	('decreased fertility', 'Phenotype', 'HP:0000144', (94, 113))	('arsenic', 'Chemical', 'MESH:D001151', (48, 55))	('decreased', 'NegReg', (94, 103))	('mercury', 'Chemical', 'MESH:D008628', (61, 68))	('arsenic', 'Var', (48, 55))	('fertility', 'CPA', (104, 113))	('pregnancy delay', 'Phenotype', 'HP:0001622', (118, 133))
20860	24247010	Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis.	('human', 'Species', '9606', (47, 52))	('tumor', 'Disease', (64, 69))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PIWI', 'Gene', '9271', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PIWI', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Epigenetic loss', 'Var', (0, 15))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
20861	24247010	In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (278, 287))	('human', 'Species', '9606', (272, 277))	('hypermethylation', 'Var', (117, 133))	('neoplasia', 'Disease', 'MESH:D009369', (278, 287))	('epigenetic silencing', 'MPA', (82, 102))	('neoplasia', 'Disease', (278, 287))
20863	24247010	We have observed the existence of promoter CpG island hypermethylation-associated silencing of PIWIL1, PIWIL2, PIWIL4, and TDRD1 in primary seminoma and non-seminoma testicular tumors, in addition to testicular germ cell tumor cell lines.	('PIWIL4', 'Gene', '143689', (111, 117))	('PIWIL2', 'Gene', '55124', (103, 109))	('TDRD1', 'Gene', '56165', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('primary seminoma', 'Disease', (132, 148))	('testicular tumors', 'Phenotype', 'HP:0010788', (166, 183))	('silencing', 'NegReg', (82, 91))	('non-seminoma testicular tumors', 'Disease', (153, 183))	('non-seminoma testicular tumors', 'Disease', 'MESH:D018239', (153, 183))	('tumor', 'Disease', (177, 182))	('TDRD1', 'Gene', (123, 128))	('PIWIL4', 'Gene', (111, 117))	('PIWIL2', 'Gene', (103, 109))	('hypermethylation-associated', 'Var', (54, 81))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('PIWIL1', 'Gene', '9271', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('PIWIL1', 'Gene', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('germ cell tumor', 'Phenotype', 'HP:0100728', (211, 226))	('primary seminoma', 'Disease', 'MESH:D018239', (132, 148))
20864	24247010	The PIWI/piRNA pathway seem to be involved in the maintenance of genomic stability and germ cell function by two different mechanisms that have been described in Drosophila melanogaster: cleavage of transposable element transcripts by PIWI proteins, a process that is mediated through piRNA base-pairing recognition, and heterochromatin-mediated transcriptional silencing associated with a gain of DNA methylation.	('transposable element transcripts', 'Gene', (199, 231))	('Drosophila melanogaster', 'Species', '7227', (162, 185))	('cleavage', 'MPA', (187, 195))	('heterochromatin-mediated transcriptional', 'Var', (321, 361))
20865	24247010	PIWI-class proteins, such as PIWIL2 and PIWIL4, are also involved in a so-denominated "ping-pong" amplification cycle, creating antisense piRNAs that are capable of repressing the transcript of origin.	('antisense', 'Var', (128, 137))	('repressing', 'MPA', (165, 175))	('PIWIL2', 'Gene', '55124', (29, 35))	('PIWIL4', 'Gene', '143689', (40, 46))	('PIWIL4', 'Gene', (40, 46))	('PIWIL2', 'Gene', (29, 35))	('transcript of origin', 'MPA', (180, 200))
20867	24247010	In this regard, DNA methylation regulated expression of piRNAs occurs in human spermatozoa and non-genetic infertility syndromes in males could be associated with epigenetic disruption of PIWI proteins.	('infertility syndromes', 'Disease', 'MESH:D007247', (107, 128))	('infertility syndromes', 'Disease', (107, 128))	('associated', 'Reg', (147, 157))	('piRNAs', 'Gene', (56, 62))	('infertility', 'Phenotype', 'HP:0000789', (107, 118))	('expression', 'MPA', (42, 52))	('human', 'Species', '9606', (73, 78))	('epigenetic disruption', 'Var', (163, 184))
20872	24247010	PIWIL2 has essential roles in the initial phases of spermatogenesis: transposon silencing in fetal gonocytes, germline stem cell self-renewal and early prophase of mammalian testis.	('silencing', 'NegReg', (80, 89))	('PIWIL2', 'Gene', '55124', (0, 6))	('PIWIL2', 'Gene', (0, 6))	('transposon', 'Var', (69, 79))	('mammalian', 'Species', '9606', (164, 173))
20875	24247010	Our data indicate that epigenetic disruption of the entire PIWI/piRNA pathway is indeed a hallmark for the development of testicular tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('testicular tumors', 'Disease', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('testicular tumors', 'Disease', 'MESH:D013736', (122, 139))	('epigenetic disruption', 'Var', (23, 44))	('PIWI/piRNA pathway', 'Pathway', (59, 77))	('testicular tumors', 'Phenotype', 'HP:0010788', (122, 139))
20882	24247010	We further tightened the link between CpG island hypermethylation of the studied PIWI-class protein genes and transcriptional inactivation by the analyses of testicular cancer cell lines.	('testicular cancer', 'Disease', (158, 175))	('PIWI-class', 'Gene', (81, 91))	('hypermethylation', 'Var', (49, 65))	('testicular cancer', 'Phenotype', 'HP:0010788', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('testicular cancer', 'Disease', 'MESH:D013736', (158, 175))
20884	24247010	2), we found that the human testicular germ cell tumor lines 833K, GCT27 and SuSa showed dense promoter CpG island hypermethylation for the described genes.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('hypermethylation', 'Var', (115, 131))	('tumor', 'Disease', (49, 54))	('human', 'Species', '9606', (22, 27))	('germ cell tumor', 'Phenotype', 'HP:0100728', (39, 54))
20886	24247010	Once we had determined the existence of promoter CpG island hypermethylation events in the described PIWI-class protein genes and the diminished expression of their corresponding transcripts in testicular tumorigenesis, both in primary tumors and cultured transformed cells, we wondered about the downstream impact of the described epigenetic inactivation.	('primary tumors', 'Disease', 'MESH:D009369', (228, 242))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('diminished', 'NegReg', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('expression', 'MPA', (145, 155))	('PIWI-class protein genes', 'Gene', (101, 125))	('hypermethylation', 'Var', (60, 76))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('primary tumors', 'Disease', (228, 242))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', (236, 241))
20890	24247010	The diminished expression of the piRNAs DQ598918, DQ589977 and DQ601609 occurred both in seminoma and non-seminoma tumors (Fig.	('DQ598918', 'Var', (40, 48))	('seminoma', 'Disease', 'MESH:D018239', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DQ589977', 'Var', (50, 58))	('seminoma', 'Disease', (89, 97))	('seminoma', 'Disease', (106, 114))	('diminished', 'NegReg', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (15, 25))	('DQ601609', 'Var', (63, 71))	('non-seminoma tumors', 'Disease', (102, 121))	('non-seminoma tumors', 'Disease', 'MESH:D018239', (102, 121))	('seminoma', 'Disease', 'MESH:D018239', (106, 114))
20893	24247010	Thus, we proceeded to determine in our studied set of primary testicular tumors that harbor PIWIL1, PIWIL2, PIWIL4, and TDRD1 promoter CpG island methylation-associated silencing and piRNA diminished levels, had also undergone DNA methylation changes at the LINE1 sequence.	('PIWIL2', 'Gene', '55124', (100, 106))	('PIWIL4', 'Gene', (108, 114))	('TDRD1', 'Gene', '56165', (120, 125))	('silencing', 'NegReg', (169, 178))	('PIWIL4', 'Gene', '143689', (108, 114))	('testicular tumors', 'Disease', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PIWIL1', 'Gene', (92, 98))	('PIWIL2', 'Gene', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('PIWIL1', 'Gene', '9271', (92, 98))	('methylation-associated', 'Var', (146, 168))	('TDRD1', 'Gene', (120, 125))	('testicular tumors', 'Disease', 'MESH:D013736', (62, 79))	('testicular tumors', 'Phenotype', 'HP:0010788', (62, 79))
20896	24247010	Overall, our results show the existence of cancer specific hypermethylation events in the CpG islands of genes associated with piRNAs that leads to their transcriptional inactivation in testicular cancer.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('testicular cancer', 'Disease', 'MESH:D013736', (186, 203))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('testicular cancer', 'Phenotype', 'HP:0010788', (186, 203))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (197, 203))	('transcriptional', 'MPA', (154, 169))	('testicular cancer', 'Disease', (186, 203))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('CpG islands of genes', 'Gene', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('hypermethylation events', 'Var', (59, 82))
20897	24247010	Most importantly, the epigenetic inactivation of PIWI-class protein genes (PIWIL1, PIWIL2, and PIWIL4) and its associated protein TDRD1 in human testicular tumorigenesis occurs in a molecular context characterized by a diminished expression of the piRNAs and the DNA hypomethylation of LINE1, a PIWI/piRNA target sequence.	('PIWIL2', 'Gene', '55124', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('PIWIL1', 'Gene', (75, 81))	('diminished', 'NegReg', (219, 229))	('expression', 'MPA', (230, 240))	('PIWIL2', 'Gene', (83, 89))	('PIWIL4', 'Gene', '143689', (95, 101))	('PIWIL4', 'Gene', (95, 101))	('LINE1', 'Gene', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('human', 'Species', '9606', (139, 144))	('TDRD1', 'Gene', (130, 135))	('PIWIL1', 'Gene', '9271', (75, 81))	('tumor', 'Disease', (156, 161))	('TDRD1', 'Gene', '56165', (130, 135))	('epigenetic inactivation', 'Var', (22, 45))
20898	24247010	Interestingly, epigenetic disruption of PIWI proteins also occurs in non-genetic infertility syndromes in males and there is an epidemiological association between male infertility and testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('testicular cancer', 'Disease', (185, 202))	('infertility', 'Disease', 'MESH:D007247', (169, 180))	('male infertility', 'Phenotype', 'HP:0003251', (164, 180))	('infertility', 'Phenotype', 'HP:0000789', (169, 180))	('PIWI', 'Gene', (40, 44))	('infertility', 'Disease', (169, 180))	('infertility syndromes', 'Disease', 'MESH:D007247', (81, 102))	('occurs', 'Reg', (59, 65))	('epigenetic disruption', 'Var', (15, 36))	('infertility syndromes', 'Disease', (81, 102))	('testicular cancer', 'Disease', 'MESH:D013736', (185, 202))	('infertility', 'Disease', 'MESH:D007247', (81, 92))	('infertility', 'Disease', (81, 92))	('testicular cancer', 'Phenotype', 'HP:0010788', (185, 202))	('infertility', 'Phenotype', 'HP:0000789', (81, 92))
20911	24247010	cDNA of protein coding genes was amplified by real-time PCR using Taqman assays: PIWIL1 (Hs01041737), PIWIL2 (Hs00216263), PIWIL4 (Hs00381509) and TDRD1 (Hs00229805) and expression values were normalized to GAPDH (AB Assay ID 4333764F).	('TDRD1', 'Gene', '56165', (147, 152))	('Hs00216263', 'Var', (110, 120))	('PIWIL2', 'Gene', (102, 108))	('PIWIL1', 'Gene', (81, 87))	('Hs00381509', 'Var', (131, 141))	('GAPDH', 'Gene', '2597', (207, 212))	('Hs01041737', 'Var', (89, 99))	('PIWIL4', 'Gene', '143689', (123, 129))	('PIWIL1', 'Gene', '9271', (81, 87))	('PIWIL4', 'Gene', (123, 129))	('PIWIL2', 'Gene', '55124', (102, 108))	('GAPDH', 'Gene', (207, 212))	('TDRD1', 'Gene', (147, 152))
20912	24247010	Expression values of piRNAs DQ598918 (CSQJAPI), DQ589977 (CSMSF6U) and DQ601609 (CSVI3FS) were normalized to RNU19 (AB Assay ID 001003).	('DQ589977', 'Var', (48, 56))	('DQ601609', 'Var', (71, 79))	('DQ598918', 'Var', (28, 36))	('RNU19', 'Gene', (109, 114))	('RNU19', 'Gene', '26821', (109, 114))
21053	18827809	Putatively, these precursors of malignancy may be promoted by factors acting during early childhood (Dieckmann and Pichlmeier, 2004), such as high-calorie nutrition.	('malignancy', 'Disease', 'MESH:D009369', (32, 42))	('malignancy', 'Disease', (32, 42))	('promoted', 'PosReg', (50, 58))	('high-calorie nutrition', 'Var', (142, 164))
21075	18827809	>185 cm) are distinctly more frequent among cases than in controls, as with the subgroups of seminoma and non-seminoma.	('frequent', 'Reg', (29, 37))	('non-seminoma', 'Disease', (106, 118))	('seminoma', 'Disease', 'MESH:D018239', (110, 118))	('seminoma', 'Disease', 'MESH:D018239', (93, 101))	('non-seminoma', 'Disease', 'MESH:D018239', (106, 118))	('seminoma', 'Disease', (93, 101))	('seminoma', 'Disease', (110, 118))	('>185 cm', 'Var', (0, 7))
21113	18827809	Two ecological studies support the hypothesis, one showing a correlation between high-fat intake and the incidence of GCT (Armstrong and Doll, 1975) and the other reporting an association of dairy products specifically cheese, with the incidence of testicular cancer (Ganmaa et al, 2002).	('GCT', 'Gene', (118, 121))	('high-fat', 'Var', (81, 89))	('testicular cancer', 'Phenotype', 'HP:0010788', (249, 266))	('testicular cancer', 'Disease', 'MESH:D013736', (249, 266))	('GCT', 'Gene', '25797', (118, 121))	('association', 'Interaction', (176, 187))	('testicular cancer', 'Disease', (249, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
21120	18827809	According to that hypothesis, high-calorie intake during early childhood could advance length growth and promote GCT precursor cells at the same time.	('promote', 'PosReg', (105, 112))	('GCT', 'Gene', (113, 116))	('advance length growth', 'Phenotype', 'HP:0000098', (79, 100))	('GCT', 'Gene', '25797', (113, 116))	('advance', 'PosReg', (79, 86))	('length growth', 'CPA', (87, 100))	('high-calorie', 'Var', (30, 42))
21171	17411461	Cowden syndrome (CS), an autosomal dominant disease associated with mutations in the PTEN tumor suppressor gene on chromosome 10q10.22-23, is associated with elevated risks of breast and thyroid cancer, as well as diverse benign neoplasms including gastrointestinal hamartomatous polyps, lipomas, giant fibroadenomas of the breast, hemangiomas, and multiple early-onset uterine leiomyomas.	('fibroadenomas of the breast', 'Phenotype', 'HP:0010619', (303, 330))	('Cowden syndrome', 'Disease', (0, 15))	('PTEN', 'Gene', (85, 89))	('lipomas', 'Phenotype', 'HP:0012032', (288, 295))	('benign neoplasms', 'Disease', (222, 238))	('leiomyomas', 'Disease', (378, 388))	('benign neoplasms', 'Disease', 'MESH:D009369', (222, 238))	('lipomas', 'Disease', (288, 295))	('tumor', 'Disease', (90, 95))	('multiple', 'Disease', (349, 357))	('lipomas', 'Disease', 'MESH:D008067', (288, 295))	('associated', 'Reg', (142, 152))	('leiomyomas', 'Disease', 'MESH:D007889', (378, 388))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (370, 388))	('PTEN', 'Gene', '5728', (85, 89))	('gastrointestinal hamartomatous polyps', 'Disease', (249, 286))	('giant fibroadenomas of the breast, hemangiomas', 'Disease', 'OMIM:615554', (297, 343))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('thyroid cancer', 'Phenotype', 'HP:0002890', (187, 201))	('associated', 'Reg', (52, 62))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (25, 51))	('hamartomatous polyps', 'Phenotype', 'HP:0004390', (266, 286))	('hemangiomas', 'Phenotype', 'HP:0001028', (332, 343))	('gastrointestinal hamartomatous polyps', 'Disease', 'MESH:D011127', (249, 286))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('autosomal dominant disease', 'Disease', (25, 51))	('neoplasms', 'Phenotype', 'HP:0002664', (229, 238))	('Cowden syndrome', 'Disease', 'MESH:D006223', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('gastrointestinal hamartomatous', 'Phenotype', 'HP:0004390', (249, 279))	('neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('mutations', 'Var', (68, 77))	('breast and thyroid cancer', 'Disease', 'MESH:D013964', (176, 201))
21177	17411461	The patient underwent commercial genetic testing for germline mutations in the PTEN gene, with no mutation detected.	('germline mutations', 'Var', (53, 71))	('PTEN', 'Gene', (79, 83))	('patient', 'Species', '9606', (4, 11))	('PTEN', 'Gene', '5728', (79, 83))
21178	17411461	However, a mutation is identified by conventional testing in only 80% of patients who meet the CS clinical criteria, as they can have a large deletion or mutations in the promoter region of PTEN.	('PTEN', 'Gene', (190, 194))	('PTEN', 'Gene', '5728', (190, 194))	('mutations in', 'Var', (154, 166))	('deletion', 'Var', (142, 150))	('patients', 'Species', '9606', (73, 81))
21180	17411461	CNC is associated with germline mutations in the PRKAR1A gene on chromosome 17q22-24, which are detected in 50-65% of CNC patients.	('PRKAR1A', 'Gene', '5573', (49, 56))	('germline mutations', 'Var', (23, 41))	('CNC', 'Disease', (0, 3))	('associated', 'Reg', (7, 17))	('PRKAR1A', 'Gene', (49, 56))	('patients', 'Species', '9606', (122, 130))
21186	17411461	It is associated with germline mutations in the MEN1 gene, on chromosome 11q13.	('associated', 'Reg', (6, 16))	('germline mutations', 'Var', (22, 40))	('MEN1', 'Gene', '4221', (48, 52))	('MEN1', 'Gene', (48, 52))
21193	17411461	We therefore tested the patient for mutations in AIP; none were detected (CA Stratakis, personal communication).	('patient', 'Species', '9606', (24, 31))	('mutations', 'Var', (36, 45))	('tested', 'Reg', (13, 19))	('AIP', 'Gene', '9049', (49, 52))	('AIP', 'Gene', (49, 52))
21217	31592278	The pathogenesis of testicular germ cell tumours remains unknown; however, although recently questioned, cryptorchidism is the main risk factor, and molecular studies have shown strong evidence of an association between genetic alterations and testicular germ cell tumours.	('testicular germ cell tumours', 'Disease', (20, 48))	('cryptorchidism', 'Phenotype', 'HP:0000028', (105, 119))	('testicular germ cell tumours', 'Disease', (244, 272))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumours', 'Phenotype', 'HP:0002664', (265, 272))	('cryptorchidism', 'Disease', (105, 119))	('cryptorchidism', 'Disease', 'MESH:D003456', (105, 119))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (20, 48))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (244, 272))	('genetic alterations', 'Var', (220, 239))
21248	23353098	Epigenetic changes are amongst the earliest lesions to occur during carcinogenesis and are essentially reversible (unlike mutations).	('carcinogenesis', 'Disease', (68, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('Epigenetic changes', 'Var', (0, 18))
21260	23353098	Risk factors for RCC include age (50-70 years), cigarette smoking, obesity, hypertension and silencing of the VHL tumor suppressor gene, which drives tumor angiogenesis through VEGF over-expression.	('VEGF', 'Gene', '7422', (177, 181))	('obesity', 'Disease', 'MESH:D009765', (67, 74))	('silencing', 'Var', (93, 102))	('over-expression', 'PosReg', (182, 197))	('hypertension', 'Disease', (76, 88))	('obesity', 'Disease', (67, 74))	('VHL tumor', 'Disease', 'MESH:D006623', (110, 119))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('hypertension', 'Phenotype', 'HP:0000822', (76, 88))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('VEGF', 'Gene', (177, 181))	('hypertension', 'Disease', 'MESH:D006973', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('RCC', 'Disease', (17, 20))	('VHL tumor', 'Disease', (110, 119))
21277	23353098	Overexpression of ERBB2 has been found to be an independent predictor of survival in a proportion of muscle-invasive TCC.	('muscle-invasive TCC', 'Disease', (101, 120))	('ERBB2', 'Gene', '2064', (18, 23))	('Overexpression', 'Var', (0, 14))	('ERBB2', 'Gene', (18, 23))	('TCC', 'Phenotype', 'HP:0006740', (117, 120))
21289	23353098	There is strong evidence to show that methylation patterns are clonally inherited during prostate tumor progression.	('prostate tumor', 'Disease', 'MESH:D011471', (89, 103))	('methylation', 'Var', (38, 49))	('prostate tumor', 'Disease', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('prostate tumor', 'Phenotype', 'HP:0100787', (89, 103))
21297	23353098	Add to this the 'epigenetic progenitor model of cancer', and we can begin to understand how epigenetic alterations in precursor cells can create genomic instability, which fosters additional genetic 'hits', such as point mutations and deletions, unwanted transcription of proviral and retrotransposon repeats, leading to disruption of their surrounding genes, further epigenetic catastrophe and rapid acquisition of the cancerous phenotype.	('deletions', 'Var', (235, 244))	('fosters', 'Reg', (172, 179))	('alterations', 'Var', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', (420, 429))	('epigenetic', 'Var', (92, 102))	('epigenetic catastrophe', 'CPA', (368, 390))	('disruption', 'Reg', (321, 331))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('cancerous', 'Disease', 'MESH:D009369', (420, 429))	("'hits'", 'PosReg', (199, 205))	('point mutations', 'Var', (215, 230))
21301	23353098	Via active demethylation of tumor suppressor genes and cytotoxicity arising from incorporation into nucleic acids, these DNMTi exert potent anti-tumorigenic activity.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('toxicity', 'Disease', (59, 67))	('tumor suppressor genes', 'Gene', (28, 50))	('cytotoxicity', 'Disease', (55, 67))	('demethylation', 'Var', (11, 24))	('anti-tumorigenic activity', 'CPA', (140, 165))	('DNMTi', 'Var', (121, 126))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
21306	23353098	In renal cancer, TGFbeta receptor type II expression, in addition to TGFbeta responsiveness, was restored by 5-Aza-CdR.	('TGFbeta receptor', 'Gene', (17, 33))	('5-Aza-CdR', 'Var', (109, 118))	('renal cancer', 'Disease', (3, 15))	('expression', 'MPA', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('renal cancer', 'Phenotype', 'HP:0009726', (3, 15))	('restored', 'PosReg', (97, 105))	('renal cancer', 'Disease', 'MESH:D007680', (3, 15))
21307	23353098	Furthermore, combined treatment with 5-Aza-CdR and genistein, a non-toxic isoflavone, significantly induced cell cycle arrest and halted proliferation across three renal carcinoma cell lines, over genistein alone.	('halted', 'NegReg', (130, 136))	('5-Aza-CdR', 'Var', (37, 46))	('arrest', 'Disease', (119, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('renal carcinoma', 'Disease', 'MESH:C538614', (164, 179))	('genistein', 'Chemical', 'MESH:D019833', (51, 60))	('renal carcinoma', 'Disease', (164, 179))	('isoflavone', 'Chemical', 'MESH:D007529', (74, 84))	('induced', 'Reg', (100, 107))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('renal carcinoma', 'Phenotype', 'HP:0005584', (164, 179))	('proliferation', 'CPA', (137, 150))	('genistein', 'Chemical', 'MESH:D019833', (197, 206))
21309	23353098	Following promising results by demethylating the p16 gene promoter and globally decreasing hypermethylated regions in T24 human bladder carcinoma cells, studies on zebularine were escalated to in vivo models.	('decreasing', 'NegReg', (80, 90))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (128, 145))	('bladder carcinoma', 'Disease', 'MESH:D001749', (128, 145))	('hypermethylated regions', 'MPA', (91, 114))	('p16', 'Gene', (49, 52))	('bladder carcinoma', 'Disease', (128, 145))	('demethylating', 'Var', (31, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('zebularine', 'Chemical', 'MESH:C009131', (164, 174))	('p16', 'Gene', '1029', (49, 52))
21311	23353098	Combined treatment of prostate cancer cell line DU145 with docetaxel (TaxotereR) and either 5-Aza-CdR or 5-Aza-CR enhanced docetaxel sensitivity through demethylation and reactivation of DNA damage response gene GADD45A and tumor suppressors E-cadherin and maspin and significantly reduced proliferation over either agent alone.	('docetaxel sensitivity', 'MPA', (123, 144))	('demethylation', 'Var', (153, 166))	('GADD45A', 'Gene', '1647', (212, 219))	('docetaxel', 'Chemical', 'MESH:D000077143', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('TaxotereR', 'Chemical', '-', (70, 79))	('reduced', 'NegReg', (282, 289))	('maspin', 'Gene', (257, 263))	('E-cadherin', 'Protein', (242, 252))	('enhanced', 'PosReg', (114, 122))	('GADD45A', 'Gene', (212, 219))	('proliferation', 'CPA', (290, 303))	('maspin', 'Gene', '5268', (257, 263))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('reactivation', 'PosReg', (171, 183))	('docetaxel', 'Chemical', 'MESH:D000077143', (123, 132))
21312	23353098	Similarly, 5-Aza-CdR was found to enhance the apoptotic effect of cisplatinum (trade name: cisplatin) in DU145 cells.	('enhance', 'PosReg', (34, 41))	('cisplatinum', 'Chemical', 'MESH:D002945', (66, 77))	('5-Aza-CdR', 'Var', (11, 20))	('apoptotic effect', 'CPA', (46, 62))
21313	23353098	In RCC, cytotoxicity of vinblastine was increased both in vitro and in a Caki-1 xenograft model by co-treatment with 5-Aza-CdR.	('vinblastine', 'Chemical', 'MESH:D014747', (24, 35))	('cytotoxicity of vinblastine', 'MPA', (8, 35))	('5-Aza-CdR', 'Var', (117, 126))	('increased', 'PosReg', (40, 49))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))
21314	23353098	Hypermethylation of the pro-apoptotic XAF1 gene has been associated with the apoptotic resistant phenotype of RCC that emerges post-immunotherapy.	('RCC', 'Disease', (110, 113))	('XAF1', 'Gene', (38, 42))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('Hypermethylation', 'Var', (0, 16))	('apoptotic resistant phenotype', 'MPA', (77, 106))	('associated with', 'Reg', (57, 72))	('XAF1', 'Gene', '54739', (38, 42))
21317	23353098	Hypermethylation of homeobox gene TLX3 has been associated with chemoresistance in 21% of patients and overexpression of TLX3 restored chemosensitivity.	('TLX3', 'Gene', (121, 125))	('chemosensitivity', 'MPA', (135, 151))	('TLX3', 'Gene', '30012', (34, 38))	('associated', 'Reg', (48, 58))	('Hypermethylation', 'Var', (0, 16))	('TLX3', 'Gene', '30012', (121, 125))	('chemoresistance', 'CPA', (64, 79))	('TLX3', 'Gene', (34, 38))
21325	23353098	It was recently shown that curcumin is also capable of demethylating and reactivating noncoding microRNA genes, namely tumor suppressor microRNA miR-203 in bladder cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('reactivating', 'MPA', (73, 85))	('curcumin', 'Chemical', 'MESH:D003474', (27, 35))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))	('demethylating', 'Var', (55, 68))	('miR-203', 'Gene', (145, 152))	('miR-203', 'Gene', '406986', (145, 152))
21337	23353098	Similarly in mouse models of prostate cancer, the combination of panobinostat with the mTOR inhibitor everolimus resulted in enhanced anti-tumor activity (over either agent alone) mediated by increased p21 and p27 expression and reduced angiogenesis and tumor proliferation via androgen receptor, c-Myc and HIF-1alpha signaling.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('prostate cancer', 'Disease', (29, 44))	('expression', 'MPA', (214, 224))	('p27', 'Gene', (210, 213))	('anti-tumor activity', 'CPA', (134, 153))	('HIF-1alpha', 'Gene', '15251', (307, 317))	('HIF-1alpha', 'Gene', (307, 317))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('reduced', 'NegReg', (229, 236))	('tumor proliferation', 'CPA', (254, 273))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('panobinostat', 'Var', (65, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (29, 44))	('enhanced', 'PosReg', (125, 133))	('p27', 'Gene', '12576', (210, 213))	('p21', 'Protein', (202, 205))	('angiogenesis', 'CPA', (237, 249))	('increased', 'PosReg', (192, 201))
21342	23353098	EZH2 belongs to the polycomb group of transcriptional repressors, and forms the catalytic subunit of the Polycomb repressive complex 2 (PRC2), which catalyzes trimethylation on H3K27, triggering gene silencing.	('EZH2', 'Gene', '2146', (0, 4))	('trimethylation', 'Var', (159, 173))	('EZH2', 'Gene', (0, 4))	('H3K27', 'Protein', (177, 182))	('triggering', 'Reg', (184, 194))	('gene', 'MPA', (195, 199))
21344	23353098	Several selective small molecule inhibitors of EZH2 have recently been described that decrease global H3K27me3 levels and reactivate silenced PRC2 target genes, such as GSK126 and EPZ005687.	('EZH2', 'Gene', (47, 51))	('PRC2', 'Gene', (142, 146))	('GSK126', 'Chemical', 'MESH:C577920', (169, 175))	('reactivate silenced', 'MPA', (122, 141))	('decrease', 'NegReg', (86, 94))	('global H3K27me3 levels', 'MPA', (95, 117))	('inhibitors', 'Var', (33, 43))
21350	23353098	For example, epigallocatechin-3-gallate (the polyphenol from green tea) has been shown to cause cell cycle arrest and induce apoptosis in prostate cancer cells by upregulating p21 and Bax through H3 acetylation (increasing promoter accessibility), causing epigenetic modifications and down-regulating HDACs through increasing their proteasomal degradation.	('H3 acetylation', 'Protein', (196, 210))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('cell cycle arrest', 'CPA', (96, 113))	('apoptosis', 'CPA', (125, 134))	('Bax', 'Gene', (184, 187))	('increasing', 'PosReg', (315, 325))	('Bax', 'Gene', '581', (184, 187))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('proteasomal degradation', 'MPA', (332, 355))	('epigenetic modifications', 'MPA', (256, 280))	('epigallocatechin-3-gallate', 'Var', (13, 39))	('HDACs', 'Gene', (301, 306))	('induce', 'PosReg', (118, 124))	('down-regulating', 'NegReg', (285, 300))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (13, 39))	('causing', 'Reg', (248, 255))	('p21', 'Protein', (176, 179))	('upregulating', 'PosReg', (163, 175))	('cause', 'PosReg', (90, 95))
21353	24829558	It is also known that undescended testes, if untreated, lead to an increased risk of testicular tumors, usually seminomas, arising from mutant germ cells.	('undescended testes', 'Phenotype', 'HP:0000028', (22, 40))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('testicular tumors', 'Disease', (85, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('testicular tumors', 'Disease', 'MESH:D013736', (85, 102))	('testicular tumors', 'Phenotype', 'HP:0010788', (85, 102))	('seminomas', 'Disease', 'MESH:D018239', (112, 121))	('seminomas', 'Disease', (112, 121))	('mutant', 'Var', (136, 142))
21370	24829558	The hyperthermia, between 35 and 37 C rather than 33 C, evoked by the abnormal position of the testis may respond for the impaired spermatogenesis.	('abnormal', 'Var', (70, 78))	('spermatogenesis', 'CPA', (131, 146))	('hyperthermia', 'Phenotype', 'HP:0001945', (4, 16))	('hyperthermia', 'Disease', 'MESH:D005334', (4, 16))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (122, 146))	('hyperthermia', 'Disease', (4, 16))
21373	24829558	It is known that undescended testes, if untreated, lead to an increased risk of TC, usually seminomas, arising from mutant germ cells.	('undescended testes', 'Phenotype', 'HP:0000028', (17, 35))	('TC', 'Phenotype', 'HP:0010788', (80, 82))	('seminomas', 'Disease', 'MESH:D018239', (92, 101))	('seminomas', 'Disease', (92, 101))	('mutant', 'Var', (116, 122))
21399	24829558	A current hypothesis is that, due to the high temperature anomaly of undescended testis, an abnormal apoptosis allows some gonocytes to persist and become CIS with progressive mutation and/or cellular unbalance, and eventually malignancy in adulthood.	('malignancy', 'Disease', 'MESH:D009369', (227, 237))	('undescended testis', 'Phenotype', 'HP:0000028', (69, 87))	('temperature anomaly', 'Phenotype', 'HP:0004370', (46, 65))	('anomaly', 'Disease', 'MESH:D000014', (58, 65))	('malignancy', 'Disease', (227, 237))	('anomaly', 'Disease', (58, 65))	('mutation', 'Var', (176, 184))	('CIS', 'Phenotype', 'HP:0030075', (155, 158))
21400	24829558	These abnormal gonocytes are kept in a defined environment "suspended animation" in the germ-line and, due to the accumulation of mutations, may undergo transformation becoming the source of the CIS.	('transformation', 'CPA', (153, 167))	('undergo', 'Reg', (145, 152))	('mutations', 'Var', (130, 139))	('men', 'Species', '9606', (54, 57))	('CIS', 'Phenotype', 'HP:0030075', (195, 198))
21403	24829558	A specific association of mutations in INSL3 with cryptorchidism has been described but its possible role in TC development and infertility needs to be clarified.	('infertility', 'Disease', 'MESH:D007247', (128, 139))	('association', 'Interaction', (11, 22))	('INSL3', 'Gene', '3640', (39, 44))	('infertility', 'Phenotype', 'HP:0000789', (128, 139))	('mutations', 'Var', (26, 35))	('TC', 'Phenotype', 'HP:0010788', (109, 111))	('infertility', 'Disease', (128, 139))	('cryptorchidism', 'Disease', (50, 64))	('men', 'Species', '9606', (119, 122))	('cryptorchidism', 'Phenotype', 'HP:0000028', (50, 64))	('INSL3', 'Gene', (39, 44))
21407	24829558	demonstrated common genetic variants associated to an increased risk of testicular germ cell cancer (TGCC) and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance.	('cancer', 'Disease', (93, 99))	('KITLG', 'Gene', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('germ cell cancer', 'Phenotype', 'HP:0100728', (83, 99))	('variants', 'Var', (28, 36))	('c-KIT ligand', 'Gene', '4254', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (37, 47))	('KITLG', 'Gene', '4254', (152, 157))	('c-KIT ligand', 'Gene', (159, 171))
21411	24829558	Thus, mutations in testosterone gene expression may change the level of testosterone in vivo and hypothetically the risk of developing TC.	('testosterone', 'Gene', (19, 31))	('TC', 'Phenotype', 'HP:0010788', (135, 137))	('change', 'Reg', (52, 58))	('level of testosterone', 'MPA', (63, 84))	('testosterone', 'Chemical', 'MESH:D013739', (72, 84))	('mutations', 'Var', (6, 15))	('testosterone', 'Chemical', 'MESH:D013739', (19, 31))
21480	19654912	This stimulation was reproduced by E2-BSA, an impermeable E2 conjugate (Figure 1B), but not by E2, which triggered a significant decrease of cell proliferation at a physiologic intratesticular concentration of 10-9 M (Figure 1B), in agreement with our previous study.	('rat', 'Species', '10116', (180, 183))	('decrease', 'NegReg', (129, 137))	('rat', 'Species', '10116', (200, 203))	('rat', 'Species', '10116', (153, 156))	('men', 'Species', '9606', (238, 241))	('cell proliferation', 'CPA', (141, 159))	('E2-BSA', 'Var', (35, 41))
21488	19654912	This activation was PKA dependent because H89 completely abolished CREB phosphorylation (data not shown).	('CREB', 'Gene', '1385', (67, 71))	('H89', 'Chemical', 'MESH:C063509', (42, 45))	('abolished', 'NegReg', (57, 66))	('CREB', 'Gene', (67, 71))	('H89', 'Var', (42, 45))
21497	19654912	NF449 blocked the promoting effect of BPA, illustrating the Galphas dependence of the PKA activation and the G-protein-coupled nature of the receptor involved in BPA stimulation.	('Galphas', 'Chemical', '-', (60, 67))	('BPA', 'Chemical', 'MESH:C006780', (38, 41))	('NF449', 'Var', (0, 5))	('BPA', 'Chemical', 'MESH:C006780', (162, 165))	('blocked', 'NegReg', (6, 13))	('rat', 'Species', '10116', (49, 52))
21498	19654912	We have previously shown that E2-BSA, which triggers an effect quite similar to that of BPA, also induces a Galphai-dependent activation of the mitogen-activated protein kinase (MAPK)/ERK1/2 pathway.	('ERK1/2', 'Gene', (184, 190))	('ERK1/2', 'Gene', '5595;5594', (184, 190))	('E2-BSA', 'Var', (30, 36))	('activation', 'PosReg', (126, 136))	('MAPK', 'Gene', (178, 182))	('MAPK', 'Gene', '5595;5594;50689;5595;50689', (178, 182))	('Galphai', 'Chemical', '-', (108, 115))	('Galphai-dependent', 'MPA', (108, 125))	('BPA', 'Chemical', 'MESH:C006780', (88, 91))
21503	19654912	KT5823, an inhibitor of PKG activation, prevented BPA-induced JKT-1 proliferation (Figure 6).	('BPA', 'Chemical', 'MESH:C006780', (50, 53))	('KT5823', 'Chemical', 'MESH:C073601', (0, 6))	('prevented', 'NegReg', (40, 49))	('JKT-1', 'CellLine', 'CVCL:T011', (62, 67))	('rat', 'Species', '10116', (75, 78))	('JKT-1', 'Gene', (62, 67))	('KT5823', 'Var', (0, 6))	('PKG', 'Gene', '5592', (24, 27))	('PKG', 'Gene', (24, 27))
21530	19654912	Despite the mild difference in the activated protein kinases, it is likely that this promoting effect induced by E2-BSA and BPA is mediated via the same GPCR membrane receptor, an ncmER.	('GPCR', 'Gene', (153, 157))	('GPCR', 'Gene', '151', (153, 157))	('E2-BSA', 'Var', (113, 119))	('BPA', 'Chemical', 'MESH:C006780', (124, 127))	('protein kinases', 'Enzyme', (45, 60))
21534	19654912	Thus, GPR30 is a candidate for our ncmER in JKT-1 seminoma cells, activated by E2-BSA or BPA and able to transduce the PKA and ERK or PKG signaling pathways.	('seminoma', 'Disease', (50, 58))	('BPA', 'Chemical', 'MESH:C006780', (89, 92))	('seminoma', 'Disease', 'MESH:D018239', (50, 58))	('transduce', 'Reg', (105, 114))	('ERK', 'Gene', '5594', (127, 130))	('PKG', 'Gene', '5592', (134, 137))	('PKG', 'Gene', (134, 137))	('ERK', 'Gene', (127, 130))	('GPR30', 'Var', (6, 11))	('JKT-1', 'CellLine', 'CVCL:T011', (44, 49))	('E2-BSA', 'Var', (79, 85))
21537	19654912	Thus, we propose that GPR30 could represent the ncmER in JKT-1 seminoma cells, able to activate PKA, ERK, or PKG pathways.	('PKG', 'Gene', '5592', (109, 112))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('seminoma', 'Disease', 'MESH:D018239', (63, 71))	('PKG', 'Gene', (109, 112))	('PKA', 'Pathway', (96, 99))	('seminoma', 'Disease', (63, 71))	('GPR30', 'Var', (22, 27))	('activate', 'PosReg', (87, 95))	('JKT-1', 'CellLine', 'CVCL:T011', (57, 62))
21548	31419517	The three CYP26 family enzymes, CYP26A1, CYP26B1 and CYP26C1 have all been shown to metabolize all-trans-retinoic acid (atRA) as well as 9-cisRA and 13-cisRA isomers and primary metabolites 4-OH-RA and 4-oxo-RA with high efficiency.	('metabolize', 'MPA', (84, 94))	('9-cisRA', 'Chemical', '-', (137, 144))	('4-oxo-RA', 'Chemical', 'MESH:C002202', (202, 210))	('atRA', 'Chemical', 'MESH:D014212', (120, 124))	('CYP26B1', 'Var', (41, 48))	('13-cisRA', 'Chemical', '-', (149, 157))	('4-OH-RA', 'Chemical', '-', (190, 197))	('CYP26A1', 'Var', (32, 39))	('CYP26C1', 'Var', (53, 60))	('all-trans-retinoic acid', 'Chemical', 'MESH:D014212', (95, 118))
21551	31419517	In humans and in animal models the expression patterns of CYP26 enzymes have been shown to be tissue and cell type specific, and the expression of the CYP26 enzymes is believed to regulate the formation of critical atRA concentration gradients in various tissue types.	('rat', 'Species', '10116', (227, 230))	('CYP26', 'Gene', (58, 63))	('formation of critical atRA concentration gradients', 'MPA', (193, 243))	('CYP26', 'Var', (151, 156))	('humans', 'Species', '9606', (3, 9))	('regulate', 'Reg', (180, 188))	('atRA', 'Chemical', 'MESH:D014212', (215, 219))
21553	31419517	Interestingly, some of these genetic variants result in increased activity of the CYP26 enzymes potentially leading to complex gene-environment interactions due to variability in dietary intake of retinoids.	('retinoids', 'Chemical', 'MESH:D012176', (197, 206))	('CYP26 enzymes', 'Enzyme', (82, 95))	('increased', 'PosReg', (56, 65))	('activity', 'MPA', (66, 74))	('variants', 'Var', (37, 45))	('leading to', 'Reg', (108, 118))
21604	31419517	In addition, based on enzyme kinetic analysis and the expression levels of CYP3A4, CYP3A5, CYP2C8 and CYP26A1 in the human liver, CYP26A1 is the main contributor to atRA clearance in the adult human liver.	('CYP2C8', 'Gene', '1558', (91, 97))	('CYP3A5', 'Gene', (83, 89))	('CYP2C8', 'Gene', (91, 97))	('CYP3A4', 'Gene', '1576', (75, 81))	('human', 'Species', '9606', (117, 122))	('atRA', 'Chemical', 'MESH:D014212', (165, 169))	('CYP3A5', 'Gene', '1577', (83, 89))	('CYP26A1', 'Var', (130, 137))	('CYP3A4', 'Gene', (75, 81))	('human', 'Species', '9606', (193, 198))
21615	31419517	CYP26A1 was characterized as a RA hydroxylase as it was found to catalyze hydroxylation of RA and the gene expression was inducible by exposure to exogenous RA.	('RA', 'Chemical', 'MESH:D014212', (157, 159))	('CYP26A1', 'Var', (0, 7))	('RA', 'Chemical', 'MESH:D014212', (31, 33))	('catalyze', 'MPA', (65, 73))	('hydroxylation', 'MPA', (74, 87))	('RA', 'Chemical', 'MESH:D014212', (91, 93))
21629	31419517	For example, CYP26A1 sequence similarity is higher than 65% between human, mouse and zebrafish, CYP26B1 sequence similarity is > 70% and CYP26C1 >50%.	('human', 'Species', '9606', (68, 73))	('CYP26A1', 'Gene', (13, 20))	('CYP26B1', 'Var', (96, 103))	('mouse', 'Species', '10090', (75, 80))	('zebrafish', 'Species', '7955', (85, 94))	('CYP26C1', 'Var', (137, 144))
21637	31419517	The CYP26 enzymes are collectively believed to be the main atRA hydroxylases, and the endogenous substrate of all three enzymes has been assumed to be atRA.	('atRA hydroxylases', 'Disease', (59, 76))	('atRA', 'Chemical', 'MESH:D014212', (59, 63))	('atRA', 'Chemical', 'MESH:D014212', (151, 155))	('rat', 'Species', '10116', (102, 105))	('CYP26 enzymes', 'Var', (4, 17))	('atRA hydroxylases', 'Disease', 'MESH:D054882', (59, 76))
21655	31419517	Of the CYP26 family enzymes, CYP26A1 has been shown to be mainly an enzyme that clears active retinoids rather than an enzyme forming active retinoids such as 4-oxo-RA.	('4-oxo-RA', 'Chemical', 'MESH:C002202', (159, 167))	('clears active retinoids', 'MPA', (80, 103))	('retinoids', 'Chemical', 'MESH:D012176', (141, 150))	('retinoids', 'Chemical', 'MESH:D012176', (94, 103))	('CYP26A1', 'Var', (29, 36))	('rat', 'Species', '10116', (104, 107))
21660	31419517	Among the three CYP26A1 enzymes, CYP26A1 has the highest catalytic activity towards atRA indicated by the highest Clint, while CYP26B1 appears to be a high affinity low capacity atRA hydroxylase and exhibits the lowest Clint of atRA amongst the three CYP26s (Table 1).	('C', 'Chemical', 'MESH:D002244', (251, 252))	('C', 'Chemical', 'MESH:D002244', (219, 220))	('atRA', 'Chemical', 'MESH:D014212', (228, 232))	('atRA', 'Chemical', 'MESH:D014212', (84, 88))	('highest catalytic activity towards atRA indicated', 'MPA', (49, 98))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('CYP26B1', 'Var', (127, 134))	('atRA', 'Chemical', 'MESH:D014212', (178, 182))	('Clint', 'MPA', (219, 224))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('Clint', 'MPA', (114, 119))	('CYP26A1', 'Var', (33, 40))	('C', 'Chemical', 'MESH:D002244', (127, 128))
21661	31419517	CYP26A1 hydroxylates atRA nearly as efficiently at C-16 and C-18 as in C-4 while CYP26B1 and CYP26C1 predominantly form the 4-OH-RA metabolite (Table 1).	('C-4', 'Chemical', 'MESH:C058899', (71, 74))	('CYP26B1', 'Var', (81, 88))	('4-OH-RA', 'MPA', (124, 131))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('CYP26A1', 'Var', (0, 7))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('4-OH-RA', 'Chemical', '-', (124, 131))	('CYP26C1', 'Var', (93, 100))	('atRA', 'Chemical', 'MESH:D014212', (21, 25))	('C-18', 'Gene', '27241', (60, 64))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C-18', 'Gene', (60, 64))
21664	31419517	The dominant 4-OH- metabolite formed by human CYP26A1 is (4S)-OH-RA while CYP26C1 converted atRA preferably to (4R)-OH-atRA.	('4-OH', 'Chemical', '-', (13, 17))	('atRA', 'Chemical', 'MESH:D014212', (92, 96))	('atRA', 'Chemical', 'MESH:D014212', (119, 123))	('(4R)-OH-atRA', 'Chemical', '-', (111, 123))	('(4S)-OH-RA', 'Chemical', '-', (57, 67))	('CYP26A1', 'Var', (46, 53))	('CYP26C1', 'Var', (74, 81))	('human', 'Species', '9606', (40, 45))
21669	31419517	Of the three enzymes, CYP26C1 has the highest affinity towards 9-cisRA and CYP26A1 and CYP26B1 showed approximately 13- and 55-fold higher Km values than CYP26C1 towards 9-cisRA, respectively (Table 1).	('higher', 'PosReg', (132, 138))	('9-cisRA', 'MPA', (63, 70))	('CYP26B1', 'Var', (87, 94))	('Km values', 'MPA', (139, 148))	('9-cisRA', 'Chemical', '-', (63, 70))	('9-cisRA', 'Chemical', '-', (170, 177))	('CYP26C1', 'Var', (22, 29))	('CYP26A1', 'Var', (75, 82))	('affinity', 'MPA', (46, 54))
21670	31419517	Somewhat surprisingly, the Clint of 9-cisRA by CYP26C1 was nearly as high as that of atRA by CYP26A1 while the Clint towards atRA by CYP26C1 was only about 10% of that by CYP26A1.	('C', 'Chemical', 'MESH:D002244', (93, 94))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('CYP26C1', 'Var', (47, 54))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('atRA', 'Chemical', 'MESH:D014212', (85, 89))	('Clint', 'MPA', (27, 32))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('atRA', 'Chemical', 'MESH:D014212', (125, 129))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('9-cisRA', 'Chemical', '-', (36, 43))
21671	31419517	This finding prompted the hypothesis that high clearance of 9-cisRA by CYP26C1 may be the reason why this RA isomer cannot usually be detected in biological samples.	('RA', 'Chemical', 'MESH:D014212', (106, 108))	('clearance', 'MPA', (47, 56))	('RA', 'Chemical', 'MESH:D014212', (65, 67))	('9-cisRA', 'Chemical', '-', (60, 67))	('CYP26C1', 'Var', (71, 78))
21675	31419517	The Km values of 4-OH-atRA and 18-OH-atRA with CYP26A1 and CYP26B1 were all in the nanomolar range, indicating similar affinity of these substrates as atRA.	('CYP26A1', 'Var', (47, 54))	('atRA', 'Chemical', 'MESH:D014212', (37, 41))	('4-OH-atRA', 'Chemical', '-', (17, 26))	('atRA', 'Chemical', 'MESH:D014212', (22, 26))	('atRA', 'Chemical', 'MESH:D014212', (151, 155))	('CYP26B1', 'Var', (59, 66))	('18-OH-atRA', 'Chemical', '-', (31, 41))	('rat', 'Species', '10116', (142, 145))
21676	31419517	In contrast, CYP26C1 was most efficient in clearing 4-oxo-atRA showing 10-fold higher Clint towards this substrate than other two CYP26 enzymes.	('rat', 'Species', '10116', (110, 113))	('CYP26C1', 'Var', (13, 20))	('Clint towards this substrate', 'MPA', (86, 114))	('clearing 4-oxo-atRA', 'MPA', (43, 62))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('4-oxo-atRA', 'Chemical', 'MESH:C002202', (52, 62))	('higher', 'PosReg', (79, 85))	('C', 'Chemical', 'MESH:D002244', (13, 14))
21677	31419517	Both CYP26A1 and CYP26B1 preferred (4S)-OH-atRA as a substrate over (4R)-OH-atRA (Table 1) to yield dihydroxylated metabolites.	('dihydroxylated metabolites', 'MPA', (100, 126))	('CYP26B1', 'Var', (17, 24))	('(4S)-OH-atRA', 'Chemical', '-', (35, 47))	('rat', 'Species', '10116', (58, 61))	('CYP26A1', 'Var', (5, 12))	('(4R)-OH-atRA', 'Chemical', '-', (68, 80))
21688	31419517	In addition to atRA channeling, the experiments with recombinant CYP26C1 suggest that CRABPs may also deliver atRA metabolites for further oxidation.	('CRABP', 'Gene', (86, 91))	('atRA metabolites', 'MPA', (110, 126))	('men', 'Species', '9606', (42, 45))	('CYP26C1', 'Var', (65, 72))	('atRA', 'Chemical', 'MESH:D014212', (110, 114))	('CRABP', 'Gene', '1381', (86, 91))	('atRA', 'Chemical', 'MESH:D014212', (15, 19))
21690	31419517	In contrast, CRABPI and CRABPII had no impact of 9cisRA metabolism by CYP26C1.	('CRABPI', 'Gene', (13, 19))	('CRABPI', 'Gene', (24, 30))	('CRABPI', 'Gene', '25061', (24, 30))	('CRABPII', 'Gene', '29563', (24, 31))	('CYP26C1', 'Var', (70, 77))	('CRABPII', 'Gene', (24, 31))	('9cisRA metabolism', 'MPA', (49, 66))	('9cisRA', 'Chemical', '-', (49, 55))	('CRABPI', 'Gene', '25061', (13, 19))
21698	31419517	The classic CYP26 inhibitor R115866 (talarozole), could only be docked to the CYP3A4 based homology model.	('R115866', 'Chemical', 'MESH:C406527', (28, 35))	('CYP3A4', 'Gene', '1576', (78, 84))	('R115866', 'Var', (28, 35))	('talarozole', 'Chemical', 'MESH:C406527', (37, 47))	('CYP3A4', 'Gene', (78, 84))
21704	31419517	The C-4 of atRA was predicted to be closer to the heme iron in the CYP26A1 model than in the CYP26B1 model, a finding likely in agreement with the later observed lower catalytic activity of CYP26B1 in comparison to CYP26A1.	('iron', 'Chemical', 'MESH:D007501', (55, 59))	('heme', 'Chemical', 'MESH:D006418', (50, 54))	('C-4', 'Chemical', 'MESH:C058899', (4, 7))	('lower', 'NegReg', (162, 167))	('CYP26A1', 'Var', (67, 74))	('catalytic activity', 'MPA', (168, 186))	('atRA', 'Chemical', 'MESH:D014212', (11, 15))	('men', 'Species', '9606', (133, 136))	('closer', 'PosReg', (36, 42))
21705	31419517	Interestingly, the developed homology models suggested some distinct differences in the active site architecture between CYP26A1 and CYP26B1, with the CYP26B1 active site having more hydrogen bonding interactions than CYP26A1, providing potential avenues to developing inhibitors that are selective towards the different CYP26 enzymes.	('hydrogen bonding interactions', 'MPA', (183, 212))	('more', 'PosReg', (178, 182))	('hydrogen', 'Chemical', 'MESH:D006859', (183, 191))	('CYP26B1', 'Var', (151, 158))
21706	31419517	One may speculate that the higher number of hydrogen bonding interactions in the CYP26B1 active site in comparison to CYP26A1 could explain the higher affinity of atRA to CYP26B1 in comparison to CYP26A1 that was later observed.	('hydrogen', 'Chemical', 'MESH:D006859', (44, 52))	('CYP26B1', 'Var', (171, 178))	('affinity', 'MPA', (151, 159))	('atRA', 'Chemical', 'MESH:D014212', (163, 167))	('hydrogen bonding interactions', 'MPA', (44, 73))
21709	31419517	The study predicted similar active site volumes of the CYP26A1 and CYP26B1 and similar hydrophobic binding sites, but some differences in the residues that interacted with the carboxylic acid moiety of atRA.	('CYP26B1', 'Var', (67, 74))	('residues', 'MPA', (142, 150))	('CYP26A1', 'Var', (55, 62))	('differences', 'Reg', (123, 134))	('interacted', 'Interaction', (156, 166))	('atRA', 'Chemical', 'MESH:D014212', (202, 206))	('hydrophobic binding', 'MPA', (87, 106))	('carboxylic acid', 'Chemical', 'MESH:D002264', (176, 191))
21712	31419517	The docking simulations successfully predicted the oxidation sites of tazarotenic acid by CYP26A1 and CYP26B1 providing additional confidence towards the active site architecture of the homology models.	('CYP26A1', 'Var', (90, 97))	('tazarotenic acid', 'Chemical', 'MESH:C000609782', (70, 86))	('CYP26B1', 'Var', (102, 109))	('oxidation sites', 'MPA', (51, 66))
21718	31419517	It is likely that fluconazole binds to CYP26A1 as it has been shown to inhibit tazarotenic acid metabolism by CYP26A1, although the inhibition of CYP26A1 mediated 9-cis-RA metabolism by fluconazole is equivocal.	('fluconazole', 'Chemical', 'MESH:D015725', (186, 197))	('inhibit', 'NegReg', (71, 78))	('CYP26A1', 'Var', (110, 117))	('9-cis-RA', 'Chemical', 'MESH:D000077556', (163, 171))	('tazarotenic acid', 'Chemical', 'MESH:C000609782', (79, 95))	('tazarotenic acid metabolism', 'MPA', (79, 106))	('fluconazole', 'Chemical', 'MESH:D015725', (18, 29))
21726	31419517	The orientation of atRA within the CYP26A1 active site was predicted to be such that the beta-ionone ring was on a plane parallel to the heme allowing similar distances of C-16, C-18 and C-4 from the heme iron.	('atRA', 'Chemical', 'MESH:D014212', (19, 23))	('heme', 'Chemical', 'MESH:D006418', (200, 204))	('C-18', 'Gene', (178, 182))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('heme', 'Chemical', 'MESH:D006418', (137, 141))	('iron', 'Chemical', 'MESH:D007501', (205, 209))	('C-16', 'Var', (172, 176))	('beta-ionone', 'Chemical', 'MESH:C008157', (89, 100))	('C-18', 'Gene', '27241', (178, 182))	('C-4', 'Chemical', 'MESH:C058899', (187, 190))	('C', 'Chemical', 'MESH:D002244', (172, 173))	('C', 'Chemical', 'MESH:D002244', (178, 179))
21730	31419517	These include Trp112, Phe222, Phe299, Pro371 and Phe374.	('Phe222', 'Chemical', '-', (22, 28))	('Phe374', 'Var', (49, 55))	('Phe299', 'Chemical', '-', (30, 36))	('Phe299', 'Var', (30, 36))	('Pro371', 'Var', (38, 44))	('Phe374', 'Chemical', '-', (49, 55))	('Trp112', 'Var', (14, 20))	('Trp112', 'Chemical', '-', (14, 20))	('Pro371', 'Chemical', '-', (38, 44))	('Phe222', 'Var', (22, 28))
21732	31419517	Three of the models have predicted Arg90 to interact with atRA carboxylic acid moiety.	('Arg90', 'Chemical', '-', (35, 40))	('atRA carboxylic acid', 'Chemical', '-', (58, 78))	('interact', 'Interaction', (44, 52))	('Arg90', 'Var', (35, 40))
21733	31419517	One model predicted Arg86 to interact with atRA carboxylate and another that Arg64 interacted with the carboxylate moiety.	('Arg64', 'Chemical', '-', (77, 82))	('interacted', 'Interaction', (83, 93))	('Arg64', 'Var', (77, 82))	('interact', 'Interaction', (29, 37))	('Arg86', 'Var', (20, 25))	('atRA carboxylate', 'Chemical', '-', (43, 59))	('carboxylate', 'Chemical', '-', (48, 59))	('Arg86', 'Chemical', '-', (20, 25))	('carboxylate', 'Chemical', '-', (103, 114))	('atRA carboxylate', 'MPA', (43, 59))
21740	31419517	The CYP26C1 model also predicted the existence of a hairpin loop structure (Lys484-Lys504) unique to CYP26C1, which forced atRA to orient differently in the CYP26C1 active site in comparison to atRA bound to CYP120A1.	('CYP', 'Gene', (101, 104))	('atRA', 'Chemical', 'MESH:D014212', (194, 198))	('CYP', 'Gene', (208, 211))	('atRA', 'Chemical', 'MESH:D014212', (123, 127))	('Lys504', 'Chemical', '-', (83, 89))	('CYP', 'Gene', '4051', (101, 104))	('CYP', 'Gene', '4051', (208, 211))	('CYP', 'Gene', (157, 160))	('CYP', 'Gene', '4051', (157, 160))	('CYP', 'Gene', (4, 7))	('Lys484-Lys504', 'Var', (76, 89))	('CYP', 'Gene', '4051', (4, 7))	('Lys484', 'Chemical', '-', (76, 82))
21746	31419517	Both the Cyp26a1-/- and Cyp26b1-/- mice died during gestation or shortly after birth.	('Cyp26a1-/-', 'Var', (9, 19))	('mice', 'Species', '10090', (35, 39))	('Cyp26b1-/-', 'Var', (24, 34))
21748	31419517	The Cyp26a1-/- mice exhibited defects of hind-brain patterning, spina bifida and caudal regression as well as sirenomelia and vertebral transformation.	('caudal regression', 'CPA', (81, 98))	('hind-brain patterning', 'CPA', (41, 62))	('sirenomelia', 'Disease', (110, 121))	('defects', 'NegReg', (30, 37))	('sirenomelia', 'Phenotype', 'HP:0010497', (110, 121))	('spina bifida', 'Phenotype', 'HP:0002414', (64, 76))	('sirenomelia', 'Disease', 'MESH:D004480', (110, 121))	('mice', 'Species', '10090', (15, 19))	('Cyp26a1-/-', 'Var', (4, 14))
21749	31419517	In comparison, Cyp26b1-/- mice had skeletal abnormalities and defects that were most pronounced in limb development (phocomelia, oligodactyly, meromelia) and in craniofacial abnormalities (micrognathia, reduced ossification of calvaria, abnormal tooth buds).	('phocomelia', 'Disease', (117, 127))	('limb development', 'CPA', (99, 115))	('craniofacial abnormalities', 'Disease', 'MESH:D019465', (161, 187))	('reduced', 'NegReg', (203, 210))	('abnormal tooth', 'Phenotype', 'HP:0000164', (237, 251))	('reduced ossification of calvaria', 'Phenotype', 'HP:0005474', (203, 235))	('meromelia', 'Phenotype', 'HP:0030728', (143, 152))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (35, 57))	('oligodactyly', 'Phenotype', 'HP:0012165', (129, 141))	('oligodactyly', 'Disease', (129, 141))	('Cyp26b1-/-', 'Var', (15, 25))	('phocomelia', 'Phenotype', 'HP:0009829', (117, 127))	('craniofacial abnormalities', 'Disease', (161, 187))	('men', 'Species', '9606', (111, 114))	('skeletal abnormalities and defects', 'Disease', 'MESH:D000014', (35, 69))	('reduced ossification', 'Phenotype', 'HP:0002750', (203, 223))	('mice', 'Species', '10090', (26, 30))	('micrognathia', 'Phenotype', 'HP:0000347', (189, 201))	('phocomelia', 'Disease', 'MESH:D004480', (117, 127))
21750	31419517	The Cyp26c1-/- mice did not have an apparent phenotype but the severity of the Cyp26a1-/- phenotype was increased in the Cyp26a1-/-Cyp26c1-/- double knockout mice.	('Cyp26a1-/-Cyp26c1-/-', 'Var', (121, 141))	('increased', 'PosReg', (104, 113))	('mice', 'Species', '10090', (158, 162))	('Cyp26a1-/-', 'Disease', (79, 89))	('mice', 'Species', '10090', (15, 19))
21753	31419517	The gene expression pattern of cyp26a1 was analyzed in developing zebrafish and cyp26a1 was found to be expressed in the anterior neural ectoderm in a complementary pattern with hoxb1b.	('zebrafish', 'Species', '7955', (66, 75))	('hoxb1b', 'Gene', (178, 184))	('hoxb1b', 'Gene', '30374', (178, 184))	('cyp26a1', 'Var', (80, 87))	('men', 'Species', '9606', (157, 160))
21755	31419517	In addition, the authors suggested that cyp26a1 was functionally an enzyme that suppressed the expression of posterior genes in the zebrafish embryo via its role as atRA depleting enzyme.	('atRA', 'Chemical', 'MESH:D014212', (165, 169))	('posterior genes', 'Gene', (109, 124))	('zebrafish', 'Species', '7955', (132, 141))	('suppressed', 'NegReg', (80, 90))	('cyp26a1', 'Var', (40, 47))	('expression', 'MPA', (95, 105))
21756	31419517	Consistent with the role of cyp26a1 in body axis patterning, the phenotype of a zebrafish mutant giraffe was shown to be due to mutations in cyp26a1 resulting in variety of body patterning defects in the fins, tail, spinal cord and hindbrain.	('mutations', 'Var', (128, 137))	('cyp26a1', 'Gene', (141, 148))	('body patterning defects', 'CPA', (173, 196))	('zebrafish', 'Species', '7955', (80, 89))	('giraffe', 'Species', '9894', (97, 104))	('resulting in', 'Reg', (149, 161))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('due', 'Reg', (121, 124))
21758	31419517	The stocksteif mutant, associated with cyp26b1, showed severe hyperossification in the developing zebrafish vertebral column.	('stocksteif', 'Gene', (4, 14))	('stocksteif', 'Gene', '324188', (4, 14))	('hyperossification', 'Disease', (62, 79))	('hyperossification', 'Disease', 'None', (62, 79))	('mutant', 'Var', (15, 21))	('zebrafish', 'Species', '7955', (98, 107))
21759	31419517	Importantly, the phenotype of the stocksteif (cyp26b1) mutant was replicated by treating the zebrafish embryos with the cyp26 inhibitor talarozole (R115866) or with atRA.	('cyp26', 'Gene', '30381', (46, 51))	('talarozole', 'Chemical', 'MESH:C406527', (136, 146))	('stocksteif', 'Gene', (34, 44))	('R115866', 'Chemical', 'MESH:C406527', (148, 155))	('atRA', 'Chemical', 'MESH:D014212', (165, 169))	('R115866', 'Var', (148, 155))	('cyp26', 'Gene', (46, 51))	('mutant', 'Var', (55, 61))	('zebrafish', 'Species', '7955', (93, 102))	('cyp26', 'Gene', '30381', (120, 125))	('stocksteif', 'Gene', '324188', (34, 44))	('cyp26', 'Gene', (120, 125))
21761	31419517	The role of cyp26b1 in ossification and osteoblasts was independently shown at the same time in the dolphin mutant.	('osteoblasts', 'CPA', (40, 51))	('mutant', 'Var', (108, 114))	('cyp26b1', 'Var', (12, 19))	('dolphin', 'Species', '9728', (100, 107))	('ossification', 'CPA', (23, 35))
21762	31419517	The phenotype of the dolphin mutant was shown to be caused by the loss of function of cyp26b1 in this mutant, and this mutation was shown to lead to over-ossification of craniofacial bones and axial skeleton.	('mutant', 'Var', (102, 108))	('-ossification of craniofacial bones', 'Phenotype', 'HP:0004493', (153, 188))	('mutant', 'Var', (29, 35))	('cyp26b1', 'Gene', (86, 93))	('over-ossification', 'CPA', (149, 166))	('loss of function', 'NegReg', (66, 82))	('axial skeleton', 'CPA', (193, 207))	('dolphin', 'Species', '9728', (21, 28))
21763	31419517	Overall the effects of cyp26b1 mutation suggested that the depletion of atRA by cyp26b1 was necessary to attenuate ossification in vivo likely through osteoblast activity.	('attenuate', 'NegReg', (105, 114))	('osteoblast', 'CPA', (151, 161))	('ossification', 'CPA', (115, 127))	('cyp26b1', 'Var', (80, 87))	('cyp26b1', 'Gene', (23, 30))	('atRA', 'Chemical', 'MESH:D014212', (72, 76))	('depletion of atRA', 'MPA', (59, 76))
21768	31419517	In mouse embryos, Cyp26a1 was expressed in mesenchyme that is neural crest derived while Cyp26b1 was found in the ectodermal and endodermal areas.	('Cyp26b1', 'Var', (89, 96))	('Cyp26a1', 'Var', (18, 25))	('mouse', 'Species', '10090', (3, 8))
21773	31419517	It has been suggested that Cyp26b1 plays a critical role in sex-specific timing of meiotic initiation via modulating the concentrations and actions of atRA synthesized by the mesonephros.	('actions', 'MPA', (140, 147))	('Cyp26b1', 'Var', (27, 34))	('concentrations', 'MPA', (121, 135))	('modulating', 'Reg', (106, 116))	('atRA', 'Chemical', 'MESH:D014212', (151, 155))	('rat', 'Species', '10116', (128, 131))
21774	31419517	Strikingly, Cyp26b1 expression was male-specific by E12.5 in the mice suggesting that Cyp26b1 degrades atRA in the developing testis hence preventing the initiation of meiosis.	('degrades', 'NegReg', (94, 102))	('Cyp26b1', 'Var', (86, 93))	('atRA', 'MPA', (103, 107))	('preventing', 'NegReg', (139, 149))	('mice', 'Species', '10090', (65, 69))	('atRA', 'Chemical', 'MESH:D014212', (103, 107))	('initiation of meiosis', 'CPA', (154, 175))
21776	31419517	In the same study it was also shown that meiosis occurred earlier than normal during fetal development in the ovaries of the Cyp26b1-/- mice.	('meiosis', 'CPA', (41, 48))	('mice', 'Species', '10090', (136, 140))	('ovaries', 'Disease', 'MESH:D010051', (110, 117))	('ovaries', 'Disease', (110, 117))	('Cyp26b1-/-', 'Var', (125, 135))	('men', 'Species', '9606', (98, 101))
21777	31419517	In male mouse embryos, Cyp26b1 was found to be expressed in the Sertoli cells, and when Cyp26b1 was selectively deleted in the Sertoli cells, male germ cells entered the mitotic cycle at E15.5-E16.5.	('Sertoli cells', 'Phenotype', 'HP:0100619', (64, 77))	('Cyp26b1', 'Gene', (88, 95))	('Sertoli cell', 'Phenotype', 'HP:0100619', (64, 76))	('Sertoli cell', 'Phenotype', 'HP:0100619', (127, 139))	('mitotic cycle', 'CPA', (170, 183))	('Sertoli cells', 'Phenotype', 'HP:0100619', (127, 140))	('mouse', 'Species', '10090', (8, 13))	('entered', 'Reg', (158, 165))	('deleted', 'Var', (112, 119))
21778	31419517	Importantly, it was found that Cyp26b1 in Sertoli cells not only prevents meiosis but also maintains the mitotic quiescence of the germ cells during embryonic development.	('mitotic quiescence', 'MPA', (105, 123))	('Cyp26b1', 'Var', (31, 38))	('Sertoli cell', 'Phenotype', 'HP:0100619', (42, 54))	('men', 'Species', '9606', (166, 169))	('meiosis', 'CPA', (74, 81))	('prevents', 'NegReg', (65, 73))	('maintains', 'PosReg', (91, 100))	('Sertoli cells', 'Phenotype', 'HP:0100619', (42, 55))
21779	31419517	These findings of Sertoli-cell specific knockouts are consistent with the characterization of the testes of the global Cyp26b1-/- mice, in which relative atRA levels were increased in E12.5 and germ cells were virtually absent in the neonates, likely due to apoptotic extinction of the germ cells during development.	('mice', 'Species', '10090', (130, 134))	('absent', 'NegReg', (220, 226))	('atRA', 'Chemical', 'MESH:D014212', (154, 158))	('Cyp26b1-/-', 'Var', (119, 129))	('E12.5', 'Var', (184, 189))	('men', 'Species', '9606', (311, 314))	('relative atRA levels', 'MPA', (145, 165))	('increased', 'PosReg', (171, 180))
21782	31419517	Using cell-type specific knockout mouse models it was shown that Cyp26 enzymes and Cyp26b1 in particular play an important role in regulating spermatogenesis.	('Cyp26b1', 'Var', (83, 90))	('Cyp26 enzymes', 'Var', (65, 78))	('spermatogenesis', 'CPA', (142, 157))	('mouse', 'Species', '10090', (34, 39))
21785	31419517	In the female reproductive tract, Cyp26b1 transcripts and protein have been detected in the postnatal ovary and the expression of Cyp26b1 was found to be downregulated by activin and TGF-beta.	('expression', 'MPA', (116, 126))	('ovary', 'Disease', (102, 107))	('ovary', 'Disease', 'MESH:D010051', (102, 107))	('downregulated', 'NegReg', (154, 167))	('TGF-beta', 'Gene', (183, 191))	('Cyp26b1', 'Gene', (34, 41))	('activin', 'Gene', (171, 178))	('Cyp26b1', 'Var', (130, 137))	('activin', 'Gene', '83729', (171, 178))	('TGF-beta', 'Gene', '7039', (183, 191))
21786	31419517	Interestingly, Cyp26b1 expression was lost in the mature follicles and Cyp26b1 enzyme was considered to be capable of decreasing the granulosa cell proliferation by degrading atRA, a factor inducing proliferation of this cell type.	('atRA', 'MPA', (175, 179))	('rat', 'Species', '10116', (155, 158))	('decreasing', 'NegReg', (118, 128))	('atRA', 'Chemical', 'MESH:D014212', (175, 179))	('granulosa cell proliferation', 'CPA', (133, 161))	('degrading', 'NegReg', (165, 174))	('rat', 'Species', '10116', (206, 209))	('Cyp26b1 enzyme', 'Var', (71, 85))
21788	31419517	Indeed, both Cyp26a1 and Cyp26b1 mRNA appear to be expressed in the adult brain but the expression level of Cyp26a1 seems variable as it was shown to be low in the mouse and rat brain in some studies but robust in the mouse brain in other studies.	('low', 'NegReg', (153, 156))	('Cyp26a1', 'Var', (108, 115))	('Cyp26b1', 'Var', (25, 32))	('mouse', 'Species', '10090', (164, 169))	('rat', 'Species', '10116', (174, 177))	('mouse', 'Species', '10090', (218, 223))
21791	31419517	In contrast to Cyp26a1, in the rat brain Cyp26b1 mRNA expression was fairly robust with mRNA detected in all the structures analyzed including the striatum, meninges, thalamus, hypothalamus, olfactory bulb, hippocampus, cerebellum and cortex.	('Cyp26b1', 'Var', (41, 48))	('hypothalamus', 'Disease', (177, 189))	('hypothalamus', 'Disease', 'MESH:D007029', (177, 189))	('men', 'Species', '9606', (157, 160))	('rat', 'Species', '10116', (31, 34))
21792	31419517	Interestingly, the Cyp26b1 expression in the rat hippocampus was shown to be restricted to the hilus of the dentate gyrus between the suprapyramidal and infrapyramidal blades, and chemical inhibition of Cyp26b1 was shown to increase the relative atRA levels in the hippocampus.	('Cyp26b1', 'Var', (203, 210))	('atRA', 'Chemical', 'MESH:D014212', (246, 250))	('relative atRA levels', 'MPA', (237, 257))	('chemical inhibition', 'Var', (180, 199))	('increase', 'PosReg', (224, 232))	('Cyp26b1', 'Gene', (19, 26))	('rat', 'Species', '10116', (45, 48))
21793	31419517	This increase in atRA concentrations also decreased cell proliferation, an observation supporting the authors' hypothesis that Cyp26b1 in the hippocampus acts in a paracrine fashion to restrict the distribution and steepness of RA concentration gradients.	('restrict', 'NegReg', (185, 193))	('decreased', 'NegReg', (42, 51))	('cell proliferation', 'CPA', (52, 70))	('atRA', 'Chemical', 'MESH:D014212', (17, 21))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (64, 67))	('RA', 'Chemical', 'MESH:D014212', (228, 230))	('distribution', 'MPA', (198, 210))	('RA', 'Chemical', 'MESH:D014212', (19, 21))	('Cyp26b1', 'Var', (127, 134))	('rat', 'Species', '10116', (238, 241))
21794	31419517	Taken together these findings suggest that Cyp26 enzymes play important roles in maintaining retinoid gradients in the brain but further studies are needed to capture the individual role of Cyp26a1 and Cyp26b1 in maintaining brain tissue health, in neuronal differentiation and in the pathogenesis of neurodegenerative diseases.	('Cyp26b1', 'Var', (202, 209))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (301, 327))	('neuronal differentiation', 'CPA', (249, 273))	('Cyp26a1', 'Var', (190, 197))	('neurodegenerative diseases', 'Disease', (301, 327))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (301, 327))	('retinoid', 'Chemical', 'MESH:D012176', (93, 101))
21795	31419517	Surprisingly, in a recent study global conditional knock-out of Cyp26a1 in adult and juvenile mice was shown to neither have major impact on vitamin A homeostasis and tissue retinoid concentrations nor result in major adverse retinoid toxicities, suggesting that Cyp26b1 is the main Cyp26 enzyme responsible for endogenous atRA homeostasis in postnatal animals.	('knock-out', 'Var', (51, 60))	('rat', 'Species', '10116', (190, 193))	('vitamin A', 'Chemical', 'MESH:D014801', (141, 150))	('retinoid', 'Chemical', 'MESH:D012176', (174, 182))	('mice', 'Species', '10090', (94, 98))	('vitamin A homeostasis', 'MPA', (141, 162))	('retinoid', 'Chemical', 'MESH:D012176', (226, 234))	('Cyp26a1', 'Var', (64, 71))	('atRA', 'Chemical', 'MESH:D014212', (323, 327))	('impact', 'Reg', (131, 137))	('adverse retinoid toxicities', 'Disease', (218, 245))	('adverse retinoid toxicities', 'Disease', 'MESH:D064420', (218, 245))
21798	31419517	When Cyp26a1 and Cyp26b1 were inhibited with talarozole in adult mice, following a single dose administration of talarozole, atRA concentrations increased transiently in the liver, testis and serum but the magnitude of increase in atRA concentrations in serum could only be explained by inhibition of extrahepatic Cyp26b1.	('talarozole', 'Chemical', 'MESH:C406527', (113, 123))	('rat', 'Species', '10116', (103, 106))	('inhibited', 'NegReg', (30, 39))	('rat', 'Species', '10116', (243, 246))	('mice', 'Species', '10090', (65, 69))	('increased', 'PosReg', (145, 154))	('atRA', 'MPA', (125, 129))	('rat', 'Species', '10116', (137, 140))	('talarozole', 'Chemical', 'MESH:C406527', (45, 55))	('atRA', 'Chemical', 'MESH:D014212', (125, 129))	('atRA', 'Chemical', 'MESH:D014212', (231, 235))	('Cyp26a1', 'Gene', (5, 12))	('Cyp26b1', 'Var', (17, 24))
21801	31419517	Cyp26b1 was concluded to play a role in Mast cell activation and in skin inflammatory responses by regulating atRA concentrations and atRA clearance in the skin.	('atRA', 'MPA', (134, 138))	('skin inflammatory responses', 'CPA', (68, 95))	('atRA concentrations', 'MPA', (110, 129))	('atRA', 'Chemical', 'MESH:D014212', (134, 138))	('regulating', 'Reg', (99, 109))	('atRA', 'Chemical', 'MESH:D014212', (110, 114))	('rat', 'Species', '10116', (122, 125))	('Cyp26b1', 'Var', (0, 7))
21802	31419517	As Cyp26b1 was expressed in the skin fibroblasts it was shown to regulate the atRA signal that subsequently results in Mast cell maturation locally in the skin.	('results in', 'Reg', (108, 118))	('atRA', 'Chemical', 'MESH:D014212', (78, 82))	('atRA signal', 'MPA', (78, 89))	('rat', 'Species', '10116', (133, 136))	('regulate', 'Reg', (65, 73))	('Mast cell maturation', 'CPA', (119, 139))	('Cyp26b1', 'Var', (3, 10))
21803	31419517	Inhibition of the Cyp26b1 by liarozole resulted in upregulation of the P2X7, the receptor of extracellular ATP in skin Mast cells, resulting in retinoid dermatitis similar to what was observed in mice treated with RA.	('upregulation', 'PosReg', (51, 63))	('liarozole', 'Chemical', 'MESH:C061121', (29, 38))	('mice', 'Species', '10090', (196, 200))	('P2X7', 'Enzyme', (71, 75))	('retinoid dermatitis', 'Disease', 'MESH:D003872', (144, 163))	('retinoid dermatitis', 'Disease', (144, 163))	('RA', 'Chemical', 'MESH:D014212', (214, 216))	('Cyp26b1', 'Enzyme', (18, 25))	('Inhibition', 'Var', (0, 10))	('ATP', 'Chemical', 'MESH:D000255', (107, 110))	('dermatitis', 'Phenotype', 'HP:0011123', (153, 163))
21804	31419517	These studies suggest that Cyp26b1 expression in skin fibroblasts degrades atRA and hence reduces the paracrine atRA signal that acts on Mast cells to activate inflammatory pathways.	('atRA', 'MPA', (75, 79))	('Cyp26b1', 'Var', (27, 34))	('atRA', 'Chemical', 'MESH:D014212', (112, 116))	('paracrine atRA signal', 'MPA', (102, 123))	('atRA', 'Chemical', 'MESH:D014212', (75, 79))	('inflammatory pathways', 'Pathway', (160, 181))	('reduces', 'NegReg', (90, 97))	('degrades', 'NegReg', (66, 74))
21805	31419517	Cyp26b1 has been shown to be the only Cyp26 enzyme expressed in CD4+ and CD8+ T-cells from mouse lymphoid tissues, and Cyp26b1 expression was specific for the CD44+ effector/memory T-cells.	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CD44', 'Gene', (159, 163))	('CD4', 'Gene', '12504', (64, 67))	('CD4', 'Gene', (159, 162))	('C', 'Chemical', 'MESH:D002244', (159, 160))	('CD44', 'Gene', '12505', (159, 163))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('Cyp26b1', 'Gene', (0, 7))	('C', 'Chemical', 'MESH:D002244', (73, 74))	('CD4', 'Gene', '12504', (159, 162))	('Cyp26b1', 'Var', (119, 126))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('CD4', 'Gene', (64, 67))	('mouse', 'Species', '10090', (91, 96))	('C', 'Chemical', 'MESH:D002244', (38, 39))
21808	31419517	Naive CD4+ T-cells did not have any detectable Cyp26b1 expression but iTreg and TH17 cells both had Cyp26b1 with TH17 cells having significantly higher Cyp26b1 mRNA expression than iTreg cells.	('CD4', 'Gene', (6, 9))	('Cyp26b1', 'Var', (100, 107))	('mRNA expression', 'MPA', (160, 175))	('CD4', 'Gene', '12504', (6, 9))	('Cyp26b1', 'Var', (152, 159))	('higher', 'PosReg', (145, 151))
21810	31419517	In addition, deletion of Cyp26b1 in the T-cells led to a greater frequency of IL17 producing TH17-cells and in CD4+CD25+Foxp3+iTreg cells.	('greater', 'PosReg', (57, 64))	('CD25', 'Gene', '3559', (115, 119))	('Cyp26b1', 'Gene', (25, 32))	('deletion', 'Var', (13, 21))	('CD4', 'Gene', (111, 114))	('Foxp3', 'Gene', '50943', (120, 125))	('IL17', 'Gene', (78, 82))	('CD4', 'Gene', '12504', (111, 114))	('IL17', 'Gene', '3605', (78, 82))	('CD25', 'Gene', (115, 119))	('Foxp3', 'Gene', (120, 125))
21811	31419517	These findings suggest that increased atRA concentrations stimulate IL17 production by TH17 cells and iTreg responses, and Cyp26b1 acts to degrade this atRA and hence limits TH17 and iTreg cell differentiation.	('degrade', 'NegReg', (139, 146))	('rat', 'Species', '10116', (50, 53))	('limits', 'NegReg', (167, 173))	('atRA', 'Chemical', 'MESH:D014212', (38, 42))	('Cyp26b1', 'Var', (123, 130))	('atRA', 'Chemical', 'MESH:D014212', (152, 156))	('IL17', 'Gene', (68, 72))	('IL17', 'Gene', '3605', (68, 72))
21812	31419517	These in vitro findings were shown to be relevant also in vivo in mice as the T-cells isolated from the mice deficient in Cyp26b1 in T-cells failed to induce intestinal inflammation in a mouse model of colitis.	('colitis', 'Disease', (202, 209))	('deficient', 'Var', (109, 118))	('induce', 'Reg', (151, 157))	('intestinal inflammation', 'Disease', 'MESH:D007249', (158, 181))	('intestinal inflammation', 'Disease', (158, 181))	('mice', 'Species', '10090', (104, 108))	('mice', 'Species', '10090', (66, 70))	('colitis', 'Phenotype', 'HP:0002583', (202, 209))	('mouse', 'Species', '10090', (187, 192))	('colitis', 'Disease', 'MESH:D003092', (202, 209))	('Cyp26b1', 'Var', (122, 129))
21813	31419517	Hence the authors concluded that Cyp26b1 enzyme expression is critical in intestinal inflammation and T-cell responses despite lack of effect of Cyp26b1 deletion on homing of the T-cells to the gut.	('lack', 'NegReg', (127, 131))	('intestinal inflammation', 'Disease', 'MESH:D007249', (74, 97))	('deletion', 'Var', (153, 161))	('intestinal inflammation', 'Disease', (74, 97))	('Cyp26b1', 'Gene', (145, 152))
21822	31419517	In a recent study in a panel of human fetal livers mRNA of both CYP26A1 and CYP26B1 were detected although at low levels.	('CYP26A1', 'Var', (64, 71))	('CYP26B1', 'Var', (76, 83))	('human', 'Species', '9606', (32, 37))
21827	31419517	While robust CYP26B1 mRNA expression was detected in the cephalic tissues between gestational ages 57 and 110 days, the absolute expression level normalized to GAPDH expression was 5-10 times higher in these early gestational days than in fetal brains of gestational age 112-224 days or adult brain.	('expression', 'MPA', (129, 139))	('CYP26B1', 'Var', (13, 20))	('higher', 'PosReg', (192, 198))	('GAPDH', 'Gene', '2597', (160, 165))	('GAPDH', 'Gene', (160, 165))
21831	31419517	In adult tissues from individual donors CYP26A1 mRNA was found only in the liver, placenta and testis while CYP26B1 mRNA was detected in the brain, kidney, spleen, thymus, placenta, pancreas, prostate, testis, ovary and intestine.	('ovary', 'Disease', 'MESH:D010051', (210, 215))	('ovary', 'Disease', (210, 215))	('CYP26B1', 'Var', (108, 115))	('CYP26A1', 'Var', (40, 47))
21833	31419517	Generally, of the tissues studied, CYP26B1 mRNA expression was 10-100 times higher than CYP26A1 in the human skin, adipose, cerebellum and vein demonstrating particularly notable expression of CYP26B1 in comparison to CYP26A1.	('mRNA expression', 'MPA', (43, 58))	('human', 'Species', '9606', (103, 108))	('CYP26B1', 'Gene', (35, 42))	('rat', 'Species', '10116', (151, 154))	('higher', 'PosReg', (76, 82))	('CYP26B1', 'Var', (193, 200))
21840	31419517	For example, when CYP26A1 and CYP26B1 protein expression was evaluated in human tissues by western blot, significant expression was detected in the lung, pancreas, skin and uterus.	('human', 'Species', '9606', (74, 79))	('CYP26B1', 'Var', (30, 37))	('expression', 'MPA', (117, 127))
21841	31419517	Similarly, CYP26A1 and CYP26B1 mRNAs were robustly detected in the bone marrow stroma while it appeared that only CYP26A1, although at low levels, was present in the CD34+CD38- human hematopoietic cells.	('CD34', 'Gene', (166, 170))	('CD34', 'Gene', '947', (166, 170))	('CYP26B1', 'Var', (23, 30))	('bone marrow stroma', 'Disease', (67, 85))	('CYP26A1', 'Var', (11, 18))	('CD38', 'Gene', '952', (171, 175))	('bone marrow stroma', 'Disease', 'MESH:D001855', (67, 85))	('human', 'Species', '9606', (177, 182))	('CD38', 'Gene', (171, 175))
21842	31419517	This expression pattern of CYP26 enzymes in the bone marrow niche is important as the authors showed that clearance of atRA by the CYP26 enzymes in the stroma is important in decreasing retinoid signaling and maintaining the primitive hematopoietic cells.	('CYP26 enzymes', 'Var', (131, 144))	('atRA', 'Chemical', 'MESH:D014212', (119, 123))	('retinoid', 'Chemical', 'MESH:D012176', (186, 194))	('decreasing', 'NegReg', (175, 185))	('retinoid signaling', 'MPA', (186, 204))	('primitive hematopoietic cells', 'CPA', (225, 254))
21844	31419517	CYP26A1 and CYP26B1 have both been detected in adult human brain but at expression levels lower than the human liver.	('human', 'Species', '9606', (105, 110))	('human', 'Species', '9606', (53, 58))	('CYP26B1', 'Var', (12, 19))	('CYP26A1', 'Var', (0, 7))
21856	31419517	Yet, the variability in CYP26A1 expression in the human liver is predicted to contribute to a considerable variability in the overall clearance of atRA in the liver as CYP26A1 was predicted to be the main human liver RA hydroxylase.	('variability', 'Var', (9, 20))	('RA', 'Chemical', 'MESH:D014212', (217, 219))	('atRA', 'Chemical', 'MESH:D014212', (147, 151))	('CYP26A1', 'Gene', (24, 31))	('contribute', 'Reg', (78, 88))	('RA', 'Chemical', 'MESH:D014212', (149, 151))	('clearance of atRA in', 'MPA', (134, 154))	('human', 'Species', '9606', (205, 210))	('human', 'Species', '9606', (50, 55))	('variability', 'MPA', (107, 118))
21872	31419517	An interesting aspect of CYP26A1 induction is that the metabolites generated by CYP26A1, 4-OH-RA and 18-OH-RA and the sequential metabolite 4-oxo-RA that is likely formed by an alcohol dehydrogenase, all also induce CYP26A1 mRNA expression in liver models.	('induce', 'Reg', (209, 215))	('18-OH-RA', 'Chemical', '-', (101, 109))	('4-OH-RA', 'Var', (89, 96))	('rat', 'Species', '10116', (71, 74))	('4-oxo-RA', 'Chemical', 'MESH:C002202', (140, 148))	('alcohol dehydrogenase', 'Gene', '10327', (177, 198))	('4-OH-RA', 'Chemical', '-', (89, 96))	('alcohol dehydrogenase', 'Gene', (177, 198))	('CYP26A1', 'Enzyme', (216, 223))	('CYP26A1', 'Var', (80, 87))	('mRNA expression', 'MPA', (224, 239))
21873	31419517	This induction can be explained by the RAR activation by the atRA metabolites, and overall suggests that CYP26A1 functions predominantly to degrade active retinoids rather than forming an active metabolite.	('rat', 'Species', '10116', (165, 168))	('atRA', 'Chemical', 'MESH:D014212', (61, 65))	('degrade', 'NegReg', (140, 147))	('retinoids', 'Chemical', 'MESH:D012176', (155, 164))	('CYP26A1', 'Var', (105, 112))	('active retinoids', 'MPA', (148, 164))
21874	31419517	In addition to the clear role of exogenously administered atRA in inducing CYP26A1 expression, it has also been shown that dietary deficiency of vitamin A in the rat model results in very low Cyp26a1 expression while Cyp26a1 is detectable in vitamin A sufficient diet fed rats.	('dietary deficiency of vitamin A', 'Phenotype', 'HP:0004905', (123, 154))	('rat', 'Species', '10116', (162, 165))	('low', 'NegReg', (188, 191))	('vitamin A', 'Chemical', 'MESH:D014801', (145, 154))	('rats', 'Species', '10116', (272, 276))	('deficiency', 'Var', (131, 141))	('atRA', 'Chemical', 'MESH:D014212', (58, 62))	('vitamin A', 'Chemical', 'MESH:D014801', (242, 251))	('CYP26A1', 'Gene', (75, 82))	('rat', 'Species', '10116', (272, 275))	('Cyp26a1 expression', 'MPA', (192, 210))
21885	31419517	In vivo in rats, Cyp26b1 was shown to be inducible in the lungs by atRA treatment as well as by treatment with a synthetic RARalpha agonist AM580.	('atRA', 'Chemical', 'MESH:D014212', (67, 71))	('men', 'Species', '9606', (101, 104))	('men', 'Species', '9606', (77, 80))	('inducible', 'PosReg', (41, 50))	('rats', 'Species', '10116', (11, 15))	('Cyp26b1', 'Var', (17, 24))
21888	31419517	In immortalized lymphoblast cells from human subjects, CYP26B1 was shown to be highly inducible by atRA treatment while CYP26A1 was not.	('atRA', 'Chemical', 'MESH:D014212', (99, 103))	('inducible', 'Reg', (86, 95))	('CYP26B1', 'Var', (55, 62))	('men', 'Species', '9606', (109, 112))	('human', 'Species', '9606', (39, 44))
21892	31419517	This is notable as the authors hypothesized that the attenuation of Cyp26b1 in T-cells by TGFbeta may function to protect the atRA signaling in T-cells and leading to naive T-cell differentiation to iTreg cells.	('TGFbeta', 'Gene', '7039', (90, 97))	('leading to', 'Reg', (156, 166))	('attenuation', 'Var', (53, 64))	('atRA', 'Chemical', 'MESH:D014212', (126, 130))	('atRA signaling', 'MPA', (126, 140))	('protect', 'PosReg', (114, 121))	('TGFbeta', 'Gene', (90, 97))	('Cyp26b1', 'Var', (68, 75))	('naive T-cell differentiation', 'CPA', (167, 195))
21893	31419517	On the other hand, one may hypothesize that the induction of Cyp26b1 by IL-4 and TNF-alpha functions to decrease atRA signaling and hence decreases IL-17 production and TH17 cell differentiation.	('atRA', 'Chemical', 'MESH:D014212', (113, 117))	('TNF-alpha', 'Gene', (81, 90))	('IL-4', 'Gene', '3565', (72, 76))	('IL-17', 'Gene', (148, 153))	('decreases', 'NegReg', (138, 147))	('IL-17', 'Gene', '3605', (148, 153))	('atRA signaling', 'MPA', (113, 127))	('TH17 cell differentiation', 'CPA', (169, 194))	('decrease', 'NegReg', (104, 112))	('TNF-alpha', 'Gene', '7124', (81, 90))	('Cyp26b1', 'Var', (61, 68))	('IL-4', 'Gene', (72, 76))
21894	31419517	In contrast to CYP26A1, until now no RARE has been identified in the promoter of CYP26B1 although CYP26B1 responds to increased atRA concentrations.	('rat', 'Species', '10116', (140, 143))	('responds to increased atRA concentrations', 'MPA', (106, 147))	('CYP26B1', 'Var', (98, 105))	('atRA', 'Chemical', 'MESH:D014212', (128, 132))
21896	31419517	In studies of vitamin A deficient quail embryos in which retinoid concentrations cannot be detected, the expression of Cyp26a1, Cyp26b1 and Cyp26c1 was unaffected in some developing organs but absent in others, suggesting that multiple regulatory mechanisms are at play in modulating the expression patterns of these enzymes in the developing embryo.	('vitamin A', 'Chemical', 'MESH:D014801', (14, 23))	('vitamin A deficient', 'Phenotype', 'HP:0004905', (14, 33))	('Cyp26b1', 'Var', (128, 135))	('retinoid', 'Chemical', 'MESH:D012176', (57, 65))	('Cyp26a1', 'Var', (119, 126))	('Cyp26c1', 'Var', (140, 147))	('quail', 'Species', '9091', (34, 39))	('rat', 'Species', '10116', (73, 76))
21898	31419517	Taken together these findings suggest that much more work is needed to characterize the regulatory pathways that control CYP26A1 and CYP26B1 gene and protein expression patterns and hence retinoid signaling in different tissues and cell types and in various human pathogenic conditions.	('CYP26B1', 'Var', (133, 140))	('retinoid', 'Chemical', 'MESH:D012176', (188, 196))	('human', 'Species', '9606', (258, 263))	('CYP26A1', 'Gene', (121, 128))
21899	31419517	CYP26 enzymes are critical for appropriate embryonic development and organogenesis, and therefore, loss-of-function mutations in CYP26A1 or CYP26B1 will likely manifest themselves even in heterozygous individuals with some malformations or developmental abnormalities.	('malformations or developmental abnormalities', 'Disease', 'MESH:D000014', (223, 267))	('men', 'Species', '9606', (247, 250))	('CYP26B1', 'Gene', (140, 147))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (240, 267))	('mutations', 'Var', (116, 125))	('malformations or developmental abnormalities', 'Disease', (223, 267))	('men', 'Species', '9606', (60, 63))	('CYP26A1', 'Gene', (129, 136))	('loss-of-function', 'NegReg', (99, 115))
21900	31419517	One may also predict based on mouse models, that homozygous loss-of-function mutations in CYP26A1 or CYP26B1 will lead to early embryonic death and loss of the pregnancies.	('embryonic death', 'Disease', (128, 143))	('loss', 'NegReg', (148, 152))	('mouse', 'Species', '10090', (30, 35))	('CYP26A1', 'Gene', (90, 97))	('pregnancies', 'CPA', (160, 171))	('mutations', 'Var', (77, 86))	('embryonic death', 'Disease', 'MESH:D003643', (128, 143))	('loss-of-function', 'NegReg', (60, 76))	('CYP26B1', 'Gene', (101, 108))
21901	31419517	Indeed, one case that had homozygous loss of function mutation (Arg363Leu) of CYP26B1 was identified (Table 2) after in utero death.	('loss of function', 'NegReg', (37, 53))	('CYP26B1', 'Gene', (78, 85))	('death', 'Disease', 'MESH:D003643', (126, 131))	('death', 'Disease', (126, 131))	('Arg363Leu', 'Var', (64, 73))	('Arg363Leu', 'SUBSTITUTION', 'None', (64, 73))
21903	31419517	Both of these siblings were also homozygous for the loss-of-function mutation (Arg363Leu) of CYP26B1 and had occipital encephaloceles and shortened upper and lower limbs.	('encephaloceles', 'Phenotype', 'HP:0002084', (119, 133))	('encephalocele', 'Phenotype', 'HP:0002084', (119, 132))	('Arg363Leu', 'SUBSTITUTION', 'None', (79, 88))	('loss-of-function', 'NegReg', (52, 68))	('occipital encephaloceles', 'Phenotype', 'HP:0002085', (109, 133))	('CYP26B1', 'Gene', (93, 100))	('occipital encephaloceles', 'Disease', (109, 133))	('lower limbs', 'Phenotype', 'HP:0006385', (158, 169))	('Arg363Leu', 'Var', (79, 88))
21905	31419517	The authors sequenced an additional cohort of subjects with malformations of the skull and discovered another CYP26B1 variant, Ser146Pro substitution (Table 2), in an individual with diagnosis of Antley-Bixler syndrome.	('Ser146Pro', 'SUBSTITUTION', 'None', (127, 136))	('Antley-Bixler syndrome', 'Disease', (196, 218))	('malformations', 'Disease', 'MESH:D000014', (60, 73))	('malformations', 'Disease', (60, 73))	('CYP26B1', 'Gene', (110, 117))	('Antley-Bixler syndrome', 'Disease', 'MESH:D054882', (196, 218))	('Ser146Pro', 'Var', (127, 136))
21906	31419517	Via cell transfection assays this mutation was shown to lack atRA metabolism activity and this individual was a homozygous carrier of the CYP26B1 mutation.	('atRA', 'Chemical', 'MESH:D014212', (61, 65))	('atRA metabolism activity', 'MPA', (61, 85))	('mutation', 'Var', (34, 42))	('lack', 'NegReg', (56, 60))	('CYP26B1', 'Gene', (138, 145))	('mutation', 'Var', (146, 154))
21908	31419517	In another study, a subject was identified with a homozygous genetic variant in CYP26B1 which predicts a Gly435Ser (Table 2) mutation.	('CYP26B1', 'Gene', (80, 87))	('Gly435Ser', 'SUBSTITUTION', 'None', (105, 114))	('Gly435Ser', 'Var', (105, 114))
21911	31419517	Apparent loss-of-function mutations in CYP26C1 have been identified in humans (Table 2), and even homozygous carriers of loss-of-function CYP26C1 mutations were viable as might be predicted from mouse model.	('mutations', 'Var', (146, 155))	('humans', 'Species', '9606', (71, 77))	('CYP26C1', 'Gene', (138, 145))	('mutations', 'Var', (26, 35))	('loss-of-function', 'NegReg', (121, 137))	('loss-of-function', 'NegReg', (9, 25))	('CYP26C1', 'Gene', (39, 46))	('mouse', 'Species', '10090', (195, 200))
21912	31419517	The CYP26C1 loss-of-function genetic variants were discovered through siblings who had a rare syndrome of focal facial dermal dysplasia Type IV.	('CYP26C1', 'Gene', (4, 11))	('focal facial dermal dysplasia Type IV', 'Disease', 'MESH:C537068', (106, 143))	('loss-of-function', 'NegReg', (12, 28))	('variants', 'Var', (37, 45))	('focal facial dermal dysplasia Type IV', 'Disease', (106, 143))
21913	31419517	The siblings carried two different loss-of-function mutations, one in which seven base pairs of the CYP26C1 gene were duplicated leading to a missense mutation, and second that resulted in Arg478His mutation (Table 2).	('loss-of-function', 'NegReg', (35, 51))	('CYP26C1', 'Gene', (100, 107))	('Arg478His', 'Var', (189, 198))	('Arg478His', 'SUBSTITUTION', 'None', (189, 198))	('missense mutation', 'MPA', (142, 159))
21914	31419517	Both of these variants were found to produce a CYP26C1 protein that had no activity towards atRA metabolism.	('variants', 'Var', (14, 22))	('atRA', 'Chemical', 'MESH:D014212', (92, 96))	('CYP26C1', 'Var', (47, 54))	('atRA metabolism', 'MPA', (92, 107))
21915	31419517	Notably, the CYP26C1 gene from four other unrelated patients with focal facial dermal dysplasia Type IV were sequenced and three were found to be homozygous for the seven base pair duplication mutation suggesting that loss-of-function mutations in CYP26C1 cause focal facial dermal dysplasia Type IV.	('loss-of-function', 'NegReg', (218, 234))	('focal facial dermal dysplasia Type IV', 'Disease', (66, 103))	('focal facial dermal dysplasia Type IV', 'Disease', (262, 299))	('mutations', 'Var', (235, 244))	('CYP26C1', 'Gene', (248, 255))	('focal facial dermal dysplasia Type IV', 'Disease', 'MESH:C537068', (262, 299))	('focal facial dermal dysplasia Type IV', 'Disease', 'MESH:C537068', (66, 103))	('patients', 'Species', '9606', (52, 60))
21916	31419517	In comparison Type II or III facial dermal dysplasia patients did not carry the CYP26C1 mutation.	('patients', 'Species', '9606', (53, 61))	('III facial dermal dysplasia', 'Disease', 'MESH:C537068', (25, 52))	('CYP26C1', 'Var', (80, 87))	('III facial dermal dysplasia', 'Disease', (25, 52))
21919	31419517	Several hemizygous microdeletions of CYP26 enzymes have been identified in humans that led to variety of developmental abnormalities.	('developmental abnormalities', 'Phenotype', 'HP:0001263', (105, 132))	('developmental abnormalities', 'Disease', (105, 132))	('CYP26 enzymes', 'Gene', (37, 50))	('led to', 'Reg', (87, 93))	('humans', 'Species', '9606', (75, 81))	('microdeletions', 'Var', (19, 33))	('developmental abnormalities', 'Disease', 'MESH:D006130', (105, 132))
21920	31419517	The subject with the microdeletion had advanced bone age and skeletal and dental development along with retinopathy, microcephaly and developmental delay.	('retinopathy', 'Disease', (104, 115))	('men', 'Species', '9606', (141, 144))	('bone age', 'CPA', (48, 56))	('microcephaly', 'Phenotype', 'HP:0000252', (117, 129))	('retinopathy', 'Phenotype', 'HP:0000488', (104, 115))	('developmental delay', 'Phenotype', 'HP:0001263', (134, 153))	('advanced bone age', 'Phenotype', 'HP:0005616', (39, 56))	('microdeletion', 'Var', (21, 34))	('men', 'Species', '9606', (88, 91))	('microcephaly and developmental delay', 'Disease', 'OMIM:613402', (117, 153))	('retinopathy', 'Disease', 'MESH:D012164', (104, 115))	('advanced', 'PosReg', (39, 47))
21921	31419517	The accelerated bone development was interpreted to be due to the hemizygous loss of CYP26A1 and CYP26C1 expression and elevated serum total RA.	('men', 'Species', '9606', (28, 31))	('accelerated bone development', 'Phenotype', 'HP:0005616', (4, 32))	('serum total RA', 'MPA', (129, 143))	('RA', 'Chemical', 'MESH:D014212', (141, 143))	('accelerated', 'PosReg', (4, 15))	('elevated', 'PosReg', (120, 128))	('loss', 'NegReg', (77, 81))	('CYP26C1', 'Var', (97, 104))	('rat', 'Species', '10116', (10, 13))	('expression', 'MPA', (105, 115))	('bone development', 'CPA', (16, 32))	('CYP26A1', 'Gene', (85, 92))
21922	31419517	However, it is possible that RBP4, the retinol carrier protein also plays a role in this phenotype as the microdeletion also included RBP4.	('RBP4', 'Gene', (134, 138))	('microdeletion', 'Var', (106, 119))	('retinol', 'Chemical', 'MESH:D014801', (39, 46))	('RBP4', 'Gene', '5950', (134, 138))	('RBP4', 'Gene', (29, 33))	('RBP4', 'Gene', '5950', (29, 33))	('included', 'Reg', (125, 133))
21923	31419517	This was not considered likely though as the subject lacked other characteristic symptoms and phenotype that are expected to be observed in individuals with RBP4 mutations.	('RBP4', 'Gene', '5950', (157, 161))	('mutations', 'Var', (162, 171))	('RBP4', 'Gene', (157, 161))
21924	31419517	Another microdeletion of about 300kb in chromosome 10 including CYP26A1 and CYP26C1 was identified in twins with optic nerve aplasia and blindness.	('CYP26A1', 'Gene', (64, 71))	('optic nerve aplasia', 'Phenotype', 'HP:0012521', (113, 132))	('blindness', 'Phenotype', 'HP:0000618', (137, 146))	('optic nerve aplasia', 'Disease', 'MESH:C563493', (113, 132))	('CYP26C1', 'Var', (76, 83))	('blindness', 'Disease', (137, 146))	('blindness', 'Disease', 'MESH:D001766', (137, 146))	('optic nerve aplasia', 'Disease', (113, 132))
21925	31419517	Surprisingly, these twins with haploinsufficiency of CYP26A1 and CYP26C1 had no other developmental defects except the optic nerve aplasia.	('haploinsufficiency', 'Disease', (31, 49))	('optic nerve aplasia', 'Phenotype', 'HP:0012521', (119, 138))	('optic nerve aplasia', 'Disease', 'MESH:C563493', (119, 138))	('developmental defects', 'Disease', (86, 107))	('CYP26C1', 'Var', (65, 72))	('CYP26A1', 'Var', (53, 60))	('developmental defects', 'Disease', 'MESH:D000014', (86, 107))	('haploinsufficiency', 'Disease', 'MESH:D058495', (31, 49))	('optic nerve aplasia', 'Disease', (119, 138))
21932	31419517	In a study that sequenced the CYP26A1 gene from 92 human participants from different races, 13 genetic variants were identified (Table 2) of which three led to amino acid changes.	('amino', 'MPA', (160, 165))	('led to', 'Reg', (153, 159))	('participants', 'Species', '9606', (57, 69))	('human', 'Species', '9606', (51, 56))	('variants', 'Var', (103, 111))	('CYP26A1', 'Gene', (30, 37))
21933	31419517	These three amino acid changes were designated rs61735552 (R173S, CYP26A1*2), rs1376885914 (F186L, CYP26A1*3) and rs146619916 (C358R, CYP26A1*4).	('rs61735552', 'Var', (47, 57))	('rs146619916', 'Mutation', 'rs146619916', (114, 125))	('rs61735552', 'Mutation', 'rs61735552', (47, 57))	('C358R', 'Var', (127, 132))	('R173S', 'Mutation', 'rs61735552', (59, 64))	('F186L', 'Mutation', 'rs1376885914', (92, 97))	('rs1376885914', 'Var', (78, 90))	('rs1376885914', 'Mutation', 'rs1376885914', (78, 90))	('C358R', 'Mutation', 'rs146619916', (127, 132))
21934	31419517	Based on the CYP26A1 homology models, none of the amino acid changes identified would be predicted to alter atRA binding within the CYP26A1 active site.	('atRA', 'Chemical', 'MESH:D014212', (108, 112))	('changes', 'Var', (61, 68))	('alter', 'Reg', (102, 107))	('atRA', 'Protein', (108, 112))
21935	31419517	However, both CYP26A1*3 and CYP26A1*4 variants exhibited significantly lower catalytic rates and metabolite production than the CYP26A1*1 when transfected into COS1 cells.	('CYP26A1*4 variants', 'Var', (28, 46))	('metabolite production', 'MPA', (97, 118))	('catalytic rates', 'MPA', (77, 92))	('variants', 'Var', (38, 46))	('COS1', 'CellLine', 'CVCL:0223', (160, 164))	('CYP26A1*3', 'Var', (14, 23))	('rat', 'Species', '10116', (87, 90))	('lower', 'NegReg', (71, 76))
21937	31419517	4-oxo-atRA and 18-OH-atRA formation catalyzed by the CYP26A1*3 protein was decreased to much greater extent than 4-OH-atRA formation while the formation of all metabolites catalyzed by the CYP26A1*4 protein appeared to be equally affected.	('18-OH-atRA formation', 'MPA', (15, 35))	('4-oxo-atRA', 'MPA', (0, 10))	('CYP26A1*3', 'Var', (53, 62))	('4-oxo-atRA', 'Chemical', 'MESH:C002202', (0, 10))	('4-OH-atRA', 'Chemical', '-', (113, 122))	('18-OH-atRA', 'Chemical', '-', (15, 25))	('decreased', 'NegReg', (75, 84))
21938	31419517	These findings suggest that the F186L variant affects the binding orientation of atRA within CYP26A1 active site.	('binding', 'Interaction', (58, 65))	('affects', 'Reg', (46, 53))	('atRA', 'Chemical', 'MESH:D014212', (81, 85))	('F186L', 'Mutation', 'rs1376885914', (32, 37))	('F186L', 'Var', (32, 37))
21939	31419517	No difference in the metabolite formation rates was observed in the CYP26A1*2 protein when compared to CYP26A1*1 in COS cells.	('C', 'Chemical', 'MESH:D002244', (103, 104))	('metabolite formation', 'MPA', (21, 41))	('CYP26A1*2', 'Var', (68, 77))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('rat', 'Species', '10116', (42, 45))
21944	31419517	Of most interest, a genetic variant causing a frameshift and consequently a premature stop codon in CYP26A1 was identified in a patient with spina bifida.	('spina bifida', 'Phenotype', 'HP:0002414', (141, 153))	('CYP26A1', 'Gene', (100, 107))	('frameshift', 'Var', (46, 56))	('premature', 'MPA', (76, 85))	('causing', 'Reg', (36, 43))	('patient', 'Species', '9606', (128, 135))
21946	31419517	In another study of the role of genetic variants in retinoid metabolizing genes in neural tube defects, a number of variants were identified both in CYP26A1 and CYP26B1.	('neural tube defects', 'Disease', (83, 102))	('variants', 'Var', (116, 124))	('retinoid', 'Chemical', 'MESH:D012176', (52, 60))	('neural tube defects', 'Phenotype', 'HP:0045005', (83, 102))	('CYP26B1', 'Gene', (161, 168))	('CYP26A1', 'Gene', (149, 156))	('variants', 'Var', (40, 48))
21947	31419517	In comparison, two of the variants identified in the CYP26B1 gene caused an amino acid change (L264S, G278R) in the CYP26B1 protein (Table 2).	('CYP26B1', 'Gene', (53, 60))	('caused', 'Reg', (66, 72))	('CYP26B1', 'Gene', (116, 123))	('L264S', 'Var', (95, 100))	('L264S', 'Mutation', 'rs2241057', (95, 100))	('G278R', 'Var', (102, 107))	('G278R', 'Mutation', 'rs371681434', (102, 107))
21948	31419517	In addition to exploring the role of CYP26 genetic variants in developmental defects, the potential link between genetic variation in CYP26A1 or CYP26B1 and various malignancies has also been studied, likely due to the role atRA plays in regulating cell cycle and cell proliferation.	('rat', 'Species', '10116', (276, 279))	('developmental defects', 'Disease', (63, 84))	('malignancies', 'Disease', 'MESH:D009369', (165, 177))	('variants', 'Var', (51, 59))	('atRA', 'Chemical', 'MESH:D014212', (224, 228))	('developmental defects', 'Disease', 'MESH:D000014', (63, 84))	('variation', 'Var', (121, 130))	('malignancies', 'Disease', (165, 177))	('CYP26B1', 'Gene', (145, 152))	('CYP26A1', 'Gene', (134, 141))	('cell', 'CPA', (249, 253))
21949	31419517	A genome-wide association study aiming to identify genetic variants that are associated with esophageal squamous cell carcinoma characterized a genetic variant in CYP26B1 that results in an Arg323Trp change in exon 5 (Table 2).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Arg323Trp', 'Var', (190, 199))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('CYP26B1', 'Gene', (163, 170))	('Arg323Trp', 'SUBSTITUTION', 'None', (190, 199))
21950	31419517	This variant was a low frequency variant and was significantly associated (OR 1.82) with esophageal squamous cell carcinoma with an interaction with lifestyle.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('associated', 'Reg', (63, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('variant', 'Var', (5, 12))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
21951	31419517	When the variant was characterized via transfection into KYSE cells, the Arg323Trp mutant was found to have up to 35% higher activity than the wild type enzyme.	('higher', 'PosReg', (118, 124))	('activity', 'MPA', (125, 133))	('Arg323Trp', 'Var', (73, 82))	('Arg323Trp', 'SUBSTITUTION', 'None', (73, 82))
21952	31419517	Consistent with the presumed role of CYP26B1 in modulating endogenous retinoid homeostasis the authors also discovered that serum atRA concentrations were significantly lower in the subjects that were heterozygous for the CYP26B1 mutation (g.72360331G>A).	('CYP26B1', 'Gene', (222, 229))	('atRA', 'Chemical', 'MESH:D014212', (130, 134))	('g.72360331G>A', 'Mutation', 'rs138478634', (240, 253))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (222, 223))	('serum atRA concentrations', 'MPA', (124, 149))	('retinoid homeostasis', 'Disease', 'MESH:D008232', (70, 90))	('retinoid homeostasis', 'Disease', (70, 90))	('g.72360331G>A', 'Var', (240, 253))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('lower', 'NegReg', (169, 174))	('rat', 'Species', '10116', (142, 145))
21953	31419517	Another study identified the CYP26B1 L264S variant (Table 2), which also has increased activity, as a candidate single nucleotide polymorphism (SNP) that influences prostate specific antigen levels and as such potentially contributes to prostate cancer.	('L264S', 'SUBSTITUTION', 'None', (37, 42))	('CYP26B1', 'Gene', (29, 36))	('L264S', 'Var', (37, 42))	('prostate specific antigen', 'Gene', '354', (165, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (237, 252))	('prostate cancer', 'Disease', (237, 252))	('contributes to', 'Reg', (222, 236))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('prostate specific antigen', 'Gene', (165, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (237, 252))	('influences', 'Reg', (154, 164))
21955	31419517	The presence of rs4411227 SNP (C/G and C/C) was significantly higher in the group of subjects with oral and pharyngeal cancer despite the lack of change in protein sequence in the presence of this SNP.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (108, 125))	('rs4411227', 'Mutation', 'rs4411227', (16, 25))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('higher', 'PosReg', (62, 68))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('rs4411227 SNP', 'Var', (16, 29))
21956	31419517	Similarly, carriers of the rs9309462 (C/T) mutation in CYP26B1 were significantly more likely to have oral and pharyngeal cancer.	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (111, 128))	('cancer', 'Disease', (122, 128))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('rs9309462 (C/T', 'Var', (27, 41))	('CYP26B1', 'Gene', (55, 62))	('rs9309462', 'Mutation', 'rs9309462', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('C', 'Chemical', 'MESH:D002244', (38, 39))
21957	31419517	Interestingly, the study also showed that oral cancers had lower expression of CYP26A1 and CYP26B1 mRNA than the noncancerous adjacent tissue.	('oral cancers', 'Disease', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (116, 122))	('lower', 'NegReg', (59, 64))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('CYP26A1', 'Var', (79, 86))	('CYP26B1 mRNA', 'Var', (91, 103))	('expression', 'MPA', (65, 75))	('oral cancers', 'Disease', 'MESH:D009369', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
21958	31419517	The L264S SNP in CYP26B1 has been evaluated in a number of studies and the allele frequency is 0.17 based on GnomAD database (http://gnomad-old.broadinstitute.org).	('L264S', 'Var', (4, 9))	('L264S', 'Mutation', 'rs2241057', (4, 9))	('CYP26B1', 'Gene', (17, 24))
21959	31419517	This amino acid change has been shown to increase the activity of CYP26B1 via transfection into COS-1 cells and macrophage-like THP-1 cells resulting in decreased atRA concentrations.	('THP-1', 'CellLine', 'CVCL:0006', (128, 133))	('transfection', 'Var', (78, 90))	('atRA concentrations', 'MPA', (163, 182))	('CYP26B1', 'Gene', (66, 73))	('decreased', 'NegReg', (153, 162))	('COS-1', 'CellLine', 'CVCL:0223', (96, 101))	('activity', 'MPA', (54, 62))	('rat', 'Species', '10116', (175, 178))	('atRA', 'Chemical', 'MESH:D014212', (163, 167))	('increase', 'PosReg', (41, 49))
21960	31419517	Interestingly, it was found that in the Stockholm Coronary Atherosclerosis Risk Factor subgroup, presence of this CYP26B1 variant was associated with slightly larger atherosclerotic lesions.	('larger', 'PosReg', (159, 165))	('Atherosclerosis', 'Disease', 'MESH:D050197', (59, 74))	('Atherosclerosis', 'Disease', (59, 74))	('presence', 'Var', (97, 105))	('Coronary Atherosclerosis', 'Phenotype', 'HP:0001677', (50, 74))	('atherosclerotic lesions', 'Disease', (166, 189))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('Atherosclerosis', 'Phenotype', 'HP:0002621', (59, 74))	('atherosclerotic lesions', 'Phenotype', 'HP:0031678', (166, 189))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('atherosclerotic lesions', 'Disease', 'MESH:D050197', (166, 189))	('CYP26B1', 'Gene', (114, 121))
21961	31419517	The authors also found that CYP26B1 mRNA was expressed at higher levels in atherosclerotic lesions when compared to atherosclerosis free arteries, and CYP26B1 expression colocalized with macrophages leading the authors to suggest that CYP26B1 activity may influence development and progression of atherosclerosis.	('development', 'CPA', (266, 277))	('atherosclerosis', 'Phenotype', 'HP:0002621', (297, 312))	('CYP26B1', 'Var', (235, 242))	('atherosclerosis', 'Disease', (297, 312))	('influence', 'Reg', (256, 265))	('atherosclerosis', 'Disease', 'MESH:D050197', (116, 131))	('atherosclerosis', 'Phenotype', 'HP:0002621', (116, 131))	('atherosclerotic lesions', 'Phenotype', 'HP:0031678', (75, 98))	('atherosclerotic lesions', 'Disease', (75, 98))	('CYP26B1', 'Gene', (28, 35))	('higher', 'PosReg', (58, 64))	('atherosclerosis', 'Disease', (116, 131))	('men', 'Species', '9606', (273, 276))	('atherosclerotic lesions', 'Disease', 'MESH:D050197', (75, 98))	('atherosclerosis', 'Disease', 'MESH:D050197', (297, 312))
21963	31419517	The increase in CYP26B1 activity due to the L264S SNP has also been proposed to affect the development of Crohn's disease and particularly early onset Crohn's disease.	('activity', 'MPA', (24, 32))	('affect', 'Reg', (80, 86))	("Crohn's disease", 'Disease', (106, 121))	("Crohn's disease", 'Disease', (151, 166))	("Crohn's disease", 'Disease', 'MESH:D003424', (106, 121))	("Crohn's disease", 'Disease', 'MESH:D003424', (151, 166))	('L264S', 'Var', (44, 49))	('L264S', 'Mutation', 'rs2241057', (44, 49))	('CYP26B1', 'Enzyme', (16, 23))	('men', 'Species', '9606', (98, 101))	('increase', 'PosReg', (4, 12))	("Crohn's disease", 'Phenotype', 'HP:0100280', (106, 121))	("Crohn's disease", 'Phenotype', 'HP:0100280', (151, 166))
21964	31419517	While the frequency of the wild type allele was higher in the Crohn's disease patients (OR 2.2 confidence interval 1.0-4.7, p=0.03/0.09), no difference in the frequencies of CYP26B1 genotypes were observed in Ulcerative colitis and Inflammatory Bowel Disease patients when compared to controls.	("Crohn's disease", 'Phenotype', 'HP:0100280', (62, 77))	("Crohn's disease", 'Disease', 'MESH:D003424', (62, 77))	('patients', 'Species', '9606', (259, 267))	("Crohn's disease", 'Disease', (62, 77))	('Ulcerative colitis and Inflammatory Bowel Disease', 'Disease', 'MESH:D003093', (209, 258))	('CYP26B1', 'Var', (174, 181))	('patients', 'Species', '9606', (78, 86))	('higher', 'PosReg', (48, 54))	('colitis', 'Phenotype', 'HP:0002583', (220, 227))	('Inflammatory Bowel Disease', 'Phenotype', 'HP:0002037', (232, 258))	('Ulcerative colitis', 'Phenotype', 'HP:0100279', (209, 227))
21966	31419517	Based on the expression and importance of CYP26B1 in Th17 and iTreg cell activation it is likely that the higher activity L264S CYP26B1 protein depletes atRA in the T-cells modulating inflammatory pathways and potentially making carriers less prone to Chron's disease.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('atRA', 'Chemical', 'MESH:D014212', (153, 157))	('inflammatory pathways', 'Pathway', (184, 205))	('C', 'Chemical', 'MESH:D002244', (128, 129))	("Chron's disease", 'Disease', (252, 267))	('C', 'Chemical', 'MESH:D002244', (252, 253))	('modulating', 'Reg', (173, 183))	('L264S', 'Mutation', 'rs2241057', (122, 127))	('L264S CYP26B1', 'Var', (122, 135))	('CYP26B1', 'Var', (128, 135))
21967	31419517	Based on these studies this increased activity CYP26B1 SNP seems to be relatively common and further studies are needed to establish its role in human health and in overall retinoid homeostasis in various tissues.	('increased', 'PosReg', (28, 37))	('activity', 'MPA', (38, 46))	('human', 'Species', '9606', (145, 150))	('retinoid homeostasis', 'Disease', 'MESH:D008232', (173, 193))	('retinoid homeostasis', 'Disease', (173, 193))	('CYP26B1 SNP', 'Var', (47, 58))
21972	31419517	13-cisRA has also been recently investigated for the treatment of male infertility with promising results, but further studies are needed to define its efficacy for this indication.	('13-cisRA', 'Chemical', '-', (0, 8))	('13-cisRA', 'Var', (0, 8))	('infertility', 'Phenotype', 'HP:0000789', (71, 82))	('male infertility', 'Disease', 'MESH:D007248', (66, 82))	('male infertility', 'Phenotype', 'HP:0003251', (66, 82))	('male infertility', 'Disease', (66, 82))	('men', 'Species', '9606', (58, 61))
21980	31419517	The oral clearance of atRA decreases with increasing doses and this decrease has been explained by classic saturation kinetics of metabolic enzymes, particularly CYP26A1, which leads to increased oral bioavailability and decreased systemic clearance.	('oral bioavailability', 'MPA', (196, 216))	('rat', 'Species', '10116', (111, 114))	('decreases', 'NegReg', (27, 36))	('atRA', 'Chemical', 'MESH:D014212', (22, 26))	('increased', 'PosReg', (186, 195))	('decreased', 'NegReg', (221, 230))	('oral clearance', 'MPA', (4, 18))	('CYP26A1', 'Var', (162, 169))	('systemic clearance', 'MPA', (231, 249))
22007	31419517	Further, existing data suggests that genetic variants in these enzymes may play a role in development of human disease and in particular in rare diseases.	('genetic variants', 'Var', (37, 53))	('men', 'Species', '9606', (97, 100))	('play', 'Reg', (75, 79))	('role', 'Reg', (82, 86))	('human disease', 'Disease', (105, 118))	('human', 'Species', '9606', (105, 110))	('rare diseases', 'Disease', (140, 153))
22011	31419517	Finally, some of the data presented in this review strongly suggest that CYP26 enzymes may also metabolize synthetic retinoids such as tazarotenic acid.	('metabolize', 'MPA', (96, 106))	('retinoids', 'Chemical', 'MESH:D012176', (117, 126))	('tazarotenic acid', 'Chemical', 'MESH:C000609782', (135, 151))	('CYP26 enzymes', 'Var', (73, 86))
22012	31419517	However, no systemic studies have been undertaken to determine whether CYP26A1 and CYP26B1 that are expressed in the skin contribute to the concentrations and exposure of synthetic retinoids used topically or systemically.	('retinoids', 'Chemical', 'MESH:D012176', (181, 190))	('contribute', 'Reg', (122, 132))	('CYP26B1', 'Var', (83, 90))	('rat', 'Species', '10116', (147, 150))	('concentrations', 'MPA', (140, 154))	('exposure', 'MPA', (159, 167))
22017	27477696	Our data demonstrate that miRNAs with an AAGUGC motif in their seed sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors.	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (26, 29))	('cancer', 'Disease', (91, 97))	('sensitivity', 'MPA', (121, 132))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('increase', 'PosReg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AAGUGC', 'Var', (41, 47))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
22028	27477696	One of the reasons for this incomplete knowledge of oncogenic pro-growth signaling is the multiple levels of regulation used by the cancer cells, that is, epigenetic, transcriptional, translational and posttranslational regulation.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('epigenetic', 'Var', (155, 165))
22031	27477696	miRNAs are small, non-coding RNAs that repress gene expression through base pairing between the miRNA seed sequence (5' nucleotides 1-8) and 3' untranslated regions (3'UTRs) of mRNAs, causing mRNA degradation, translation inhibition or both.	('mRNA degradation', 'MPA', (192, 208))	('gene expression', 'MPA', (47, 62))	('expression', 'Species', '29278', (52, 62))	('base pairing', 'Var', (71, 83))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('translation', 'MPA', (210, 221))	('repress', 'NegReg', (39, 46))
22054	27477696	Flow cytometry analysis showed that miR-372 expression resulted in altered cell cycle distribution in all four miR-372 models, with a general trend of a decrease in the G0/G1 population, and an increase of the S and G2/M populations (Figure 2b).	('G0/G1 population', 'CPA', (169, 185))	('miR-372', 'Gene', '442917', (111, 118))	('miR-372', 'Gene', '442917', (36, 43))	('cell cycle distribution', 'CPA', (75, 98))	('expression', 'Var', (44, 54))	('increase', 'PosReg', (194, 202))	('expression', 'Species', '29278', (44, 54))	('altered', 'Reg', (67, 74))	('miR-372', 'Gene', (111, 118))	('miR-372', 'Gene', (36, 43))	('decrease', 'NegReg', (153, 161))
22055	27477696	In concordance with the results from the functional genomics screen, miR-372 expression resulted in an increased proliferation index, defined as the ratio between S/G2/M cells and G0/G1 cells in three of the miR-372 models (A549, NCI-H1703 and SK-MES-1, Figure 2c).	('miR-372', 'Gene', '442917', (69, 76))	('miR-372', 'Gene', (208, 215))	('expression', 'Species', '29278', (77, 87))	('SK-MES-1', 'CellLine', 'CVCL:0630', (244, 252))	('S/G2', 'Var', (163, 167))	('increased', 'PosReg', (103, 112))	('A549', 'CellLine', 'CVCL:0023', (224, 228))	('S/G2', 'SUBSTITUTION', 'None', (163, 167))	('miR-372', 'Gene', '442917', (208, 215))	('miR-372', 'Gene', (69, 76))	('proliferation index', 'CPA', (113, 132))	('NCI-H1703', 'CellLine', 'CVCL:1490', (230, 239))
22096	27477696	Importantly, tumors with high oncomotif-miRNA expression clustered together irrespective of the relative contribution of different miRNAs, as shown for the three cases with the highest oncomotif-miRNA expression (indicated with an asterisk) but different dominating miRNAs (C19MC cluster miRNAs, miR-371~373 cluster miRNAs and miR-93, respectively, Supplementary Figure 3b).	('miR', 'Gene', '220972', (195, 198))	('miR', 'Gene', '220972', (296, 299))	('expression', 'Species', '29278', (46, 56))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (266, 269))	('miR', 'Gene', '220972', (288, 291))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('C19MC cluster', 'Var', (274, 287))	('miR', 'Gene', (195, 198))	('miR', 'Gene', (296, 299))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('miR', 'Gene', (131, 134))	('miR', 'Gene', '220972', (327, 330))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (288, 291))	('tumors', 'Disease', (13, 19))	('miR', 'Gene', '220972', (316, 319))	('expression', 'Species', '29278', (201, 211))	('miR', 'Gene', (327, 330))	('miR', 'Gene', (40, 43))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('miR', 'Gene', (316, 319))	('miR', 'Gene', '220972', (266, 269))
22097	27477696	When analyzing oncomotif-miRNA expression in relation to common genetic alterations in LUAD, the top two findings were significantly higher expression of oncomotif-miRNAs in tumors harboring TP53 mutation and MYC amplifications (Supplementary Figures 5a and b).	('expression', 'Species', '29278', (140, 150))	('tumors', 'Disease', (174, 180))	('expression', 'MPA', (140, 150))	('mutation', 'Var', (196, 204))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('miR', 'Gene', (164, 167))	('miR', 'Gene', '220972', (164, 167))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('expression', 'Species', '29278', (31, 41))	('TP53', 'Gene', (191, 195))	('higher', 'PosReg', (133, 139))	('miR', 'Gene', (25, 28))	('miR', 'Gene', '220972', (25, 28))	('MYC amplifications', 'Var', (209, 227))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
22098	27477696	In addition, but with lower significance, oncomotif-miRNA expression was higher in tumors with mutated KEAP1 or RB1, and in tumors with TERT amplification.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('expression', 'Species', '29278', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (83, 89))	('KEAP1', 'Gene', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutated', 'Var', (95, 102))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('RB1', 'Gene', (112, 115))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('higher', 'PosReg', (73, 79))
22100	27477696	To test whether these results were independent of genetic alterations associated with oncomotif-miRNA expression, we performed univariate and multivariate survival analysis including also TP53, KEAP1 and RB1 mutation as well as MYC or TERT amplification.	('expression', 'Species', '29278', (102, 112))	('mutation', 'Var', (208, 216))	('RB1', 'Gene', (204, 207))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('MYC', 'Var', (228, 231))	('KEAP1', 'Gene', (194, 199))	('TP53', 'Gene', (188, 192))
22102	27477696	In summary, our analyses show that oncomotif-miRNA expression in LUAD is strongly associated with E2F-driven tumor cell proliferation, TP53 mutation, MYC amplification and shorter relapse-free survival.	('relapse-free survival', 'CPA', (180, 201))	('associated', 'Reg', (82, 92))	('shorter', 'NegReg', (172, 179))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('mutation', 'Var', (140, 148))	('expression', 'Species', '29278', (51, 61))	('miR', 'Gene', '220972', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('LUAD', 'Gene', (65, 69))	('amplification', 'Var', (154, 167))	('miR', 'Gene', (45, 48))	('TP53', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MYC', 'Gene', (150, 153))	('tumor', 'Disease', (109, 114))
22115	27477696	A striking exception from this general pattern was noticed in TGCT where the miR-371~373 cluster was dominating together with the miR-302~367 and C19MC clusters.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('C19MC', 'Var', (146, 151))	('miR', 'Gene', '220972', (77, 80))
22117	27477696	Similar to the results in LUAD, sporadic high expression of oncomotif-miRNAs from the miR-371~373 and C19MC clusters was noticed in several other cancer types (Supplementary Figure 7b).	('C19MC', 'Var', (102, 107))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('expression', 'Species', '29278', (46, 56))	('miR', 'Gene', '220972', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('miR', 'Gene', (70, 73))	('expression', 'MPA', (46, 56))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))
22127	27477696	Also, in BRCA, the expression of oncomotif-miRNAs was higher in tumors harboring TP53 mutation and MYC copy number gain (Supplementary Figure 8b).	('tumors', 'Disease', (64, 70))	('expression', 'MPA', (19, 29))	('miR', 'Gene', '220972', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('miR', 'Gene', (43, 46))	('higher', 'PosReg', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('BRCA', 'Phenotype', 'HP:0003002', (9, 13))	('BRCA', 'Gene', '672', (9, 13))	('BRCA', 'Gene', (9, 13))	('gain', 'PosReg', (115, 119))	('mutation', 'Var', (86, 94))	('MYC', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'Species', '29278', (19, 29))	('TP53', 'Gene', (81, 85))
22148	27477696	This model is further supported by the fact that ectopic expression of oncomotif-miRNAs results in increased proliferation.	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('increased', 'PosReg', (99, 108))	('proliferation', 'CPA', (109, 122))	('expression', 'Species', '29278', (57, 67))	('ectopic expression', 'Var', (49, 67))
22150	27477696	Oncogenic growth signaling, for example, through EGFR or KRAS, results in cyclinD/cdk4-dependent hyperphosphorylation of retinoblastoma protein (RB1), release of activating E2F transcription factors (E2F1-3) from RB1 inhibition and E2F-dependent transcription of genes involved in cell cycle progression.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('E2F1', 'Gene', '100036852', (200, 204))	('E2F1', 'Gene', (200, 204))	('hyperphosphorylation of retinoblastoma', 'Disease', (97, 135))	('KRAS', 'Var', (57, 61))	('release', 'MPA', (151, 158))	('hyperphosphorylation of retinoblastoma', 'Disease', 'MESH:D012175', (97, 135))	('retinoblastoma', 'Phenotype', 'HP:0009919', (121, 135))	('inhibition', 'NegReg', (217, 227))	('transcription', 'MPA', (246, 259))
22163	27477696	In addition, oncomotif-miRNA-dependent inhibition of TGFBR2 would result in further hampering of the senescence program by decreasing the level of additional CDK inhibitors activated by TGF-beta signaling.	('inhibition', 'Var', (39, 49))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('level of', 'MPA', (138, 146))	('senescence program', 'CPA', (101, 119))	('decreasing', 'NegReg', (123, 133))	('hampering', 'NegReg', (84, 93))	('CDK inhibitors', 'MPA', (158, 172))	('TGFBR2', 'Gene', (53, 59))	('TGFBR2', 'Gene', '373815', (53, 59))
22166	27477696	Unfortunately, the apoptosis system is commonly disabled in cancer, for example, through mutation of TP53, which would allow the oncogenic signaling to continue.	('apoptosis', 'CPA', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutation', 'Var', (89, 97))	('cancer', 'Disease', (60, 66))	('TP53', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
22167	27477696	We have shown here that the expression of oncomotif-miRNAs in both LUAD and breast cancer is significantly higher in tumors harboring TP53 mutations, indicating that the oncogenic signaling including oncomotif-miRNAs is tolerated in cells with the apoptotic machinery inactivated.	('TP53', 'Gene', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('miR', 'Gene', '220972', (210, 213))	('LUAD', 'Disease', (67, 71))	('miR', 'Gene', '220972', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('expression', 'Species', '29278', (28, 38))	('tumors', 'Disease', (117, 123))	('miR', 'Gene', (210, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('higher', 'PosReg', (107, 113))	('miR', 'Gene', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('mutations', 'Var', (139, 148))	('expression', 'MPA', (28, 38))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))
22168	27477696	Previous studies have described connections between all individual oncomotif-miRNA containing miRNA clusters and cancer as exemplified by miR-17~92 cluster in lymphoma, miR-106a~363 cluster in T-cell leukemia, miR-106b~25 cluster in gastric cancer, C19MC cluster in CNS-PNET, miR-371~373 cluster in testicular cancer and miR-302~367 cluster in germ cell tumors.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (321, 324))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('germ cell tumor', 'Phenotype', 'HP:0100728', (344, 359))	('cancer', 'Disease', (113, 119))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', '220972', (169, 172))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('miR', 'Gene', (321, 324))	('cancer', 'Disease', (310, 316))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('tumors', 'Phenotype', 'HP:0002664', (354, 360))	('leukemia', 'Phenotype', 'HP:0001909', (200, 208))	('miR', 'Gene', (138, 141))	('miR', 'Gene', (210, 213))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('miR', 'Gene', (169, 172))	('testicular cancer', 'Disease', 'MESH:D013736', (299, 316))	('T-cell leukemia', 'Disease', 'MESH:D015458', (193, 208))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('lymphoma', 'Disease', (159, 167))	('miR', 'Gene', '220972', (94, 97))	('gastric cancer', 'Disease', (233, 247))	('tumors', 'Disease', (354, 360))	('lymphoma', 'Disease', 'MESH:D008223', (159, 167))	('C19MC', 'Var', (249, 254))	('miR', 'Gene', '220972', (276, 279))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('miR', 'Gene', '220972', (77, 80))	('T-cell leukemia', 'Disease', (193, 208))	('testicular cancer', 'Disease', (299, 316))	('germ cell tumors', 'Phenotype', 'HP:0100728', (344, 360))	('miR', 'Gene', (94, 97))	('cancer', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (354, 360))	('gastric cancer', 'Disease', 'MESH:D013274', (233, 247))	('testicular cancer', 'Phenotype', 'HP:0010788', (299, 316))	('miR', 'Gene', (276, 279))
22177	27477696	The addicted cells would then be more sensitive to treatments such as EGFR inhibitors that target upstream signaling.	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('inhibitors', 'Var', (75, 85))
22197	27477696	In cancer, especially when pushed by MYC amplification and without the inhibitory effects of a functional TP53 system, this feed-forward loop becomes a self-propagating, continuous oncogenic driver of uncontrolled cell growth.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('MYC', 'Var', (37, 40))
22275	27477696	Heatmaps were produced using the heatmap.2 function from the gplots package in R. Differences in oncomotif-miRNA expression in the LUAD and BRCA data sets between tumors harboring TP53 mutations and MYC amplifications were examined using the Wilcoxon rank-sum test from the R stats package.	('BRCA', 'Gene', '672', (140, 144))	('BRCA', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TP53', 'Gene', (180, 184))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('miR', 'Gene', '220972', (107, 110))	('mutations', 'Var', (185, 194))	('miR', 'Gene', (107, 110))	('expression', 'Species', '29278', (113, 123))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))
22288	21332505	DBP exposure reduced foetal GC number by ~60% by e15.5 and prolonged GC proliferation, OCT4 and DMRT1 immunoexpression; these effects were induced in the period immediately after testis differentiation (e13.5-e15.5).	('DMRT1', 'Gene', (96, 101))	('foetal GC number', 'CPA', (21, 37))	('DBP', 'Chemical', 'MESH:D003993', (0, 3))	('OCT4', 'Gene', (87, 91))	('prolonged', 'PosReg', (59, 68))	('GC proliferation', 'CPA', (69, 85))	('rat', 'Species', '10116', (79, 82))	('reduced', 'NegReg', (13, 20))	('immunoexpression', 'MPA', (102, 118))	('e15.5', 'Var', (49, 54))
22289	21332505	In contrast, DBP-induced GC aggregation stemmed from late gestation effects (beyond e19.5).	('late gestation', 'Phenotype', 'HP:0001622', (53, 67))	('DBP', 'Chemical', 'MESH:D003993', (13, 16))	('GC aggregation', 'CPA', (25, 39))	('DBP-induced', 'Var', (13, 24))
22302	21332505	DBP/DEHP exposure of rats does not lead to formation of recognizable CIS cells or to development of TGCC in adulthood, but an earlier study showed that foetal exposure of rats to DBP resulted in delayed 'differentiation' of some foetal gonocytes, an effect potentially relevant to CIS origins.	('DBP', 'Var', (179, 182))	('rats', 'Species', '10116', (171, 175))	('DBP', 'Chemical', 'MESH:D003993', (0, 3))	("'differentiation'", 'CPA', (203, 220))	('DBP', 'Chemical', 'MESH:D003993', (179, 182))	('delayed', 'NegReg', (195, 202))	('rats', 'Species', '10116', (21, 25))	('DEHP', 'Chemical', 'MESH:D004051', (4, 8))	('foetal exposure', 'Phenotype', 'HP:0031437', (152, 167))	('men', 'Species', '9606', (92, 95))
22308	21332505	In some studies, DBP or vehicle was administered from e13.5 to e15.5 (termed 'early window') and exposed animals subsequently killed on e17.5, e19.5 or e21.5.	('DBP', 'Chemical', 'MESH:D003993', (17, 20))	('e17.5', 'Var', (136, 141))	('e19.5', 'Var', (143, 148))
22312	21332505	Animals exposed to DBP in foetal life were killed at various foetal (e14.5, e15.5, e17.5, e19.5, e21.5) or postnatal (postnatal days 6, 8, 10, 15) ages depending on the experiment.	('e17.5', 'Var', (83, 88))	('e21.5', 'Var', (97, 102))	('e19.5', 'Var', (90, 95))	('DBP', 'Chemical', 'MESH:D003993', (19, 22))	('e15.5', 'Var', (76, 81))	('men', 'Species', '9606', (175, 178))	('e14.5', 'Var', (69, 74))
22329	21332505	GCs were counted at e14.5, e15.5, e17.5, e19.5, e21.5, Pnd6 and Pnd15 in control and DBP-exposed animals (n = 5-8 per group).	('e21.5', 'Var', (48, 53))	('e19.5', 'Var', (41, 46))	('e15.5', 'Var', (27, 32))	('e14.5', 'Var', (20, 25))	('DBP', 'Chemical', 'MESH:D003993', (85, 88))	('Pnd15', 'Gene', (64, 69))	('e17.5', 'Var', (34, 39))
22334	21332505	DMRT1 was chosen because (i) it plays a highly conserved role in sexual differentiation; (ii) it is expressed in foetal GCs and Sertoli cells; (iii) its knockout in mice results in abnormal GC development; (iv) DMRT1 is associated with maintenance of pluripotency and can regulate a number of pluripotency-associated genes, including OCT4.	('OCT4', 'Gene', (334, 338))	('mice', 'Species', '10090', (165, 169))	('knockout', 'Var', (153, 161))	('results in', 'Reg', (170, 180))	('GC development', 'CPA', (190, 204))	('men', 'Species', '9606', (200, 203))	('DMRT1', 'Gene', (211, 216))	('regulate', 'Reg', (272, 280))	('Sertoli cell', 'Phenotype', 'HP:0100619', (128, 140))	('Sertoli cells', 'Phenotype', 'HP:0100619', (128, 141))
22335	21332505	To calculate the GC PI, or the percentage of GCs expressing OCT4 or DMRT1, 30-50 random fields were examined per testis and GCs were counted as positive or negative for the marker in question (BrdU, OCT4 or DMRT1).	('OCT4', 'Var', (60, 64))	('BrdU', 'Chemical', '-', (193, 197))	('DMRT1', 'Var', (68, 73))	('DMRT1', 'Var', (207, 212))
22345	21332505	The magnitude of the DBP-induced reduction increased from e14.5 (29% reduction) to e15.5 (60% reduction), but thereafter, somewhat lesser reductions were found at e17.5 (48% reduction) and at e19.5-e21.5 (28-38%), perhaps reflecting some recovery of GC numbers because of prolongation of GC proliferation in DBP-exposed animals (see next).	('DBP', 'Chemical', 'MESH:D003993', (21, 24))	('e19.5-e21.5', 'Var', (192, 203))	('reduction', 'NegReg', (33, 42))	('reduction', 'NegReg', (94, 103))	('e17.5', 'Var', (163, 168))	('rat', 'Species', '10116', (298, 301))	('DBP', 'Chemical', 'MESH:D003993', (308, 311))	('e15.5', 'Var', (83, 88))	('GC proliferation', 'CPA', (288, 304))	('reduction', 'NegReg', (69, 78))	('prolongation', 'PosReg', (272, 284))	('e14.5', 'Var', (58, 63))
22351	21332505	We also examined testes from animals 8 h after initial dosing of DBP on e13.5, but at this age, seminiferous cord formation was only initiating and it was thus difficult to identify apoptotic cells (which were rare in any case) unequivocally as GCs.	('DBP', 'Chemical', 'MESH:D003993', (65, 68))	('seminiferous cord formation', 'CPA', (96, 123))	('DBP', 'Var', (65, 68))
22352	21332505	Therefore, although we were unable to demonstrate DBP-induced GC apoptosis soon after treatment on e13.3 or e14.5, this was primarily because of technical/sampling limitations.	('e14.5', 'Var', (108, 113))	('e13.3', 'Var', (99, 104))	('men', 'Species', '9606', (91, 94))	('DBP', 'Chemical', 'MESH:D003993', (50, 53))	('rat', 'Species', '10116', (45, 48))
22354	21332505	In foetal life, GC proliferation was >50% in controls and DBP-exposed animals at e15.5 (Fig.	('e15.5', 'Var', (81, 86))	('DBP', 'Chemical', 'MESH:D003993', (58, 61))	('rat', 'Species', '10116', (26, 29))	('GC proliferation', 'CPA', (16, 32))
22355	21332505	At e17.5, most GCs (>98%) in controls had entered quiescence and this was complete by e19.5, whereas in DBP-exposed animals, significantly more GCs were still proliferating at e17.5 in comparison with controls, although only occasional BrdU-positive cells were evident at e19.5, and none at e21.5 (Fig.	('DBP', 'Chemical', 'MESH:D003993', (104, 107))	('rat', 'Species', '10116', (166, 169))	('quiescence', 'MPA', (50, 60))	('e19.5', 'Var', (86, 91))	('BrdU', 'Chemical', '-', (236, 240))
22358	21332505	The reduced proliferation at around Pnd6 will presumably have exacerbated the reduction in numbers of GCs already present from foetal life in DBP-exposed animals, and presumably explains the greater reduction in GC numbers evident in postnatal compared with foetal life (Fig.	('reduced', 'NegReg', (4, 11))	('DBP', 'Chemical', 'MESH:D003993', (142, 145))	('reduction', 'NegReg', (78, 87))	('Pnd6', 'Var', (36, 40))	('rat', 'Species', '10116', (19, 22))	('proliferation', 'CPA', (12, 25))	('exacerbated', 'PosReg', (62, 73))
22360	21332505	In DBP-exposed animals, significantly more GCs (~50%) expressed OCT4 at e17.5, compared with controls, but by e19.5, most GCs were OCT4-immunonegative (Fig.	('OCT4', 'Protein', (64, 68))	('DBP', 'Chemical', 'MESH:D003993', (3, 6))	('e19.5', 'Var', (110, 115))	('OCT4-immunonegative', 'MPA', (131, 150))
22361	21332505	There was no difference between control and DBP-exposed foetuses in OCT4 mRNA expression, which declined progressively between e15.5 and e21.5 (Fig.	('e21.5', 'Var', (137, 142))	('e15.5', 'Var', (127, 132))	('OCT4', 'Protein', (68, 72))	('DBP', 'Chemical', 'MESH:D003993', (44, 47))	('declined', 'NegReg', (96, 104))
22363	21332505	In contrast, significantly more (>15%) GCs in DBP-exposed animals still expressed DMRT1 at e19.5 than in controls, although only occasional DMRT1-immunopositive GCs were still evident by e21.5 (Fig.	('e19.5', 'Var', (91, 96))	('more', 'PosReg', (27, 31))	('e21.5', 'Var', (187, 192))	('DBP', 'Chemical', 'MESH:D003993', (46, 49))	('DMRT1', 'Var', (82, 87))
22367	21332505	Restriction of DBP exposure to the period e13.5-e15.5 induced similar effects to longer period treatment on GC number (e21.5) and prolongation of expression of OCT4 (e17.5) and DMRT1 (e19.5) (Fig.	('men', 'Species', '9606', (100, 103))	('e17.5', 'Var', (166, 171))	('e13.5-e15.5', 'Var', (42, 53))	('OCT4', 'Gene', (160, 164))	('prolongation', 'PosReg', (130, 142))	('DMRT1', 'Gene', (177, 182))	('DBP', 'Chemical', 'MESH:D003993', (15, 18))	('expression', 'MPA', (146, 156))	('e19.5', 'Var', (184, 189))	('e21.5', 'Var', (119, 124))
22368	21332505	DBP-induced GC aggregation becomes evident at e19.5-e21.5 and was assessed at e21.5 in animals exposed in either an early or late time window or throughout the period e13.5-e20.5.	('e21.5', 'Var', (78, 83))	('GC aggregation', 'CPA', (12, 26))	('DBP', 'Chemical', 'MESH:D003993', (0, 3))
22371	21332505	Our results show that DBP exposure in the period immediately following testis differentiation in the rat (~e13.5) causes a major reduction in foetal GC number and delays differentiation of some foetal GCs as manifest by delayed switching off of OCT4 and DMRT1, delayed entry into quiescence, delayed re-emergence from quiescence (after birth) and delayed re-expression of DMRT1.	('switching off', 'MPA', (228, 241))	('DMRT1', 'Gene', (372, 377))	('rat', 'Species', '10116', (101, 104))	('reduction', 'NegReg', (129, 138))	('OCT4', 'Protein', (245, 249))	('foetal GC number', 'CPA', (142, 158))	('differentiation', 'CPA', (170, 185))	('DBP', 'Chemical', 'MESH:D003993', (22, 25))	('DBP', 'Var', (22, 25))	('delays', 'NegReg', (163, 169))
22373	21332505	The 30-50% reduction in GC numbers induced by DBP also stems from this period.	('DBP', 'Var', (46, 49))	('reduction', 'NegReg', (11, 20))	('DBP', 'Chemical', 'MESH:D003993', (46, 49))	('GC numbers', 'CPA', (24, 34))
22378	21332505	It is therefore of interest that the DBP-induced loss of foetal GCs in the rat occurs similarly early (i.e.	('loss', 'NegReg', (49, 53))	('rat', 'Species', '10116', (75, 78))	('DBP-induced', 'Var', (37, 48))	('DBP', 'Chemical', 'MESH:D003993', (37, 40))	('foetal', 'Protein', (57, 63))
22380	21332505	Indeed, restricting DBP exposure to e13.5-e15.5 resulted in as big a reduction in GC numbers at e21.5 as did continuous exposure from e13.5 to e20.5.	('DBP', 'Chemical', 'MESH:D003993', (20, 23))	('e21.5', 'Var', (96, 101))	('e13.5-e15.5', 'Var', (36, 47))	('reduction', 'NegReg', (69, 78))	('GC numbers', 'CPA', (82, 92))
22384	21332505	We were unable to show that increased apoptosis explained the DBP-induced reduction in GC number in rats, possibly because of the 8-24 h delay between last DBP exposure and sample collection.	('reduction', 'NegReg', (74, 83))	('GC number', 'CPA', (87, 96))	('rats', 'Species', '10116', (100, 104))	('DBP', 'Chemical', 'MESH:D003993', (156, 159))	('DBP-induced', 'Var', (62, 73))	('DBP', 'Chemical', 'MESH:D003993', (62, 65))
22385	21332505	However, in vitro studies using rat, mouse and human foetal testis explants have all shown increased GC apoptosis acutely after MEHP exposure, so it seems reasonable to conclude that transiently increased apoptosis at around e13.5-e14.5 explains our in vivo findings, especially as DBP clearly did not reduce GC proliferation.	('rat', 'Species', '10116', (32, 35))	('GC apoptosis', 'CPA', (101, 113))	('DBP', 'Chemical', 'MESH:D003993', (282, 285))	('rat', 'Species', '10116', (319, 322))	('mouse', 'Species', '10090', (37, 42))	('e13.5-e14.5', 'Var', (225, 236))	('MEHP', 'Chemical', '-', (128, 132))	('human', 'Species', '9606', (47, 52))
22389	21332505	In contrast, DMRT1 immunoexpression in Sertoli cells was unaltered at any age by DBP exposure.	('Sertoli cells', 'Phenotype', 'HP:0100619', (39, 52))	('DBP', 'Var', (81, 84))	('DBP', 'Chemical', 'MESH:D003993', (81, 84))	('DMRT1', 'Gene', (13, 18))	('Sertoli cell', 'Phenotype', 'HP:0100619', (39, 51))
22392	21332505	The DBP-induced alteration in DMRT1 expression is therefore of potential relevance to the origins/causes of human TGCC, although the pattern of change induced (delayed switching off and on) cannot be related in a straightforward manner to the mouse studies in which it was loss of DMRT1 expression that predisposed to teratoma formation.	('mouse', 'Species', '10090', (243, 248))	('DBP', 'Chemical', 'MESH:D003993', (4, 7))	('teratoma', 'Disease', (318, 326))	('teratoma', 'Phenotype', 'HP:0009792', (318, 326))	('teratoma', 'Disease', 'MESH:D013724', (318, 326))	('DMRT1', 'Gene', (281, 286))	('human', 'Species', '9606', (108, 113))	('loss', 'Var', (273, 277))	('rat', 'Species', '10116', (20, 23))	('DMRT1', 'Gene', (30, 35))	('rat', 'Species', '10116', (320, 323))	('alteration', 'Var', (16, 26))
22396	21332505	Arguably, the most important finding from the present studies is the demonstration that all of the effects of DBP exposure on foetal GC number and differentiation were shown to originate within e13.5-e15.5, when GCs are actively proliferating and expressing OCT4.	('differentiation', 'CPA', (147, 162))	('rat', 'Species', '10116', (76, 79))	('foetal GC number', 'CPA', (126, 142))	('rat', 'Species', '10116', (236, 239))	('DBP', 'Chemical', 'MESH:D003993', (110, 113))	('DBP', 'Gene', (110, 113))	('e13.5-e15.5', 'Var', (194, 205))	('OCT4', 'Protein', (258, 262))
22397	21332505	This was the case irrespective of the age at which a particular effect of DBP exposure was first detectable, namely e14.5 (reduced GC number), e17.5 (OCT4 prolongation) or e19.5 (DMRT1 prolongation).	('e17.5', 'Var', (143, 148))	('e19.5', 'Var', (172, 177))	('DBP', 'Chemical', 'MESH:D003993', (74, 77))	('e14.5', 'Var', (116, 121))	('reduced', 'NegReg', (123, 130))
22400	21332505	In contrast, GC aggregation (also reported as increased seminiferous cord diameter), which first manifests at e19.5-e21.5 in rats, was shown to be insensitive to DBP induction by exposure during e13.5-e15.5, but was induced by exposure from e19.5 to e20.5.	('e13.5-e15.5', 'Var', (195, 206))	('increased', 'PosReg', (46, 55))	('e19.5-e21.5', 'Var', (110, 121))	('rats', 'Species', '10116', (125, 129))	('GC aggregation', 'CPA', (13, 27))	('DBP', 'Chemical', 'MESH:D003993', (162, 165))
22418	19951990	Decreased proliferation and survival with low nanomolar concentrations of 5-aza-CdR is associated with ATM activation, H2AX phosphorylation, increased expression of p21, and the induction of genes known to be methylated in TGCTs (MGMT, RASSF1A and HOXA9).	('HOXA9', 'Gene', '3205', (248, 253))	('increased', 'PosReg', (141, 150))	('ATM', 'Gene', '472', (103, 106))	('MGMT', 'Gene', '4255', (230, 234))	('Decreased', 'NegReg', (0, 9))	('H2AX', 'Gene', (119, 123))	('ATM', 'Gene', (103, 106))	('p21', 'Gene', (165, 168))	('expression', 'MPA', (151, 161))	('5-aza', 'Chemical', 'MESH:D001374', (74, 79))	('survival', 'CPA', (28, 36))	('H2AX', 'Gene', '3014', (119, 123))	('phosphorylation', 'MPA', (124, 139))	('MGMT', 'Gene', (230, 234))	('5-aza-CdR', 'Var', (74, 83))	('genes', 'Gene', (191, 196))	('RASSF1A', 'Gene', '11186', (236, 243))	('proliferation', 'CPA', (10, 23))	('HOXA9', 'Gene', (248, 253))	('RASSF1A', 'Gene', (236, 243))	('p21', 'Gene', '1026', (165, 168))
22419	19951990	Notably, 5-aza-CdR hypersensitivity is associated with markedly abundant expression of the pluripotency-associated DNA methyltransferase 3B (DNMT3B) as compared to somatic tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('5-aza', 'Chemical', 'MESH:D001374', (9, 14))	('tumor', 'Disease', (172, 177))	('DNA methyltransferase 3B', 'Gene', '1789', (115, 139))	('pluripotency', 'Disease', (91, 103))	('hypersensitivity', 'Disease', 'MESH:D004342', (19, 35))	('expression', 'MPA', (73, 83))	('DNMT3B', 'Gene', '1789', (141, 147))	('pluripotency', 'Disease', 'None', (91, 103))	('hypersensitivity', 'Disease', (19, 35))	('abundant', 'PosReg', (64, 72))	('5-aza-CdR', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('DNMT3B', 'Gene', (141, 147))	('DNA methyltransferase 3B', 'Gene', (115, 139))
22438	19951990	Notably, high DNMT3B expression is validated as functionally important for 5-aza-CdR-mediated hypersensitivity in both cisplatin sensitive and resistant TGCT cells.	('hypersensitivity in', 'Disease', (94, 113))	('DNMT3B', 'Gene', (14, 20))	('hypersensitivity in', 'Disease', 'MESH:D004342', (94, 113))	('expression', 'MPA', (21, 31))	('5-aza', 'Chemical', 'MESH:D001374', (75, 80))	('DNMT3B', 'Gene', '1789', (14, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('high', 'Var', (9, 13))
22467	19951990	Two mechanisms have been proposed to account for the antitumor effects of 5-aza-CdR, namely, activation of the DNA damage response pathway and re-expression of tumor suppressor genes through DNA demethylation.	('5-aza-CdR', 'Var', (74, 83))	('activation', 'PosReg', (93, 103))	('re-expression', 'MPA', (143, 156))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('demethylation', 'Var', (195, 208))	('5-aza', 'Chemical', 'MESH:D001374', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('DNA damage response pathway', 'Pathway', (111, 138))	('tumor', 'Disease', (160, 165))
22475	19951990	Together the data suggest that low doses of 5-aza-CdR can elicit both a DNA damage response and the induction of genes known to be methylated in TGCTs.	('5-aza-CdR', 'Var', (44, 53))	('elicit', 'Reg', (58, 64))	('DNA damage response', 'MPA', (72, 91))	('induction', 'MPA', (100, 109))	('5-aza', 'Chemical', 'MESH:D001374', (44, 49))
22476	19951990	Five different lentiviral shRNAs for DNMT3B were independently used to knockdown DNMT3B.	('DNMT3B', 'Gene', '1789', (37, 43))	('DNMT3B', 'Gene', (37, 43))	('DNMT3B', 'Gene', '1789', (81, 87))	('DNMT3B', 'Gene', (81, 87))	('knockdown', 'Var', (71, 80))
22481	19951990	Since NT2/D1 cells stably expressing sh84 and NT2/D1-R1 cells stably expressing sh84, sh85 or sh86 had the most efficient knockdown of DNMT3B (Figure 4A and 4B), these cells were tested for 5-aza-CdR sensitivity.	('DNMT3B', 'Gene', (135, 141))	('DNMT3B', 'Gene', '1789', (135, 141))	('knockdown', 'MPA', (122, 131))	('5-aza', 'Chemical', 'MESH:D001374', (190, 195))	('sh84', 'Var', (80, 84))	('sh84', 'Var', (37, 41))
22483	19951990	However, knockdown of DNMT3B by itself had no apparent effect on the growth of NT2/D1 or NT2/D1-R1 cells (data not shown).	('DNMT3B', 'Gene', '1789', (22, 28))	('DNMT3B', 'Gene', (22, 28))	('knockdown', 'Var', (9, 18))
22487	19951990	NT2/D1-R1 cells and control shRNA cells demonstrated an even greater sensitivity to a prolonged 10 day treatment with 5-aza-CdR as compared to the 3 day treatment (Figure 4D).	('men', 'Species', '9606', (108, 111))	('sensitivity', 'MPA', (69, 80))	('5-aza', 'Chemical', 'MESH:D001374', (118, 123))	('5-aza-CdR', 'Var', (118, 127))	('men', 'Species', '9606', (158, 161))
22490	19951990	We previously reported that cisplatin causes a global p53-dominant transcriptional response in EC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('p53', 'Gene', (54, 57))	('EC', 'Phenotype', 'HP:0002898', (95, 97))	('cisplatin', 'Var', (28, 37))	('p53', 'Gene', '7157', (54, 57))
22498	19951990	833K-CP cells were pretreated with 2.5 nM 5-aza-CdR, a dose that results in a 10% growth inhibition (Figure 1).	('5-aza-CdR', 'Var', (42, 51))	('growth', 'MPA', (82, 88))	('5-aza', 'Chemical', 'MESH:D001374', (42, 47))
22501	19951990	Since DNMT3B knockdown reversed 5-aza-CdR hypersensitivity in cisplatin sensitive and resistant EC cells, it was of interest to investigate whether cisplatin sensitivity itself depended on DNMT3B expression.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('DNMT3B', 'Gene', '1789', (6, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('hypersensitivity in', 'Disease', (42, 61))	('DNMT3B', 'Gene', '1789', (189, 195))	('5-aza', 'Chemical', 'MESH:D001374', (32, 37))	('DNMT3B', 'Gene', (6, 12))	('EC', 'Phenotype', 'HP:0002898', (96, 98))	('knockdown', 'Var', (13, 22))	('DNMT3B', 'Gene', (189, 195))	('hypersensitivity in', 'Disease', 'MESH:D004342', (42, 61))
22502	19951990	As shown in Figure 6, DNMT3B knockdown had no appreciable effect on cisplatin sensitivity of the cisplatin resistant EC line NT2/D1-R1.	('cisplatin sensitivity', 'MPA', (68, 89))	('knockdown', 'Var', (29, 38))	('DNMT3B', 'Gene', '1789', (22, 28))	('DNMT3B', 'Gene', (22, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('EC', 'Phenotype', 'HP:0002898', (117, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
22516	19951990	We provide evidence that in EC cells, low dose 5-aza-CdR is able to activate the ATM pathway as well as induce the expression of genes known to be methylated in TGCTs (Figure 3).	('activate', 'PosReg', (68, 76))	('5-aza-CdR', 'Var', (47, 56))	('ATM', 'Gene', (81, 84))	('5-aza', 'Chemical', 'MESH:D001374', (47, 52))	('induce', 'PosReg', (104, 110))	('ATM', 'Gene', '472', (81, 84))	('expression of genes', 'MPA', (115, 134))	('EC', 'Phenotype', 'HP:0002898', (28, 30))
22519	19951990	showed that ES cells and embryos with DNMT1 knockdown were significantly less sensitive to 5-aza-CdR mediated toxicity.	('DNMT1', 'Gene', '1786', (38, 43))	('toxicity', 'Disease', 'MESH:D064420', (110, 118))	('toxicity', 'Disease', (110, 118))	('knockdown', 'Var', (44, 53))	('5-aza', 'Chemical', 'MESH:D001374', (91, 96))	('DNMT1', 'Gene', (38, 43))	('less', 'NegReg', (73, 77))
22523	19951990	In contrast, our preliminary data has thus far not detected large differences in 5-aza-CdR mediated ATM and H2AX activation in DNMT3B knockdown cells, as compared to wild-type EC cells (data not shown).	('ATM', 'Gene', '472', (100, 103))	('H2AX', 'Gene', (108, 112))	('knockdown', 'Var', (134, 143))	('activation', 'PosReg', (113, 123))	('5-aza', 'Chemical', 'MESH:D001374', (81, 86))	('DNMT3B', 'Gene', (127, 133))	('ATM', 'Gene', (100, 103))	('DNMT3B', 'Gene', '1789', (127, 133))	('H2AX', 'Gene', '3014', (108, 112))	('EC', 'Phenotype', 'HP:0002898', (176, 178))
22524	19951990	As DNMTs are known to be auxiliary components of the DNA replication and repair machinery, it is possible that depleting DNMT3B in the EC context alters downstream responses to 5-aza-CdR-mediated DNA damage that perturbs the balance between cell cycle checkpoint arrest, DNA repair, and apoptosis.	('balance', 'MPA', (225, 232))	('responses', 'MPA', (164, 173))	('EC', 'Phenotype', 'HP:0002898', (135, 137))	('apoptosis', 'CPA', (287, 296))	('perturbs', 'Reg', (212, 220))	('cell cycle', 'CPA', (241, 251))	('depleting', 'Var', (111, 120))	('5-aza', 'Chemical', 'MESH:D001374', (177, 182))	('DNMT3B', 'Gene', '1789', (121, 127))	('DNMT3B', 'Gene', (121, 127))	('alters', 'Reg', (146, 152))
22532	19951990	5-aza-CdR is FDA approved for the treatment of myelodysplastic syndrome and shows promise for the treatment of certain leukemias.	('myelodysplastic syndrome', 'Disease', (47, 71))	('5-aza-CdR', 'Var', (0, 9))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (47, 71))	('leukemias', 'Disease', 'MESH:D007938', (119, 128))	('men', 'Species', '9606', (103, 106))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (47, 71))	('leukemias', 'Phenotype', 'HP:0001909', (119, 128))	('men', 'Species', '9606', (39, 42))	('leukemias', 'Disease', (119, 128))	('5-aza', 'Chemical', 'MESH:D001374', (0, 5))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))
22536	19951990	In agreement with our data it has been shown that 5-aza-CdR can sensitize somatic tumor cells to cisplatin, but at dosages considerably higher than that shown here for EC cells.	('men', 'Species', '9606', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('5-aza', 'Chemical', 'MESH:D001374', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('sensitize', 'Reg', (64, 73))	('5-aza-CdR', 'Var', (50, 59))	('tumor', 'Disease', (82, 87))	('EC', 'Phenotype', 'HP:0002898', (168, 170))
22539	19951990	The finding that cisplatin resistant EC cells retain a high degree of sensitivity to low dose 5-aza-CdR and that pretreatment of 5-aza-CdR restores cisplatin cytotoxicity to resistant EC cells is notable since it can be clinically exploited.	('cisplatin', 'Chemical', 'MESH:D002945', (17, 26))	('restores', 'PosReg', (139, 147))	('men', 'Species', '9606', (121, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('5-aza', 'Chemical', 'MESH:D001374', (94, 99))	('5-aza', 'Chemical', 'MESH:D001374', (129, 134))	('EC', 'Phenotype', 'HP:0002898', (37, 39))	('sensitivity', 'MPA', (70, 81))	('cytotoxicity', 'Disease', (158, 170))	('EC', 'Phenotype', 'HP:0002898', (184, 186))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))	('5-aza-CdR', 'Var', (129, 138))
22542	27873769	It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment.	('activity', 'MPA', (59, 67))	('affect', 'Reg', (48, 54))	('GGN', 'Gene', (145, 148))	('GGN', 'Gene', '199720', (145, 148))	('AR', 'Gene', '367', (170, 172))	('TC', 'Phenotype', 'HP:0010788', (221, 223))	('CAG', 'Chemical', '-', (137, 140))	('GGN', 'Gene', (29, 32))	('AR', 'Gene', '367', (75, 77))	('GGN', 'Gene', '199720', (29, 32))	('CAG', 'Chemical', '-', (21, 24))	('men', 'Species', '9606', (229, 232))	('polymorphisms', 'Var', (149, 162))	('sperm production', 'CPA', (198, 214))
22543	27873769	TC patients (n = 130) delivered ejaculates at the following time points: postorchiectomy and at 6, 12, 24, 36, and 60 months posttherapy (T0, T6, T12, T24, T36, and T60).	('T0', 'Var', (138, 140))	('TC', 'Phenotype', 'HP:0010788', (0, 2))	('T12', 'Gene', (146, 149))	('T24', 'Var', (151, 154))	('patients', 'Species', '9606', (3, 11))	('T36', 'Var', (156, 159))	('T60', 'Var', (165, 168))	('T12', 'Gene', '923', (146, 149))
22547	27873769	The least active AR variant seems to be associated with a more rapid recovery of spermatogenesis.	('active', 'MPA', (10, 16))	('AR', 'Gene', '367', (17, 19))	('least', 'NegReg', (4, 9))	('spermatogenesis', 'CPA', (81, 96))	('variant', 'Var', (20, 27))
22564	27873769	Because the AR polymorphism affects the AR activity and some studies indicate that long CAG repeats are associated with male infertility, it is plausible that the genetic variant has an impact on sperm production recovery after TC.	('CAG', 'Chemical', '-', (88, 91))	('male infertility', 'Phenotype', 'HP:0003251', (120, 136))	('male infertility', 'Disease', 'MESH:D007248', (120, 136))	('AR', 'Gene', '367', (40, 42))	('long', 'Var', (83, 87))	('AR', 'Gene', '367', (12, 14))	('TC', 'Phenotype', 'HP:0010788', (228, 230))	('infertility', 'Phenotype', 'HP:0000789', (125, 136))	('sperm production recovery', 'CPA', (196, 221))	('male infertility', 'Disease', (120, 136))	('variant', 'Var', (171, 178))	('associated', 'Reg', (104, 114))	('affects', 'Reg', (28, 35))	('impact', 'Reg', (186, 192))
22567	27873769	With this study, we sought to investigate this possible genetic association between variation in the lengths of the AR CAG and GGN tracts and sperm production recovery following TC treatment in a larger cohort of TC patients.	('CAG', 'Chemical', '-', (119, 122))	('AR', 'Gene', '367', (116, 118))	('TC', 'Phenotype', 'HP:0010788', (178, 180))	('men', 'Species', '9606', (186, 189))	('patients', 'Species', '9606', (216, 224))	('sperm production', 'CPA', (142, 158))	('GGN', 'Gene', (127, 130))	('GGN', 'Gene', '199720', (127, 130))	('TC', 'Phenotype', 'HP:0010788', (213, 215))	('variation', 'Var', (84, 93))
22595	27873769	A unilateral regression model was used to analyze the association between CAG and GGN numbers and sperm concentration at all six time points (T0, T6, T12, T24, T36, and T60).	('T36', 'Var', (160, 163))	('CAG', 'Chemical', '-', (74, 77))	('T0', 'Var', (142, 144))	('T60', 'Var', (169, 172))	('T12', 'Gene', '923', (150, 153))	('GGN', 'Gene', (82, 85))	('T24', 'Var', (155, 158))	('T12', 'Gene', (150, 153))	('sperm concentration', 'CPA', (98, 117))	('GGN', 'Gene', '199720', (82, 85))	('CAG', 'Gene', (74, 77))
22601	27873769	At T12 and T36, men with 22-23 CAG exhibited lower sperm concentrations than those with other CAG numbers; this difference was only statistically significant at T12 (95% CI for ratio: 1.01-2.65; P = 0.045).	('sperm concentrations', 'MPA', (51, 71))	('T36', 'Var', (11, 14))	('lower', 'NegReg', (45, 50))	('T12', 'Gene', '923', (3, 6))	('men', 'Species', '9606', (16, 19))	('CAG', 'Chemical', '-', (31, 34))	('T12', 'Gene', (161, 164))	('T12', 'Gene', '923', (161, 164))	('T12', 'Gene', (3, 6))	('CAG', 'Chemical', '-', (94, 97))
22603	27873769	For trichotomized CAG numbers, both CAG <22 and CAG >23 exhibited higher sperm concentrations than CAG 22-23, and the difference was statistically significant (P = 0.04) for CAG <22 but not for CAG >23 (P = 0.18) (Figure 3).	('CAG', 'Chemical', '-', (194, 197))	('CAG', 'Chemical', '-', (174, 177))	('CAG', 'Chemical', '-', (99, 102))	('CAG >23', 'Var', (48, 55))	('CAG <22', 'Var', (36, 43))	('CAG', 'Chemical', '-', (48, 51))	('higher', 'PosReg', (66, 72))	('CAG <22', 'Var', (174, 181))	('sperm concentrations', 'CPA', (73, 93))	('CAG', 'Chemical', '-', (18, 21))	('CAG', 'Chemical', '-', (36, 39))
22606	27873769	This difference was primarily due to higher sperm numbers in men with short CAG tracts.	('short', 'Var', (70, 75))	('higher', 'PosReg', (37, 43))	('sperm numbers', 'CPA', (44, 57))	('men', 'Species', '9606', (61, 64))	('CAG', 'Chemical', '-', (76, 79))
22610	27873769	Previously, we reported on single-nucleotide polymorphisms (SNP) in the estrogen receptor alpha gene.	('estrogen receptor alpha', 'Gene', (72, 95))	('single-nucleotide polymorphisms', 'Var', (27, 58))	('estrogen receptor alpha', 'Gene', '2099', (72, 95))
22655	26893905	The percentage of progressively motile spermatozoa was assessed at 37  C at x100 and x400 magnification with phase optics in four to six fields chosen at random, in two preparations, the mean value being reported.	('motile spermatozoa', 'Disease', 'MESH:D000072660', (32, 50))	('x400', 'Var', (85, 89))	('motile spermatozoa', 'Disease', (32, 50))
22667	26893905	To discuss the potential use of the frozen sperm samples through Assisted Reproductive Technologies (ART), patients were stratified according to their pathology and to NMSPS categories, defined by a possibly minimal NMSPS required for each strategy: >= 4x106 for Intra-Uterine Insemination (IUI), in the range < 4 x 106 and >=2 x 106 for conventional In Vitro Fertilization (IVF) and < 2 x 106 for Intra Cytoplasmic Sperm Injection (ICSI).	('IVF', 'Disease', (375, 378))	('conventional In Vitro Fertilization', 'CPA', (338, 373))	('>= 4x106', 'Var', (250, 258))	('IVF', 'Disease', 'MESH:C537182', (375, 378))	('patients', 'Species', '9606', (107, 115))
22697	26893905	Sperm chromatin assay (SCSA) revealed sperm DNA damage due to pathology when compared to healthy fertile men.	('pathology', 'Var', (62, 71))	('men', 'Species', '9606', (105, 108))	('sperm DNA damage', 'CPA', (38, 54))
22706	26893905	In addition to common mechanisms in all types of cancer, pre-existing defects in germ cells as part of testicular dysgenesis syndrome could also be involved in case of testicular cancer, as suggested by frequent histological modifications that are found in the controlateral testis.	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (103, 124))	('testicular cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('testicular dysgenesis syndrome', 'Disease', (103, 133))	('testicular dysgenesis syndrome', 'Disease', 'MESH:D013733', (103, 133))	('testicular cancer', 'Phenotype', 'HP:0010788', (168, 185))	('testicular cancer', 'Disease', 'MESH:D013736', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('involved', 'Reg', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (179, 185))	('defects', 'Var', (70, 77))	('cancer', 'Disease', (49, 55))
22746	26431381	Inhibition of migration and invasion was mediated by PPARbeta/delta competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARalpha-dependent matrix metalloproteinase-2 expression and activity.	('RXR', 'Gene', '6256', (150, 153))	('Inhibition', 'NegReg', (0, 10))	('RARalpha', 'Gene', '5914', (192, 200))	('invasion', 'CPA', (28, 36))	('PPARbeta/delta', 'Var', (53, 67))	('retinoic acid receptor', 'Gene', '5914', (100, 122))	('RAR', 'Gene', (192, 195))	('migration', 'CPA', (14, 23))	('retinoic acid receptor', 'Gene', (100, 122))	('matrix metalloproteinase-2', 'Gene', '4313', (211, 237))	('activity', 'MPA', (253, 261))	('RAR', 'Gene', '5914', (124, 127))	('RXR', 'Gene', (150, 153))	('expression', 'MPA', (238, 248))	('RARalpha', 'Gene', (192, 200))	('attenuation', 'NegReg', (177, 188))	('retinoid X receptor', 'Gene', (129, 148))	('retinoid X receptor', 'Gene', '6256', (129, 148))	('RAR', 'Gene', '5914', (192, 195))	('RAR', 'Gene', (124, 127))	('matrix metalloproteinase-2', 'Gene', (211, 237))
22762	26431381	Ligand activation of PPARbeta/delta with GW0742 robustly enhanced expression of ANGPTL4 mRNA in NT2/D1-hPPARbeta/delta cells compared to controls (Figure 1C).	('hPPARbeta', 'Gene', '5467', (103, 112))	('expression', 'MPA', (66, 76))	('ANGPTL4', 'Gene', (80, 87))	('hPPARbeta', 'Gene', (103, 112))	('enhanced', 'PosReg', (57, 65))	('GW0742', 'Var', (41, 47))	('GW0742', 'Chemical', 'MESH:C479979', (41, 47))
22763	26431381	While the higher concentrations of GW0742 did not cause a dose dependent change in ANGPTL4 mRNA, this is likely due to limited quantity of receptor available for agonist activation, saturation of available receptors, and/or competition with endogenous agonists.	('GW0742', 'Var', (35, 41))	('GW0742', 'Chemical', 'MESH:C479979', (35, 41))	('saturation', 'MPA', (182, 192))	('mRNA', 'MPA', (91, 95))	('ANGPTL4', 'Gene', (83, 90))
22770	26431381	Enhanced expression of ANGPTL4 mRNA was also observed following ligand activation of PPARbeta/delta by GW0742 (Figure 2C).	('GW0742', 'Chemical', 'MESH:C479979', (103, 109))	('ANGPTL4', 'Gene', (23, 30))	('Enhanced', 'PosReg', (0, 8))	('activation', 'PosReg', (71, 81))	('PPARbeta/delta', 'Gene', (85, 99))	('expression', 'MPA', (9, 19))	('GW0742', 'Var', (103, 109))
22785	26431381	Expression of PPARbeta/delta was notably higher in xenografts from mice injected with NT2/D1-hPPARbeta/delta cells as compared to controls (Figure 5A), and ligand activation of PPARbeta/delta caused a marked increase in expression of ANGPTL4 in xenografts from mice injected with NT2/D1-hPPARbeta/delta cells as compared to controls (Figure 5B).	('ligand', 'Var', (156, 162))	('PPARbeta/delta', 'Gene', (177, 191))	('Expression', 'MPA', (0, 10))	('expression', 'MPA', (220, 230))	('hPPARbeta', 'Gene', (287, 296))	('ANGPTL4', 'Gene', (234, 241))	('hPPARbeta', 'Gene', '5467', (93, 102))	('mice', 'Species', '10090', (261, 265))	('increase', 'PosReg', (208, 216))	('higher', 'PosReg', (41, 47))	('hPPARbeta', 'Gene', '5467', (287, 296))	('hPPARbeta', 'Gene', (93, 102))	('PPARbeta/delta', 'Gene', (14, 28))	('mice', 'Species', '10090', (67, 71))
22792	26431381	MMP2 zymographic activity was lower in response to ligand activation of PPARbeta/delta with GW0742, and higher in response to the PPARbeta/delta antagonist GSK3787 in NT2/D1-MigR1 cells compared to controls (Figure 8A).	('lower', 'NegReg', (30, 35))	('MMP2', 'Gene', (0, 4))	('GW0742', 'Var', (92, 98))	('GSK3787', 'Chemical', 'MESH:C547957', (156, 163))	('ligand activation', 'MPA', (51, 68))	('MMP2', 'Gene', '4313', (0, 4))	('PPARbeta/delta', 'Gene', (72, 86))	('GW0742', 'Chemical', 'MESH:C479979', (92, 98))	('higher', 'PosReg', (104, 110))
22793	26431381	Co-treatment with GSK3787 and GW0742 mitigated the reduction in MMP2 activity in NT2/D1-MigR1 cells caused by ligand activation of PPARbeta/delta alone, compared to controls (Figure 8A).	('reduction', 'NegReg', (51, 60))	('GSK3787', 'Chemical', 'MESH:C547957', (18, 25))	('MMP2', 'Gene', '4313', (64, 68))	('men', 'Species', '9606', (8, 11))	('GW0742', 'Var', (30, 36))	('mitigated', 'NegReg', (37, 46))	('GW0742', 'Chemical', 'MESH:C479979', (30, 36))	('activation', 'PosReg', (117, 127))	('MMP2', 'Gene', (64, 68))	('GSK3787', 'Var', (18, 25))
22805	26431381	The binding activities were diminished using mutant oligonucleotides, and a super-shift complex was observed in the presence of an anti-RARalpha antibody for the RAR RE (Figure 9B).	('mutant', 'Var', (45, 51))	('RARalpha', 'Gene', (136, 144))	('binding', 'Interaction', (4, 11))	('RAR', 'Gene', (162, 165))	('RAR', 'Gene', '5914', (136, 139))	('diminished', 'NegReg', (28, 38))	('RARalpha', 'Gene', '5914', (136, 144))	('RAR', 'Gene', '5914', (162, 165))	('activities', 'MPA', (12, 22))	('oligonucleotides', 'Chemical', 'MESH:D009841', (52, 68))	('RAR', 'Gene', (136, 139))
22819	26431381	Results from these studies elucidated two unique mechanisms by which PPARbeta/delta inhibits tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PPARbeta/delta', 'Var', (69, 83))	('inhibits', 'NegReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
22823	26431381	However, there remains a need to distinguish whether PPARbeta/delta directly triggers cancer cell differentiation and suppresses tumorigenesis, or if it involves developmental reprogramming and causes the reversal of tumorigenesis by decreasing the pluripotency of cancer stem cells.	('men', 'Species', '9606', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('triggers', 'Reg', (77, 85))	('tumor', 'Disease', (129, 134))	('PPARbeta/delta', 'Var', (53, 67))	('pluripotency of cancer', 'Disease', (249, 271))	('tumor', 'Disease', (217, 222))	('pluripotency of cancer', 'Disease', 'MESH:D009369', (249, 271))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('decreasing', 'NegReg', (234, 244))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('suppresses', 'NegReg', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (265, 271))
22830	26431381	Additionally, NT2/D1 cells also exhibit a similar pattern of DNA methylation as testicular cancer patients at later stage of malignancy, suggesting that NT2/D1 cells are more metastatic than Tera2 cells.	('testicular cancer', 'Phenotype', 'HP:0010788', (80, 97))	('testicular cancer', 'Disease', 'MESH:D013736', (80, 97))	('NT2/D1', 'Var', (153, 159))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('testicular cancer', 'Disease', (80, 97))	('patients', 'Species', '9606', (98, 106))	('malignancy', 'Disease', (125, 135))	('metastatic', 'CPA', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Tera2', 'CellLine', 'CVCL:2777', (191, 196))	('more', 'PosReg', (170, 174))
22834	26431381	The present study used complementary analysis of migration, invasion and MMP expression and activity and revealed strong evidence supporting the prior experiments showing that PPARbeta/delta inhibits MMP-dependent activities in testicular carcinoma cells.	('testicular carcinoma', 'Disease', 'MESH:D013736', (228, 248))	('testicular carcinoma', 'Disease', (228, 248))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (228, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('inhibits', 'NegReg', (191, 199))	('PPARbeta/delta', 'Var', (176, 190))	('men', 'Species', '9606', (29, 32))	('MMP-dependent', 'CPA', (200, 213))	('men', 'Species', '9606', (157, 160))
22840	26431381	The change in CRABPII expression by PPARbeta/delta represents another novel mechanism by which PPARbeta/delta may interfere with RAR-dependent MMP signaling.	('interfere', 'NegReg', (114, 123))	('PPARbeta/delta', 'Var', (95, 109))	('CRABPII', 'Gene', '1382', (14, 21))	('RAR', 'Gene', '5914', (129, 132))	('CRABPII', 'Gene', (14, 21))	('change', 'Reg', (4, 10))	('RAR', 'Gene', (129, 132))	('PPARbeta/delta', 'Var', (36, 50))	('expression', 'MPA', (22, 32))
22847	26431381	Thus, there is accumulating evidence that PPARbeta/delta-induced necrosis may be a common therapeutic/preventive mechanism.	('necrosis', 'Disease', (65, 73))	('necrosis', 'Disease', 'MESH:D009336', (65, 73))	('PPARbeta/delta-induced', 'Var', (42, 64))
22849	26431381	Results from this present study demonstrate that PPARbeta/delta attenuates tumor progression in testicular embryonal carcinoma, in part, through interfering with RARalpha signaling and suppressing MMP2-mediated cell invasion and migration.	('testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (96, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('MMP2', 'Gene', '4313', (197, 201))	('interfering', 'NegReg', (145, 156))	('PPARbeta/delta', 'Var', (49, 63))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (107, 126))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('RARalpha', 'Gene', (162, 170))	('testicular embryonal carcinoma', 'Disease', (96, 126))	('suppressing', 'NegReg', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MMP2', 'Gene', (197, 201))	('tumor', 'Disease', (75, 80))	('RARalpha', 'Gene', '5914', (162, 170))	('attenuates', 'NegReg', (64, 74))
22851	26431381	This study suggests that specific modulation of RARalpha signaling may be a viable approach for the treatment of testicular germ cell tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('germ cell tumors', 'Phenotype', 'HP:0100728', (124, 140))	('RARalpha', 'Gene', (48, 56))	('men', 'Species', '9606', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('RARalpha', 'Gene', '5914', (48, 56))	('modulation', 'Var', (34, 44))
22918	24555040	While the characterisation of risk factors is far from being completed, one of the most promising indicators of TGCT is mutations in c-KIT and KIT ligand - .	('KIT ligand', 'Gene', (143, 153))	('KIT ligand', 'Gene', '17311', (143, 153))	('c-KIT', 'Gene', '16590', (133, 138))	('mutations', 'Var', (120, 129))	('c-KIT', 'Gene', (133, 138))
22947	24555040	Mutations in DND cause testicular teratomas and DND null mice lose their PGCs via apoptosis between E8.5 and E12.5 .	('lose', 'NegReg', (62, 66))	('mice', 'Species', '10090', (57, 61))	('teratomas', 'Phenotype', 'HP:0009792', (34, 43))	('apoptosis', 'CPA', (82, 91))	('PGCs', 'Protein', (73, 77))	('testicular teratomas', 'Phenotype', 'HP:0100616', (23, 43))	('cause', 'Reg', (17, 22))	('testicular teratomas', 'Disease', (23, 43))	('Mutations', 'Var', (0, 9))	('DND', 'Gene', (13, 16))	('teratoma', 'Phenotype', 'HP:0009792', (34, 42))	('testicular teratomas', 'Disease', 'MESH:C562472', (23, 43))
22948	24555040	At E7.5 in the mouse (3 weeks in humans) PLAP (Placental Like Alkaline Phosphatase)-positive PGCs reside in the posterior of the primitive streak and become motile shortly after this time , .	('PGCs', 'Gene', (93, 97))	('humans', 'Species', '9606', (33, 39))	('Placental Like Alkaline Phosphatase', 'Gene', (47, 82))	('PLAP', 'Gene', (41, 45))	('E7.5', 'Var', (3, 7))	('mouse', 'Species', '10090', (15, 20))	('Placental Like Alkaline Phosphatase', 'Gene', '251', (47, 82))
22953	24555040	By E13.5 the gonocytes enter either mitotic arrest in the case of testis, or meiotic arrest in the ovary.	('mitotic arrest', 'Disease', 'MESH:D006323', (36, 50))	('E13.5', 'Var', (3, 8))	('enter', 'Reg', (23, 28))	('meiotic arrest in the ovary', 'Disease', (77, 104))	('mitotic arrest', 'Disease', (36, 50))	('meiotic arrest in the ovary', 'Disease', 'MESH:D006323', (77, 104))
22960	24555040	The risk factors for type II TGCTs include family predisposition, cryptorchidism, disorders of sexual development, high maternal oestrogen during foetal development, environmental exposures, sub- or infertility, and previous TGCTs , , .	('high', 'Var', (115, 119))	('sub- or', 'Disease', (191, 198))	('TGCTs', 'Disease', (225, 230))	('infertility', 'Phenotype', 'HP:0000789', (199, 210))	('infertility', 'Disease', (199, 210))	('infertility', 'Disease', 'MESH:D007247', (199, 210))	('men', 'Species', '9606', (173, 176))	('cryptorchidism', 'Phenotype', 'HP:0000028', (66, 80))	('men', 'Species', '9606', (160, 163))	('men', 'Species', '9606', (109, 112))	('type II TGCTs', 'Disease', (21, 34))	('cryptorchidism', 'Disease', (66, 80))	('disorders of sexual development', 'Disease', (82, 113))
22961	24555040	Additionally, geographical regions with a high rate of TGCTs have lower sperm quality as well as increased rates of cryptorchidism and hypospadias when compared to regions with low rates of TGCTs .	('cryptorchidism', 'Phenotype', 'HP:0000028', (116, 130))	('hypospadias', 'Phenotype', 'HP:0000047', (135, 146))	('increased', 'PosReg', (97, 106))	('TGCTs', 'Var', (55, 60))	('sperm quality', 'CPA', (72, 85))	('lower', 'NegReg', (66, 71))	('cryptorchidism', 'Disease', (116, 130))	('hypospadias', 'Disease', 'MESH:D007021', (135, 146))	('hypospadias', 'Disease', (135, 146))
22963	24555040	Identified genetic factors, including deletions on the Y chromosome, androgen insensitivity, and KIT mutations; negatively impact germ cell development supporting the notion that the risk of TGCTs is established early , , .	('mutations', 'Var', (101, 110))	('KIT', 'Gene', (97, 100))	('TGCTs', 'Disease', (191, 196))	('impact', 'Reg', (123, 129))	('deletions', 'Var', (38, 47))	('androgen insensitivity', 'Phenotype', 'HP:0008226', (69, 91))	('germ cell development', 'CPA', (130, 151))	('negatively', 'NegReg', (112, 122))	('men', 'Species', '9606', (147, 150))
22966	24555040	A partial deletion of the AZoospermia Factor C (AZFC) region (gr/gr mutation) on the short arm of the Y chromosome is also associated with an increased risk of TGCTs .	('associated', 'Reg', (123, 133))	('AZoospermia', 'Phenotype', 'HP:0000027', (26, 37))	('AZoospermia Factor C', 'Disease', (26, 46))	('short arm', 'Phenotype', 'HP:0009824', (85, 94))	('TGCTs', 'Disease', (160, 165))	('AZoospermia Factor C', 'Disease', 'MESH:D053713', (26, 46))	('gr/gr', 'Gene', (62, 67))	('AZFC', 'Gene', (48, 52))	('partial deletion', 'Var', (2, 18))
22967	24555040	Mutations in KIT signalling and continued KIT expression are seen in CIS cells, but not more advanced stages of testicular cancer, indicating that this may be an initial feature of CIS cell specification.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('KIT', 'Gene', (42, 45))	('testicular cancer', 'Phenotype', 'HP:0010788', (112, 129))	('KIT signalling', 'Gene', (13, 27))	('testicular cancer', 'Disease', 'MESH:D013736', (112, 129))	('Mutations', 'Var', (0, 9))	('testicular cancer', 'Disease', (112, 129))	('CIS', 'Phenotype', 'HP:0030075', (181, 184))	('expression', 'MPA', (46, 56))	('CIS', 'Phenotype', 'HP:0030075', (69, 72))
22968	24555040	Furthermore, genetic association studies have identified mutations in genes encoding KIT, KIT ligand and its downstream signalling molecules such as KRAS, SPRY4, and BAK1, as likely predisposition genes for TGCTs , - .	('BAK1', 'Gene', (166, 170))	('KRAS', 'Gene', '16653', (149, 153))	('TGCTs', 'Disease', (207, 212))	('KRAS', 'Gene', (149, 153))	('KIT ligand', 'Gene', (90, 100))	('SPRY4', 'Gene', (155, 160))	('BAK1', 'Gene', '12018', (166, 170))	('KIT', 'Gene', (85, 88))	('mutations', 'Var', (57, 66))	('KIT ligand', 'Gene', '17311', (90, 100))	('SPRY4', 'Gene', '24066', (155, 160))
22971	24555040	Several members of the NOTCH signalling pathway control the mitotic to meiotic switch, and mutations in the NOTCH signalling pathway in C. elegans have been shown to elicit tumour-like expansion of germ cells .	('control', 'Reg', (48, 55))	('elicit', 'Reg', (166, 172))	('tumour', 'Disease', (173, 179))	('NOTCH', 'Gene', (108, 113))	('mitotic', 'CPA', (60, 67))	('NOTCH', 'Gene', '176282', (23, 28))	('NOTCH', 'Gene', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (91, 100))	('NOTCH', 'Gene', '176282', (108, 113))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('C. elegans', 'Species', '6239', (136, 146))
22973	24555040	Additional genetic screening of affected individuals has identified mutations in members of the NOTCH family as primary risk factors for developing these pathologies , .	('mutations', 'Var', (68, 77))	('NOTCH', 'Gene', '176282', (96, 101))	('NOTCH', 'Gene', (96, 101))
22986	24555040	Similarly, rats exposed to phthalates exhibit symptoms similar to testicular dysgenesis, which is also associated with a high risk of TGCT .	('phthalates', 'Chemical', 'MESH:C032279', (27, 37))	('associated', 'Reg', (103, 113))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (66, 87))	('testicular dysgenesis', 'Disease', (66, 87))	('rats', 'Species', '10116', (11, 15))	('phthalates', 'Var', (27, 37))	('testicular dysgenesis', 'Disease', 'MESH:D013733', (66, 87))
22988	24555040	While the power of this study is compromised by the small sample size, the analysis did demonstrate a link between specific cytochrome p450 polymorphisms and an increased rate of TGCT development .	('TGCT development', 'CPA', (179, 195))	('cytochrome p450', 'Enzyme', (124, 139))	('polymorphisms', 'Var', (140, 153))	('men', 'Species', '9606', (191, 194))
23009	24555040	However, more recently the chemokine-mediated CXCR4 pathway has demonstrated some promise in metastasis prediction - with tumours containing localised high CXCL12 expression being less likely to metastasise , .	('less', 'NegReg', (180, 184))	('CXCR4', 'Gene', (46, 51))	('metastasis', 'CPA', (93, 103))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('high', 'Var', (151, 155))	('CXCL12', 'Gene', (156, 162))	('CXCL12', 'Gene', '20315', (156, 162))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', (122, 129))	('CXCR4', 'Gene', '12767', (46, 51))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
23030	24555040	It follows that p53 mutation is usually a key step in tumorigenesis; however, in TGCTs p53 is only rarely inactivated .	('p53', 'Gene', (87, 90))	('p53', 'Gene', (16, 19))	('mutation', 'Var', (20, 28))	('p53', 'Gene', '22060', (87, 90))	('p53', 'Gene', '22060', (16, 19))
23033	24555040	Furthermore, the authors identified LATS2 (Large tumour suppressor homology 2) as a potential target of p53 signalling given that LATS2 deletion accelerates cellular proliferation and tumour development.	('p53', 'Gene', (104, 107))	('LATS2', 'Gene', (130, 135))	('LATS2', 'Gene', (36, 41))	('accelerates', 'PosReg', (145, 156))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('Large tumour suppressor homology 2', 'Gene', (43, 77))	('Large tumour suppressor homology 2', 'Gene', '50523', (43, 77))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('p53', 'Gene', '22060', (104, 107))	('deletion', 'Var', (136, 144))	('cellular proliferation', 'CPA', (157, 179))	('LATS2', 'Gene', '50523', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('LATS2', 'Gene', '50523', (130, 135))	('men', 'Species', '9606', (198, 201))	('tumour', 'Disease', (184, 190))	('tumour', 'Disease', (49, 55))
23034	24555040	This can be phenocopied in some seminomas, which do not overexpress miR-372 or miR-373, by mutations in LATS2.	('miR', 'Gene', (68, 71))	('LATS2', 'Gene', '50523', (104, 109))	('seminomas', 'Disease', 'MESH:D018239', (32, 41))	('miR', 'Gene', (79, 82))	('mutations', 'Var', (91, 100))	('miR', 'Gene', '751557', (68, 71))	('LATS2', 'Gene', (104, 109))	('seminomas', 'Disease', (32, 41))	('miR', 'Gene', '751557', (79, 82))
23042	24555040	The loss of PTEN is also associated with the transformation of CIS cells into overt cancerous tumours .	('cancerous tumours', 'Disease', 'MESH:D009369', (84, 101))	('PTEN', 'Gene', '19211', (12, 16))	('associated', 'Reg', (25, 35))	('PTEN', 'Gene', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('cancerous tumours', 'Disease', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('CIS', 'Phenotype', 'HP:0030075', (63, 66))	('loss', 'Var', (4, 8))
23043	24555040	Furthermore, increased relapse rate in TGCTs has also been found to be associated with the loss of PIK3IP1, an additional negative regulator of PIK kinase .	('relapse rate', 'CPA', (23, 35))	('TGCTs', 'Disease', (39, 44))	('PIK3IP1', 'Gene', (99, 106))	('PIK3IP1', 'Gene', '216505', (99, 106))	('loss', 'Var', (91, 95))	('increased', 'PosReg', (13, 22))
23055	24555040	Additionally, upon knockout of the miR-290 cluster, aberrant migration of germ cells has been observed with significantly fewer primordial germ cells reaching the bipotential gonad .	('fewer', 'NegReg', (122, 127))	('miR-290', 'Gene', '100049710', (35, 42))	('miR-290', 'Gene', (35, 42))	('knockout', 'Var', (19, 27))
23079	32167697	Multivariate analysis identified that positive expressions to ERCC1 and NF-kappaB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively).	('TGCT', 'Disease', (133, 137))	('ERCC1', 'Gene', (62, 67))	('positive expressions', 'Var', (38, 58))	('ERCC1', 'Gene', '2067', (62, 67))	('NF-kappaB', 'Gene', '4790', (72, 81))	('NF-kappaB', 'Gene', (72, 81))
23080	32167697	Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001).	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (60, 76))	('ERCC1', 'Gene', '2067', (37, 42))	('ERCC1', 'Gene', (37, 42))	('poor', 'NegReg', (55, 59))	('positive expression', 'Var', (14, 33))
23088	32167697	In fact, adducts between platinum and DNA inhibit cellular processes, such as replication, transcription, translation and DNA repair.	('DNA repair', 'CPA', (122, 132))	('replication', 'CPA', (78, 89))	('transcription', 'CPA', (91, 104))	('translation', 'CPA', (106, 117))	('inhibit', 'NegReg', (42, 49))	('platinum', 'Chemical', 'MESH:D010984', (25, 33))	('cellular processes', 'CPA', (50, 68))	('adducts', 'Var', (9, 16))
23090	32167697	Furthermore, cisplatin binding to the mitochondrial DNA leads to decreased ATP and thus the decrease in ATPase activity and modification of the calcium content.	('decrease', 'NegReg', (92, 100))	('ATP', 'MPA', (75, 78))	('decreased', 'NegReg', (65, 74))	('ATPase', 'Gene', '1769', (104, 110))	('activity', 'MPA', (111, 119))	('cisplatin', 'Var', (13, 22))	('ATPase', 'Gene', (104, 110))	('modification', 'Reg', (124, 136))	('ATP', 'Chemical', 'MESH:D000255', (104, 107))	('calcium', 'Chemical', 'MESH:D002118', (144, 151))	('calcium content', 'MPA', (144, 159))	('binding', 'Interaction', (23, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))
23103	32167697	A previous study showed that high expression of ERCC1 was associated with non-sensitivity to cisplatin-based CT in patients with non-seminomas TGCT, but little is known about other mechanisms involved in platinum resistance in testicular cancer.	('non-seminoma', 'Disease', (129, 141))	('patients', 'Species', '9606', (115, 123))	('high expression', 'Var', (29, 44))	('testicular cancer', 'Disease', (227, 244))	('associated', 'Reg', (58, 68))	('ERCC1', 'Gene', '2067', (48, 53))	('ERCC1', 'Gene', (48, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('non-seminoma', 'Disease', 'MESH:D018239', (129, 141))	('non-sensitivity to cisplatin-based CT', 'MPA', (74, 111))	('platinum', 'Chemical', 'MESH:D010984', (204, 212))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('seminomas', 'Disease', 'MESH:D018239', (133, 142))	('testicular cancer', 'Phenotype', 'HP:0010788', (227, 244))	('seminomas', 'Disease', (133, 142))	('testicular cancer', 'Disease', 'MESH:D013736', (227, 244))
23141	32167697	Interestingly, we showed, for the first time, that the risk for relapse is around three times as high in the group NF-kappaB positive when compared to NF-kappaB negative, and this difference remains even after the adjustment of a potential factor of influence, with the exception of the tumor maker LDH (Figure-2B).	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('NF-kappaB', 'Gene', '4790', (151, 160))	('NF-kappaB', 'Gene', '4790', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('positive', 'Var', (125, 133))	('NF-kappaB', 'Gene', (151, 160))	('NF-kappaB', 'Gene', (115, 124))	('men', 'Species', '9606', (220, 223))
23151	32167697	Our results showed that the expression of ERCC1 is associated with increased risk for TGCT relapse after treatment with platinum-based chemotherapy.	('ERCC1', 'Gene', '2067', (42, 47))	('ERCC1', 'Gene', (42, 47))	('men', 'Species', '9606', (110, 113))	('TGCT relapse', 'Disease', (86, 98))	('associated', 'Reg', (51, 61))	('expression', 'Var', (28, 38))	('platinum', 'Chemical', 'MESH:D010984', (120, 128))
23156	32167697	demonstrated that the benefit of adjuvant chemotherapy with cisplatin was lost when there was a high expression of ERCC1 in the small-cell lung cancer tumor.	('lost', 'NegReg', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Disease', (151, 156))	('ERCC1', 'Gene', '2067', (115, 120))	('ERCC1', 'Gene', (115, 120))	('cancer', 'Disease', (144, 150))	('high expression', 'Var', (96, 111))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
23157	32167697	In patients with squamous cell carcinoma, the expression of ERCC1 predicts a lower response to chemotherapy treatment.	('response to chemotherapy treatment', 'MPA', (83, 117))	('lower', 'NegReg', (77, 82))	('expression', 'Var', (46, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('patients', 'Species', '9606', (3, 11))	('men', 'Species', '9606', (113, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('ERCC1', 'Gene', '2067', (60, 65))	('ERCC1', 'Gene', (60, 65))	('squamous cell carcinoma', 'Disease', (17, 40))
23158	32167697	Interestingly, overexpression of ERCC1 gene seems to be associated with a reduction in the therapeutic efficacy of cisplatin, and the clinical response varies with polymorphisms ERCC1.	('overexpression', 'PosReg', (15, 29))	('ERCC1', 'Gene', '2067', (178, 183))	('ERCC1', 'Gene', (178, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('reduction', 'NegReg', (74, 83))	('polymorphisms', 'Var', (164, 177))	('ERCC1', 'Gene', (33, 38))	('clinical', 'Species', '191496', (134, 142))	('ERCC1', 'Gene', '2067', (33, 38))	('therapeutic efficacy of cisplatin', 'MPA', (91, 124))
23205	21868749	Adult male homozygous (p53 -/-) and female heterozygous (p53+/-) B6.129S2-Trp53tm1Tyj/J mice were obtained from Jackson Laboratories (Bar Harbor, ME) and bred in-house.	('rat', 'Species', '10116', (124, 127))	('B6.129S2', 'CellLine', 'CVCL:C319', (65, 73))	('B6.129S2-Trp53tm1Tyj/J', 'Var', (65, 87))	('mice', 'Species', '10090', (88, 92))	('p53 -/-', 'Var', (23, 30))
23214	21868749	Male p53-null mice treated with 250 mg/kg DBP in utero were separated from dams after weaning (PND 25), and housed until signs related to tumor development appeared, such as weight loss (10-15% of body weight) and lethargy, at which time they were euthanized by CO2 asphyxiation.	('men', 'Species', '9606', (151, 154))	('weight loss', 'Disease', (174, 185))	('DBP', 'Chemical', 'MESH:D003993', (42, 45))	('DBP', 'Var', (42, 45))	('tumor', 'Disease', (138, 143))	('mice', 'Species', '10090', (14, 18))	('weight loss', 'Phenotype', 'HP:0001824', (174, 185))	('rat', 'Species', '10116', (64, 67))	('lethargy', 'CPA', (214, 222))	('weight loss', 'Disease', 'MESH:D015431', (174, 185))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CO2', 'Chemical', '-', (262, 265))	('lethargy', 'Phenotype', 'HP:0001254', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
23235	21868749	Both DBP-treated p53-null and heterozygous mice had a significantly greater density of MNGs compared to their respective controls at GD19 and PND1.	('mice', 'Species', '10090', (43, 47))	('p53-null', 'Var', (17, 25))	('MNGs', 'CPA', (87, 91))	('DBP', 'Chemical', 'MESH:D003993', (5, 8))	('greater', 'PosReg', (68, 75))
23238	21868749	Also, a genotype-specific difference was apparent in unexposed animals, with a higher spontaneous rate of MNG formation in the p53-null mice compared to p53-heterozygous mice at the early time-points.	('mice', 'Species', '10090', (136, 140))	('p53-null', 'Var', (127, 135))	('rat', 'Species', '10116', (98, 101))	('MNG formation', 'CPA', (106, 119))	('mice', 'Species', '10090', (170, 174))	('higher', 'PosReg', (79, 85))
23252	21868749	In addition, rat models have demonstrated that in utero exposure to DBP and other phthalates can lead to testicular dysgenesis-like effects including hypospadias, cryptorchidism, impaired Leydig cell function, decrease in steroidogenic gene expression, and the induction of MNGs.	('hypospadias', 'Disease', (150, 161))	('impaired', 'NegReg', (179, 187))	('hypospadias', 'Phenotype', 'HP:0000047', (150, 161))	('phthalate', 'Chemical', 'MESH:C032279', (82, 91))	('MNGs', 'Disease', (274, 278))	('rat', 'Species', '10116', (36, 39))	('cryptorchidism', 'Disease', (163, 177))	('Leydig cell function', 'CPA', (188, 208))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (105, 126))	('decrease', 'NegReg', (210, 218))	('DBP', 'Chemical', 'MESH:D003993', (68, 71))	('hypospadias', 'Disease', 'MESH:D007021', (150, 161))	('steroidogenic gene expression', 'MPA', (222, 251))	('rat', 'Species', '10116', (13, 16))	('dysgenesis', 'Disease', 'MESH:D050033', (116, 126))	('cryptorchidism', 'Phenotype', 'HP:0000028', (163, 177))	('dysgenesis', 'Disease', (116, 126))	('DBP', 'Var', (68, 71))
23255	21868749	By PND 16, Sprague-Dawley MNGs were no longer present in rat testes, while there was a marked decrease in MNGs by PND 15 in Wistar rats.	('Wistar rats', 'Species', '10116', (124, 135))	('rat', 'Species', '10116', (131, 134))	('MNGs', 'MPA', (106, 110))	('rat', 'Species', '10116', (57, 60))	('PND', 'Var', (3, 6))	('decrease', 'NegReg', (94, 102))
23259	21868749	Cancer studies frequently employ the p53 deficient mouse because of the critical role of this tumor suppressor gene in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mouse', 'Species', '10090', (51, 56))	('tumor', 'Disease', (94, 99))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('p53', 'Gene', (37, 40))	('deficient', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
23265	21868749	Of particular interest is our discovery that DBP exposure acted in concert with p53 deficiency to induce a high frequency of MNGs compared to untreated p53-null mice.	('induce', 'Reg', (98, 104))	('mice', 'Species', '10090', (161, 165))	('DBP', 'Chemical', 'MESH:D003993', (45, 48))	('p53', 'Gene', (80, 83))	('MNGs', 'Disease', (125, 129))	('deficiency', 'Var', (84, 94))
23266	21868749	This gene-environment interaction, with both p53 deficiency and DBP exposure contributing to enhanced MNG formation, was most apparent at the GD19 time-point.	('p53', 'Gene', (45, 48))	('deficiency', 'Var', (49, 59))	('enhanced', 'PosReg', (93, 101))	('MNG formation', 'CPA', (102, 115))	('DBP', 'Chemical', 'MESH:D003993', (64, 67))	('men', 'Species', '9606', (17, 20))
23267	21868749	As shown in Table 1, the absence of both p53 alleles allowed for the formation of more MNGs in control mice compared to their heterozygous counterparts at early time-points.	('mice', 'Species', '10090', (103, 107))	('absence', 'Var', (25, 32))	('p53', 'Gene', (41, 44))
23269	21868749	These data, as well as previous studies, have demonstrated that DBP treatment alone is sufficient to induce MNGs, but clearly p53 plays a role in inhibiting their formation and/or accelerating their elimination.	('men', 'Species', '9606', (73, 76))	('rat', 'Species', '10116', (186, 189))	('rat', 'Species', '10116', (53, 56))	('elimination', 'MPA', (199, 210))	('MNGs', 'Disease', (108, 112))	('p53', 'Var', (126, 129))	('formation', 'MPA', (163, 172))	('accelerating', 'PosReg', (180, 192))	('inhibiting', 'NegReg', (146, 156))	('DBP', 'Chemical', 'MESH:D003993', (64, 67))
23273	21868749	To determine whether MNGs can persist later in life, we investigated the long-term effects of in utero exposure to DBP and the impact of p53 deficiency.	('p53', 'Gene', (137, 140))	('DBP', 'Chemical', 'MESH:D003993', (115, 118))	('deficiency', 'Var', (141, 151))
23283	21868749	DBP treatment was able to enhance Oct-3/4 staining during this period of replication compared to corn oil treated rats, although no positive staining was observed by GD 19.	('corn', 'Species', '4577', (97, 101))	('enhance', 'PosReg', (26, 33))	('DBP', 'Chemical', 'MESH:D003993', (0, 3))	('men', 'Species', '9606', (9, 12))	('rats', 'Species', '10116', (114, 118))	('DBP', 'Var', (0, 3))	('Oct-3/4 staining', 'MPA', (34, 50))
23288	21868749	This genotype-specific effect implicates a role for p53 in eliminating, or preventing the formation of, DBP-induced MNGs in early post-natal life.	('DBP', 'Chemical', 'MESH:D003993', (104, 107))	('preventing', 'NegReg', (75, 85))	('p53', 'Var', (52, 55))
23388	34039259	Transthoracic echocardiography revealed dilated cardiomyopathy, left ventricular indexed end diastolic volume 237 ml/m2, end systolic volume 168 ml, global hypokinesia, LVEF 29%, LV strain -9%, moderate functional mitral regurgitation, right ventricle with normal function, TAPSE 20 mm, PAPS 45 mmHg, low cardiac output 3.4 l/ min (Fig.	('dilated cardiomyopathy', 'Disease', (40, 62))	('LV strain -9', 'Var', (179, 191))	('hypokinesia', 'Disease', 'MESH:D018476', (156, 167))	('mitral regurgitation', 'Phenotype', 'HP:0001653', (214, 234))	('hypokinesia', 'Disease', (156, 167))	('LVEF', 'Var', (169, 173))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (40, 62))	('mitral regurgitation', 'Disease', 'MESH:D008944', (214, 234))	('hypokinesia', 'Phenotype', 'HP:0002375', (156, 167))	('mitral regurgitation', 'Disease', (214, 234))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (40, 62))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (48, 62))
23395	34039259	Hematological testing found Factor II Mutation with heterozygous Factor II genotype; Factor V Leiden was normal.	('Mutation', 'Var', (38, 46))	('Factor V Leiden', 'Gene', '2153', (85, 100))	('Factor V Leiden', 'Gene', (85, 100))
23406	34039259	Persons who inherit two copies of the gene, one from each parent, may be at risk as much as 20 in 1000.. Thrombophilia due to factor 2 gene mutation is considered hereditary with no cancer association and manifest mainly by DVTs.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('factor 2', 'Gene', '8458', (126, 134))	('Persons', 'Species', '9606', (0, 7))	('mutation', 'Var', (140, 148))	('Thrombophilia', 'Disease', 'MESH:D019851', (105, 118))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('Thrombophilia', 'Phenotype', 'HP:0100724', (105, 118))	('factor 2', 'Gene', (126, 134))	('cancer', 'Disease', (182, 188))	('Thrombophilia', 'Disease', (105, 118))	('DVT', 'Phenotype', 'HP:0002625', (224, 227))
23427	32614449	The regulatory and structural functions of lncRNAs have been reported to play pivotal roles in a broad scope of biological processes, and disorderly regulation of lncRNAs leads to diverse human diseases.	('disorderly regulation', 'Var', (138, 159))	('leads to', 'Reg', (171, 179))	('human', 'Species', '9606', (188, 193))	('human diseases', 'Disease', (188, 202))
23430	32614449	found that dysregulation of specific lncRNAs led to sperm counts or infertility reduced in mice.	('mice', 'Species', '10090', (91, 95))	('reduced', 'NegReg', (80, 87))	('dysregulation', 'Var', (11, 24))	('infertility', 'Phenotype', 'HP:0000789', (68, 79))	('infertility', 'Disease', 'MESH:D007247', (68, 79))	('infertility', 'Disease', (68, 79))	('sperm counts', 'CPA', (52, 64))
23452	32614449	The membranes were blocked in 5% skimmed milk in PBS containing 0.5% Tween-20 at room temperature for 1 h prior to being probed with the anti-CD63 (1:20,000, #556019; BD Pharmingen), anti-CD81 (1:5,000, #555675; BD Pharmingen) at 4 C overnight.	('1:20,000', 'Var', (148, 156))	('Tween-20', 'Chemical', 'MESH:D011136', (69, 77))	('CD81', 'Gene', (188, 192))	('CD63', 'Gene', (142, 146))	('PBS', 'Chemical', 'MESH:D007854', (49, 52))	('CD81', 'Gene', '975', (188, 192))	('CD63', 'Gene', '967', (142, 146))	('1:5,000', 'Var', (194, 201))
23477	32614449	KEGG pathway analysis revealed that the up-regulated DEGs were mainly associated with ribosome, transcriptional misregulation in cancer, alcoholism, cocaine addiction and ferroptosis in the top 10 KEGG pathways enriched (Figure 3C and Table 4).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('alcoholism', 'Disease', 'MESH:D000437', (137, 147))	('ribosome', 'Disease', (86, 94))	('DEGs', 'Var', (53, 57))	('alcoholism', 'Phenotype', 'HP:0030955', (137, 147))	('cancer', 'Disease', (129, 135))	('ferroptosis', 'Disease', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('up-regulated', 'PosReg', (40, 52))	('cocaine addiction', 'Disease', (149, 166))	('alcoholism', 'Disease', (137, 147))
23478	32614449	Through the DO analysis, we found that the up-regulated DEGs were significantly enriched among cancers (Figure 3E and Table 5), while the down-regulated DEGs were associated with reproductive system disease, retinal degeneration and mycosis in the top 10 DO enriched (Figure 3F and Table 5).	('DEGs', 'Var', (56, 60))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('retinal degeneration', 'Disease', 'MESH:D012162', (208, 228))	('down-regulated', 'NegReg', (138, 152))	('retinal degeneration', 'Disease', (208, 228))	('reproductive system disease', 'Disease', (179, 206))	('up-regulated', 'PosReg', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mycosis', 'Disease', (233, 240))	('retinal degeneration', 'Phenotype', 'HP:0000546', (208, 228))
23490	32614449	The interaction network included 11 lncRNAs (LINC00893, AC005034.3, COX10-AS1, MIR497HG, LINC00894, AC015813.1, AP000424.1, MIR17HG, LINC00667, LINC00662 and SNHG3), 35 miRNAs and 59 mRNAs (Supplementary Table S6).	('LINC00894', 'Gene', '100272228', (89, 98))	('men', 'Species', '9606', (196, 199))	('COX10-AS1', 'Gene', (68, 77))	('MIR17HG', 'Gene', (124, 131))	('LINC00662', 'Gene', (144, 153))	('LINC00667', 'Gene', '339290', (133, 142))	('MIR497HG', 'Gene', '100506755', (79, 87))	('SNHG3', 'Gene', '8420', (158, 163))	('LINC00662', 'Gene', '148189', (144, 153))	('COX10-AS1', 'Gene', '100874058;1352;5729', (68, 77))	('MIR497HG', 'Gene', (79, 87))	('LINC00893', 'Gene', (45, 54))	('AC015813.1', 'Var', (100, 110))	('MIR17HG', 'Gene', '407975', (124, 131))	('LINC00894', 'Gene', (89, 98))	('LINC00667', 'Gene', (133, 142))	('SNHG3', 'Gene', (158, 163))	('LINC00893', 'Gene', '100131434', (45, 54))
23493	32614449	In the present study, we performed an RNA-sequencing analysis between asthenozoospermia and normal group and identified 4228 significantly DEGs (2344 up-regulated and 1884 down-regulated) in seminal plasma exosomes RNA.	('DEGs', 'Var', (139, 143))	('asthenozoospermia', 'Disease', (70, 87))	('asthenozoospermia', 'Disease', 'MESH:D053627', (70, 87))	('down-regulated', 'NegReg', (172, 186))	('up-regulated', 'PosReg', (150, 162))
23506	32614449	conclude that low sperm counts were clearly associated with IGF2/H19 ICR1 hypomethylation, and idiopathic male infertility was strongly associated with imprinting defects at IGF2/H19 ICR1.	('ICR1', 'Gene', (69, 73))	('associated', 'Reg', (136, 146))	('idiopathic male infertility', 'Disease', 'MESH:D007248', (95, 122))	('H19', 'Gene', (65, 68))	('imprinting defects', 'Var', (152, 170))	('IGF2', 'Gene', (60, 64))	('ICR1', 'Gene', '3388', (183, 187))	('H19', 'Gene', '283120', (65, 68))	('IGF2', 'Gene', (174, 178))	('IGF2', 'Gene', '3481', (174, 178))	('low sperm counts', 'Phenotype', 'HP:0000798', (14, 30))	('sperm counts', 'CPA', (18, 30))	('hypomethylation', 'Var', (74, 89))	('ICR1', 'Gene', (183, 187))	('IGF2', 'Gene', '3481', (60, 64))	('idiopathic male infertility', 'Disease', (95, 122))	('ICR1', 'Gene', '3388', (69, 73))	('low', 'NegReg', (14, 17))	('associated', 'Reg', (44, 54))	('H19', 'Gene', (179, 182))	('male infertility', 'Phenotype', 'HP:0003251', (106, 122))	('infertility', 'Phenotype', 'HP:0000789', (111, 122))	('H19', 'Gene', '283120', (179, 182))
23507	32614449	indicated that the aberrant methylation of IGF2 and KCNQ1 gene may be associated with sperm DNA damage.	('KCNQ1', 'Gene', '3784', (52, 57))	('methylation', 'MPA', (28, 39))	('IGF2', 'Gene', '3481', (43, 47))	('associated', 'Reg', (70, 80))	('IGF2', 'Gene', (43, 47))	('aberrant', 'Var', (19, 27))	('KCNQ1', 'Gene', (52, 57))	('sperm DNA damage', 'Disease', (86, 102))
23579	29529997	In addition, androgen receptor and androgen metabolic pathway genetic variation studies showed that Ser312Asn polymorphism of the luteinizing hormone receptor was linked to an increased relative risk of PC and a decreased relative risk of TGCT.	('decreased', 'NegReg', (212, 221))	('Ser312Asn', 'Var', (100, 109))	('PC', 'Phenotype', 'HP:0012125', (203, 205))	('androgen receptor', 'Gene', '367', (13, 30))	('Ser312Asn', 'SUBSTITUTION', 'None', (100, 109))	('androgen receptor', 'Gene', (13, 30))	('TGCT', 'Disease', (239, 243))
23603	25462018	Polymorphisms in DNA polymerase gamma affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol gamma, the solely mitochondrial replicase in animals and fungi.	('POLG', 'Gene', (198, 202))	('mitochondrial', 'MPA', (86, 99))	('polymerase gamma', 'Gene', (21, 37))	('human', 'Species', '9606', (192, 197))	('toxicity', 'Disease', 'MESH:D064420', (100, 108))	('toxicity', 'Disease', (100, 108))	('Polymorphisms', 'Var', (0, 13))	('POLG', 'Gene', '5428', (198, 202))	('polymerase gamma', 'Gene', '5428', (21, 37))	('mutations', 'Var', (158, 167))	('mtDNA stability', 'CPA', (49, 64))	('affect', 'Reg', (38, 44))
23605	25462018	In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability.	('zalcitabine-induced mtDNA mutability', 'MPA', (84, 120))	('stavudine', 'MPA', (67, 76))	('zalcitabine', 'Chemical', 'MESH:D016047', (84, 95))	('stavudine', 'Chemical', 'MESH:D018119', (67, 76))	('instability', 'MPA', (125, 136))	('increased', 'PosReg', (53, 62))	('presence', 'Var', (31, 39))
23607	25462018	Some polymorphisms make Mip1 more sensitive to NRTIs-induced mtDNA toxicity.	('more', 'PosReg', (29, 33))	('Mip1', 'Gene', (24, 28))	('sensitive', 'MPA', (34, 43))	('Mip1', 'Gene', '79109', (24, 28))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('polymorphisms', 'Var', (5, 18))	('toxicity', 'Disease', (67, 75))
23611	25462018	To date, about 250 pathological mutations associated with severe mitochondrial disorders have been identified in POLG (http://tools.niehs.nih.gov/Polg/).	('POLG', 'Gene', (113, 117))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (65, 88))	('associated', 'Reg', (42, 52))	('POLG', 'Gene', '5428', (113, 117))	('mutations', 'Var', (32, 41))	('Polg', 'Gene', (146, 150))	('Polg', 'Gene', '5428', (146, 150))	('mitochondrial disorders', 'Disease', (65, 88))
23612	25462018	Among them, a few mutations have been recently described to be involved in stavudine-induced toxicity, in valproate-induced hepatotoxicity, in testicular cancer, in breast tumorigenesis and in idiopathic sporadic parkinsonism.	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('hepatotoxicity', 'Disease', (124, 138))	('idiopathic sporadic parkinsonism', 'Disease', (193, 225))	('toxicity', 'Disease', (130, 138))	('parkinsonism', 'Phenotype', 'HP:0001300', (213, 225))	('involved', 'Reg', (63, 71))	('valproate', 'Chemical', 'MESH:D014635', (106, 115))	('idiopathic sporadic parkinsonism', 'Disease', 'MESH:D010300', (193, 225))	('stavudine', 'Chemical', 'MESH:D018119', (75, 84))	('testicular cancer', 'Disease', 'MESH:D013736', (143, 160))	('testicular cancer', 'Phenotype', 'HP:0010788', (143, 160))	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('toxicity', 'Disease', (93, 101))	('hepatotoxicity', 'Disease', 'MESH:D056486', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('breast tumorigenesis', 'Disease', (165, 185))	('testicular cancer', 'Disease', (143, 160))	('mutations', 'Var', (18, 27))
23613	25462018	An exception is the E1143G mutation, which appears with a frequency of 3-4% in the European population (GeneSNps) and its effects on human Pol gamma have been the subject of several studies.	('E1143G', 'Var', (20, 26))	('effects', 'Reg', (122, 129))	('E1143G', 'Mutation', 'rs2307441', (20, 26))	('human', 'Species', '9606', (133, 138))
23615	25462018	Thanks to this similarity, yeast has been largely used to validate the role of human putative pathological mutations, to understand biochemical consequences associated with these mutations, to find molecules able to rescue their detrimental effects and to study the pharmacogenetics of drugs such as valproate and stavudine.	('human', 'Species', '9606', (79, 84))	('mutations', 'Var', (107, 116))	('stavudine', 'Chemical', 'MESH:D018119', (314, 323))	('yeast', 'Species', '4932', (27, 32))	('valproate', 'Chemical', 'MESH:D014635', (300, 309))	('mutations', 'Var', (179, 188))
23616	25462018	Yeast is a suitable model organism for the study of the effects of Pol gamma mutations on mtDNA stability, thanks to its ability to survive in the absence of a functional mitochondrial genome.	('mutations', 'Var', (77, 86))	('Pol gamma', 'Gene', (67, 76))	('Yeast', 'Species', '4932', (0, 5))
23617	25462018	Yeast cells containing deletions-carrying mtDNA, called rho-, or cells which have completely lost mtDNA, called rho0, are respiratory-deficient and produce small-sized colonies, called petite.	('deletions-carrying', 'Var', (23, 41))	('respiratory-deficient', 'Disease', (122, 143))	('respiratory-deficient', 'Disease', 'MESH:D012131', (122, 143))	('Yeast', 'Species', '4932', (0, 5))
23618	25462018	Petite mutants arise spontaneously with high frequency (approximately 10- 2), which is increased in the case of Mip1 mutant strains with reduced polymerase activity.	('Mip1', 'Gene', '79109', (112, 116))	('mutant', 'Var', (117, 123))	('Mip1', 'Gene', (112, 116))
23620	25462018	In fact, resistance to erythromycin is acquired through specific transversions or transitions in the mitochondrial gene encoding the 21 S rRNA.	('erythromycin', 'Chemical', 'MESH:D004917', (23, 35))	('transversions', 'Var', (65, 78))	('acquired', 'Reg', (39, 47))	('transitions', 'Var', (82, 93))
23621	25462018	EryR mutability is increased by Mip1 mutations which reduce the fidelity of replication.	('reduce', 'NegReg', (53, 59))	('Mip1', 'Gene', '79109', (32, 36))	('mutations', 'Var', (37, 46))	('EryR mutability', 'MPA', (0, 15))	('increased', 'PosReg', (19, 28))	('fidelity', 'MPA', (64, 72))	('Mip1', 'Gene', (32, 36))
23622	25462018	Yeast has also been used to evaluate the correlation between specific mutations in Mip1, corresponding to human mutations, and mtDNA mutability induced by treatment with stavudine (3'-deoxy-2',3'-didehydrothymidine, or d4T), a nucleoside reverse transcriptase inhibitor (NRTI) which has been successfully used in the highly active antiretroviral therapy (HAART).	('stavudine', 'Chemical', 'MESH:D018119', (170, 179))	('mutations', 'Var', (70, 79))	('human', 'Species', '9606', (106, 111))	('nucleoside', 'Chemical', 'MESH:D009705', (227, 237))	('Mip1', 'Gene', (83, 87))	('Yeast', 'Species', '4932', (0, 5))	("3'-didehydrothymidine", 'Chemical', '-', (193, 214))	('d4T', 'Chemical', 'MESH:D018119', (219, 222))	('Mip1', 'Gene', '79109', (83, 87))	("deoxy-2'", 'Chemical', '-', (184, 192))	('mtDNA', 'Gene', (127, 132))
23626	25462018	According to the "Pol gamma hypothesis", NRTI toxicity could be due to direct inhibition of polymerase catalytic activity, incorporation of NRTI in the nascent strand with subsequent chain termination or persistence of the analog in mitochondrial DNA because of inefficient excision.	('excision', 'MPA', (274, 282))	('inhibition', 'NegReg', (78, 88))	('polymerase catalytic', 'Enzyme', (92, 112))	('chain termination', 'MPA', (183, 200))	('toxicity', 'Disease', 'MESH:D064420', (46, 54))	('toxicity', 'Disease', (46, 54))	('incorporation', 'Var', (123, 136))
23627	25462018	Consequently, some mutations in Pol gamma can result in different biochemical properties towards the NRTI-triphosphate (NRTI-TP), such as a greater Ki by the NRTI-TP, a lower NRTI-TP discrimination or a lower excision efficiency of the NRTI from the mtDNA and can increase the susceptibility to NRTIs toxicity, as was shown for patients carrying the mutation R964C.	('Ki by', 'MPA', (148, 153))	('NRTI-triphosphate', 'Chemical', '-', (101, 118))	('lower', 'NegReg', (203, 208))	('R964C', 'Mutation', 'rs201477273', (359, 364))	('susceptibility', 'MPA', (277, 291))	('toxicity', 'Disease', 'MESH:D064420', (301, 309))	('R964C', 'Var', (359, 364))	('lower', 'NegReg', (169, 174))	('greater', 'PosReg', (140, 147))	('toxicity', 'Disease', (301, 309))	('Pol', 'Gene', (32, 35))	('patients', 'Species', '9606', (328, 336))	('excision efficiency', 'MPA', (209, 228))	('-TP', 'Chemical', 'MESH:C011314', (124, 127))	('different', 'Reg', (56, 65))	('mutations', 'Var', (19, 28))	('increase', 'Reg', (264, 272))	('NRTI-TP discrimination', 'MPA', (175, 197))	('-TP', 'Chemical', 'MESH:C011314', (179, 182))	('-TP', 'Chemical', 'MESH:C011314', (162, 165))
23628	25462018	The aim of this study is to characterize, by the use of specific ad hoc yeast models, some polymorphisms in Pol gamma, in order to assess whether they are neutral nucleotide variations or not.	('polymorphisms', 'Var', (91, 104))	('yeast', 'Species', '4932', (72, 77))	('Pol gamma', 'Gene', (108, 117))
23629	25462018	does the mutant Mip1 behave in vivo like the wt Mip1 concerning mtDNA extended and point mutability?	('Mip1', 'Gene', (16, 20))	('mutant', 'Var', (9, 15))	('Mip1', 'Gene', '79109', (16, 20))	('Mip1', 'Gene', (48, 52))	('Mip1', 'Gene', '79109', (48, 52))
23630	25462018	(iii) Does the mutation increase the toxicity induced by stavudine or zalcitabine treatment?	('toxicity', 'Disease', (37, 45))	('mutation', 'Var', (15, 23))	('increase', 'PosReg', (24, 32))	('stavudine', 'Chemical', 'MESH:D018119', (57, 66))	('zalcitabine', 'Chemical', 'MESH:D016047', (70, 81))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))
23631	25462018	We found that most of the considered polymorphisms are not neutral but rather behave as phenotypic modifiers, and that three polymorphisms, besides the R964C and E1143G mutations previously studied, showed an altered sensitivity to stavudine and/or zalcitabine toxicity.	('zalcitabine', 'Chemical', 'MESH:D016047', (249, 260))	('stavudine', 'Chemical', 'MESH:D018119', (232, 241))	('R964C', 'Mutation', 'rs201477273', (152, 157))	('toxicity', 'Disease', 'MESH:D064420', (261, 269))	('toxicity', 'Disease', (261, 269))	('R964C', 'Var', (152, 157))	('E1143G', 'Mutation', 'rs2307441', (162, 168))	('sensitivity to stavudine', 'MPA', (217, 241))	('altered', 'Reg', (209, 216))	('E1143G', 'Var', (162, 168))
23647	25462018	After overlap PCR, the MIP1 fragments containing mutations E166Q, E166R, P207L or L340V were digested with NotI and AvrII and subcloned in pFL39MIP1, whereas MIP1 fragments containing mutations Y753F, S889R, S899W, K903R or K903C were digested with AvrII and BsrGI and subcloned in the same plasmid.	('S899W', 'Mutation', 'p.S899W', (208, 213))	('S889R', 'Mutation', 'p.S889R', (201, 206))	('E166Q', 'Mutation', 'p.E166Q', (59, 64))	('P207L', 'Var', (73, 78))	('S889R', 'Var', (201, 206))	('P207L', 'Mutation', 'rs368679909', (73, 78))	('Y753F', 'Mutation', 'p.Y753F', (194, 199))	('K903R', 'Var', (215, 220))	('K903C', 'Var', (224, 229))	('L340V', 'Var', (82, 87))	('S899W', 'Var', (208, 213))	('MIP1', 'Gene', '79109', (144, 148))	('MIP1', 'Gene', (144, 148))	('E166Q', 'Var', (59, 64))	('L340V', 'Mutation', 'p.L340V', (82, 87))	('MIP1', 'Gene', '79109', (23, 27))	('MIP1', 'Gene', (23, 27))	('E166R', 'Mutation', 'p.E166R', (66, 71))	('MIP1', 'Gene', '79109', (158, 162))	('MIP1', 'Gene', (158, 162))	('E166R', 'Var', (66, 71))	('K903C', 'SUBSTITUTION', 'None', (224, 229))	('Y753F', 'Var', (194, 199))	('K903R', 'Mutation', 'p.K903R', (215, 220))
23648	25462018	mip1 mutant alleles harboring G224A, A692T, E698G, Q766R, Q766C and E900G were constructed previously.	('Q766C', 'Var', (58, 63))	('mip1', 'Gene', '79109', (0, 4))	('E698G', 'Var', (44, 49))	('mip1', 'Gene', (0, 4))	('E698G', 'Mutation', 'p.E698G', (44, 49))	('Q766R', 'Mutation', 'p.Q766R', (51, 56))	('E900G', 'Var', (68, 73))	('E900G', 'Mutation', 'p.E900G', (68, 73))	('G224A', 'Mutation', 'rs752677885', (30, 35))	('A692T', 'Var', (37, 42))	('A692T', 'Mutation', 'c.692A>T', (37, 42))	('Q766R', 'Var', (51, 56))	('Q766C', 'SUBSTITUTION', 'None', (58, 63))	('G224A', 'Var', (30, 35))
23650	25462018	Strains DWM-5A/pFL38MIP1, YLV3t3m3/pFL38MIP1 and W1BCK1-10/pFL38MIP1 were transformed by the LiAc/ssDNA/PEG method with pFL39 plasmid harboring mip1 wt and mutant alleles, thus obtaining heteroallelic strains.	('mip1', 'Gene', '79109', (144, 148))	('mip1', 'Gene', (144, 148))	('MIP1', 'Gene', (64, 68))	('MIP1', 'Gene', '79109', (20, 24))	('MIP1', 'Gene', (20, 24))	('mutant', 'Var', (156, 162))	('MIP1', 'Gene', '79109', (40, 44))	('MIP1', 'Gene', '79109', (64, 68))	('MIP1', 'Gene', (40, 44))
23651	25462018	Subsequently, pFL38MIP1 was counter-selected in the presence of 5-fluoroorotic acid as previously reported, thus obtaining mip1 mutant haploid strains.	('mip1', 'Gene', (123, 127))	('5-fluoroorotic acid', 'Chemical', 'MESH:C001242', (64, 83))	('mutant', 'Var', (128, 134))	('MIP1', 'Gene', '79109', (19, 23))	('mip1', 'Gene', '79109', (123, 127))	('MIP1', 'Gene', (19, 23))
23653	25462018	ENT1, HSV-TK and ACT1 probes were obtained by PCR-amplification using primers hENT1Fw and hENT1Rv, TK1Fw and TK1Rv, ACT1Fw and ACT1Rv, respectively.	('ENT1', 'Gene', (0, 4))	('hENT1', 'Gene', (78, 83))	('ENT1', 'Gene', (79, 83))	('ENT1', 'Gene', '2030', (91, 95))	('TK1Rv', 'Var', (109, 114))	('ACT1', 'Gene', (17, 21))	('TK1Fw', 'Var', (99, 104))	('ACT1', 'Gene', '10758', (17, 21))	('ACT1', 'Gene', '10758', (116, 120))	('ACT1', 'Gene', (116, 120))	('ACT1', 'Gene', (127, 131))	('ACT1', 'Gene', '10758', (127, 131))	('ENT1', 'Gene', '2030', (79, 83))	('hENT1', 'Gene', '2030', (90, 95))	('ENT1', 'Gene', '2030', (0, 4))	('hENT1', 'Gene', '2030', (78, 83))	('hENT1', 'Gene', (90, 95))	('ENT1', 'Gene', (91, 95))
23656	25462018	For the reverse transcription, total RNA prepared from YLV3t3m3 or YLV3t3m3DeltaH was treated with DNase I (New England Biolabs), retro-transcribed with M-MuLV Reverse Transcriptase (New England Biolabs) with oligo (dT)20primer (Euroclone) and murine RNase inhibitor (New England Biolabs).	('DNase I', 'Gene', (99, 106))	('YLV3t3m3', 'Var', (55, 63))	('YLV3t3m3DeltaH', 'Var', (67, 81))	('DNase I', 'Gene', '13419', (99, 106))	('murine', 'Species', '10090', (244, 250))
23664	25462018	The latter is a prerequisite to be able to introduce the corresponding mutation in the ortholog position of the yeast Mip1 protein.	('mutation', 'Var', (71, 79))	('yeast', 'Species', '4932', (112, 117))	('Mip1', 'Gene', '79109', (118, 122))	('Mip1', 'Gene', (118, 122))
23666	25462018	Among the 283 POLG SNPs found in the database, 81 are coding and missense, of which 17 have a frequency higher than 0.1% in either the African-American (AA) population or in the European-American (EA) population (Supplementary Table 2).	('POLG', 'Gene', '5428', (14, 18))	('missense', 'Var', (65, 73))	('POLG', 'Gene', (14, 18))
23669	25462018	Among the 28 polymorphisms selected on the basis of their frequency, two were unambiguously reported to be pathological (T251L, A467T) (http://tools.niehs.nih.gov/Polg/) and for that reason they were excluded.	('A467T', 'Var', (128, 133))	('A467T', 'Mutation', 'rs113994095', (128, 133))	('T251L', 'Var', (121, 126))	('Polg', 'Gene', (163, 167))	('T251L', 'Mutation', 'rs113994095', (121, 126))	('Polg', 'Gene', '5428', (163, 167))
23671	25462018	The remaining eight polymorphisms are variations of conserved (P241L, G268A, L392V, E1143G) or semi-conserved residues (R193Q, R964C, R1142W, R1146C), and are located in a conserved region (Supplementary Fig.	('G268A', 'Mutation', 'rs61752784', (70, 75))	('R1146C', 'Mutation', 'rs2307440', (142, 148))	('R964C', 'Mutation', 'rs201477273', (127, 132))	('P241L', 'Var', (63, 68))	('R964C', 'Var', (127, 132))	('R193Q', 'Mutation', 'rs3176162', (120, 125))	('L392V', 'Mutation', 'rs145289229', (77, 82))	('P241L', 'Mutation', 'rs1452571273', (63, 68))	('R193Q', 'Var', (120, 125))	('E1143G', 'Mutation', 'rs2307441', (84, 90))	('G268A', 'Var', (70, 75))	('R1142W', 'Var', (134, 140))	('R1142W', 'Mutation', 'rs2307442', (134, 140))	('R1146C', 'Var', (142, 148))	('E1143G', 'Var', (84, 90))	('L392V', 'Var', (77, 82))
23673	25462018	G268A has been considered associated with sporadic progressive external ophthalmoplegia (PEO) in several studies.	('external ophthalmoplegia', 'Disease', (63, 87))	('G268A', 'Var', (0, 5))	('external ophthalmoplegia', 'Disease', 'MESH:D009886', (63, 87))	('progressive external ophthalmoplegia', 'Phenotype', 'HP:0000590', (51, 87))	('G268A', 'Mutation', 'rs61752784', (0, 5))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (72, 87))	('external ophthalmoplegia', 'Phenotype', 'HP:0000544', (63, 87))	('associated', 'Reg', (26, 36))
23674	25462018	R964C was considered a pathological mutation, causing severe ataxia in heterozygosity with a second detrimental mutation.	('ataxia', 'Disease', (61, 67))	('R964C', 'Mutation', 'rs201477273', (0, 5))	('ataxia', 'Disease', 'MESH:D001259', (61, 67))	('R964C', 'Var', (0, 5))	('causing', 'Reg', (46, 53))	('ataxia', 'Phenotype', 'HP:0001251', (61, 67))
23676	25462018	It was also demonstrated that the in vitro polymerase activity of Pol gamma harboring R964C is reduced 5 to 9-fold, with a 3-fold decreased ability to discriminate between dTTP and stavudine triphosphate (d4TTP) compared to that of the wt, thus explaining the stavudine sensitivity of the subject.	('Pol gamma', 'Enzyme', (66, 75))	('d4TTP', 'Chemical', 'MESH:C053197', (205, 210))	('to 9', 'Species', '1214577', (105, 109))	('dTTP', 'Chemical', 'MESH:C024157', (172, 176))	('ability', 'MPA', (140, 147))	('R964C', 'Mutation', 'rs201477273', (86, 91))	('R964C', 'Var', (86, 91))	('stavudine', 'Chemical', 'MESH:D018119', (260, 269))	('activity', 'MPA', (54, 62))	('discriminate', 'MPA', (151, 163))	('reduced', 'NegReg', (95, 102))	('stavudine', 'Chemical', 'MESH:D018119', (181, 190))	('stavudine triphosphate', 'Chemical', 'MESH:C053197', (181, 203))	('decreased', 'NegReg', (130, 139))
23678	25462018	In addition, in heterozygosity E1143G has been statistically associated with a higher probability of developing liver failure after treatment with valproic acid or stavudine-induced lipodystrophy.	('valproic acid', 'Chemical', 'MESH:D014635', (147, 160))	('E1143G', 'Mutation', 'rs2307441', (31, 37))	('liver failure', 'Phenotype', 'HP:0001399', (112, 125))	('liver failure', 'Disease', 'MESH:D017093', (112, 125))	('lipodystrophy', 'Disease', 'MESH:D008060', (182, 195))	('E1143G', 'Var', (31, 37))	('lipodystrophy', 'Disease', (182, 195))	('liver failure', 'Disease', (112, 125))	('stavudine', 'Chemical', 'MESH:D018119', (164, 173))	('associated', 'Reg', (61, 71))	('lipodystrophy', 'Phenotype', 'HP:0009125', (182, 195))
23679	25462018	However, by performing a consensus of the results obtained via these five tools, two polymorphisms (R193Q and P241L) were predicted to be neutral, two polymorphisms (L392V and E1143G) possibly damaging and four polymorphisms (G268A, R964C, R1142W and R1146C) probably damaging (Supplementary Table 5).	('R1146C', 'Mutation', 'rs2307440', (251, 257))	('R1142W', 'Mutation', 'rs2307442', (240, 246))	('R1142W', 'Var', (240, 246))	('R964C', 'Mutation', 'rs201477273', (233, 238))	('G268A', 'Var', (226, 231))	('R964C', 'Var', (233, 238))	('L392V', 'Var', (166, 171))	('R1146C', 'Var', (251, 257))	('E1143G', 'Mutation', 'rs2307441', (176, 182))	('E1143G', 'Var', (176, 182))	('P241L', 'Var', (110, 115))	('R193Q', 'Mutation', 'rs3176162', (100, 105))	('L392V', 'Mutation', 'rs145289229', (166, 171))	('G268A', 'Mutation', 'rs61752784', (226, 231))	('P241L', 'Mutation', 'rs1452571273', (110, 115))	('R193Q', 'Var', (100, 105))	('damaging', 'Reg', (268, 276))
23680	25462018	The effect of the selected POLG polymorphisms on the mtDNA stability was evaluated in vivo in yeast strains carrying MIP1 alleles containing mutations in the equivalent positions.	('polymorphisms', 'Var', (32, 45))	('mutations', 'Var', (141, 150))	('MIP1', 'Gene', '79109', (117, 121))	('POLG', 'Gene', (27, 31))	('POLG', 'Gene', '5428', (27, 31))	('yeast', 'Species', '4932', (94, 99))	('MIP1', 'Gene', (117, 121))
23681	25462018	In order to obtain these allelic variants, mutations which determine substitutions of conserved residues (P241L, G268A, L392V, E1143G) were inserted in wt MIP1 cloned in the centromeric vector pFL39, by site-directed mutagenesis.	('G268A', 'Var', (113, 118))	('P241L', 'Var', (106, 111))	('E1143G', 'Mutation', 'rs2307441', (127, 133))	('E1143G', 'Var', (127, 133))	('P241L', 'Mutation', 'rs1452571273', (106, 111))	('L392V', 'Mutation', 'rs145289229', (120, 125))	('MIP1', 'Gene', '79109', (155, 159))	('MIP1', 'Gene', (155, 159))	('G268A', 'Mutation', 'rs61752784', (113, 118))	('L392V', 'Var', (120, 125))
23682	25462018	In the case of mutations in non-conserved positions (R193Q, R964C, R1142W, R1146C), we constructed two alleles for each polymorphism: in the former, the Mip1 amino acid was changed according to the wt Pol gamma (humanized allele); in the latter, the Mip1 amino acid was changed according to the polymorphism (mutant allele).	('Mip1', 'Gene', (250, 254))	('R964C', 'Mutation', 'rs201477273', (60, 65))	('R1146C', 'Var', (75, 81))	('R964C', 'Var', (60, 65))	('R193Q', 'Var', (53, 58))	('R193Q', 'Mutation', 'rs3176162', (53, 58))	('human', 'Species', '9606', (212, 217))	('Mip1', 'Gene', '79109', (153, 157))	('changed', 'Reg', (173, 180))	('Mip1', 'Gene', '79109', (250, 254))	('R1142W', 'Mutation', 'rs2307442', (67, 73))	('R1142W', 'Var', (67, 73))	('R1146C', 'Mutation', 'rs2307440', (75, 81))	('Mip1', 'Gene', (153, 157))
23684	25462018	By plasmid shuffling on 5-FOA, we then obtained a second series of strains containing only the mutant mip1 allelic variants (haploid strains).	('mip1', 'Gene', '79109', (102, 106))	('variants', 'Var', (115, 123))	('mutant', 'Var', (95, 101))	('mip1', 'Gene', (102, 106))
23687	25462018	Five out of eight polymorphisms (P241L, G268A, R964C, R1142W and E1143G) showed increased petite frequency at 28  C, suggesting that they affect mitochondrial stability and thus are not neutral substitutions (Fig.	('petite frequency at 28  C', 'CPA', (90, 115))	('G268A', 'Var', (40, 45))	('affect', 'Reg', (138, 144))	('mitochondrial stability', 'CPA', (145, 168))	('increased', 'PosReg', (80, 89))	('E1143G', 'Mutation', 'rs2307441', (65, 71))	('R1142W', 'Mutation', 'rs2307442', (54, 60))	('G268A', 'Mutation', 'rs61752784', (40, 45))	('E1143G', 'Var', (65, 71))	('P241L', 'Var', (33, 38))	('R1142W', 'Var', (54, 60))	('R964C', 'Mutation', 'rs201477273', (47, 52))	('P241L', 'Mutation', 'rs1452571273', (33, 38))	('R964C', 'Var', (47, 52))
23688	25462018	As mentioned above, three of them (G268A, R964C and E1143G) were already known to alter the properties of Pol gamma.	('R964C', 'Mutation', 'rs201477273', (42, 47))	('E1143G', 'Mutation', 'rs2307441', (52, 58))	('alter', 'Reg', (82, 87))	('R964C', 'Var', (42, 47))	('properties', 'MPA', (92, 102))	('G268A', 'Mutation', 'rs61752784', (35, 40))	('E1143G', 'Var', (52, 58))	('G268A', 'Var', (35, 40))
23689	25462018	In addition, the five polymorphisms, together with R1146C, showed a strong thermosensitivity, suggesting that the mutation altered the stability and/or the catalytic properties of Pol gamma at higher temperatures.	('R1146C', 'Mutation', 'rs2307440', (51, 57))	('Pol gamma', 'Enzyme', (180, 189))	('mutation', 'Var', (114, 122))	('stability', 'MPA', (135, 144))	('R1146C', 'Var', (51, 57))	('altered', 'Reg', (123, 130))	('catalytic properties', 'MPA', (156, 176))
23690	25462018	As regards point mutability, most polymorphisms increased the frequency of EryR point mutations, ranging from a ~ 2-fold increase for R1146C and E1143G mutations to ~ 4-fold increase for P241L and G268A mutations (Fig.	('G268A', 'Var', (197, 202))	('P241L', 'Mutation', 'rs1452571273', (187, 192))	('increase', 'PosReg', (121, 129))	('R1146C', 'Var', (134, 140))	('G268A', 'Mutation', 'rs61752784', (197, 202))	('E1143G', 'Mutation', 'rs2307441', (145, 151))	('E1143G', 'Var', (145, 151))	('increase', 'PosReg', (174, 182))	('R1146C', 'Mutation', 'rs2307440', (134, 140))	('P241L', 'Var', (187, 192))	('EryR', 'Gene', (75, 79))
23692	25462018	Among the recessive mutants, it is thus possible to distinguish mutant alleles, which totally or partially complement the haploinsufficient phenotype of the MIP1/mip1Delta strain or which behave as a null allele.	('mip1Delta', 'Gene', '6359', (162, 171))	('MIP1', 'Gene', '79109', (157, 161))	('MIP1', 'Gene', (157, 161))	('mip1Delta', 'Gene', (162, 171))	('haploinsufficient', 'Disease', 'MESH:D058495', (122, 139))	('haploinsufficient', 'Disease', (122, 139))	('mutant', 'Var', (64, 70))
23694	25462018	On the other hand, the two mutations in the exonuclease domains (P241L and G268A) are dominant in regard to the EryR mutant frequency, which was 2.3 to 3.2-fold higher, respectively, compared to that of the heterozygous diploid strain.	('G268A', 'Var', (75, 80))	('P241L', 'Var', (65, 70))	('P241L', 'Mutation', 'rs1452571273', (65, 70))	('G268A', 'Mutation', 'rs61752784', (75, 80))	('higher', 'PosReg', (161, 167))	('EryR', 'Disease', (112, 116))
23695	25462018	Several pathological mutations in POLG have been found in cis with one or more polymorphisms.	('POLG', 'Gene', '5428', (34, 38))	('POLG', 'Gene', (34, 38))	('mutations', 'Var', (21, 30))
23696	25462018	We have previously demonstrated in yeast that mutation equivalent to E1143G polymorphism increased the petite frequency of the A889T-equivalent mutation in MIP1 when in cis, since the presence of the former mutation decreased soluble protein levels of Mip1.	('decreased', 'NegReg', (216, 225))	('E1143G', 'Mutation', 'rs2307441', (69, 75))	('soluble protein levels', 'MPA', (226, 248))	('petite frequency', 'CPA', (103, 119))	('A889T-equivalent', 'Var', (127, 143))	('E1143G', 'Var', (69, 75))	('Mip1', 'Gene', '79109', (252, 256))	('MIP1', 'Gene', '79109', (156, 160))	('yeast', 'Species', '4932', (35, 40))	('increased', 'PosReg', (89, 98))	('MIP1', 'Gene', (156, 160))	('A889T', 'Mutation', 'rs763393580', (127, 132))	('Mip1', 'Gene', (252, 256))
23698	25462018	We showed that all the polymorphisms except for R193Q behaved as phenotypic modifiers that increased the petite frequency of the mutant Mip1A692T (Fig.	('petite frequency', 'CPA', (105, 121))	('R193Q', 'Mutation', 'rs3176162', (48, 53))	('Mip1A692T', 'Var', (136, 145))	('increased', 'PosReg', (91, 100))
23700	25462018	the polymorphism increased the petite frequency by the same degree as in the presence of wt Mip1.	('increased', 'PosReg', (17, 26))	('petite frequency', 'CPA', (31, 47))	('Mip1', 'Gene', '79109', (92, 96))	('Mip1', 'Gene', (92, 96))	('polymorphism', 'Var', (4, 16))
23701	25462018	Furthermore, two polymorphisms, L392V and R1146C, which were found to be neutral in the absence of other mutations at 28  C, caused a 1.6 and a 2.1-fold increase in the petite frequency in the presence of the A889T mutation.	('R1146C', 'Mutation', 'rs2307440', (42, 48))	('L392V', 'Mutation', 'rs145289229', (32, 37))	('R1146C', 'Var', (42, 48))	('increase', 'PosReg', (153, 161))	('petite frequency', 'CPA', (169, 185))	('L392V', 'Var', (32, 37))	('A889T', 'Mutation', 'rs763393580', (209, 214))	('A889T', 'Var', (209, 214))
23702	25462018	We then analyzed if the presence of mutations in DNA polymerase gamma correlated with a variation of mitochondrial toxicity due to NRTI treatment, in particular stavudine or zalcitabine.	('mitochondrial toxicity', 'Disease', 'MESH:D028361', (101, 123))	('mitochondrial toxicity', 'Disease', (101, 123))	('mutations', 'Var', (36, 45))	('zalcitabine', 'Chemical', 'MESH:D016047', (174, 185))	('polymerase gamma', 'Gene', '5428', (53, 69))	('stavudine', 'Chemical', 'MESH:D018119', (161, 170))	('polymerase gamma', 'Gene', (53, 69))	('variation', 'Reg', (88, 97))
23706	25462018	The observation that the mtDNA mutability increased in the YLV3 strain after treatment with d4T in galactose, but not in glucose, demonstrated that the expression of hENT1 and HSV-TK mediated the uptake and the activation of d4T and the consequent mitochondrial toxicity due to incorporation of the NRTI in the S. cerevisiae mtDNA by Mip1.	('mitochondrial toxicity', 'Disease', (248, 270))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('Mip1', 'Gene', (334, 338))	('d4T', 'Chemical', 'MESH:D018119', (225, 228))	('activation', 'PosReg', (211, 221))	('galactose', 'Chemical', 'MESH:D005690', (99, 108))	('HSV-TK', 'Gene', (176, 182))	('d4T', 'Chemical', 'MESH:D018119', (92, 95))	('uptake', 'MPA', (196, 202))	('S. cerevisiae', 'Species', '4932', (311, 324))	('hENT1', 'Gene', '2030', (166, 171))	('mitochondrial toxicity', 'Disease', 'MESH:D028361', (248, 270))	('Mip1', 'Gene', '79109', (334, 338))	('d4T', 'Var', (225, 228))	('hENT1', 'Gene', (166, 171))
23707	25462018	This model system has been validated by assessing the association between d4T toxicity and expression of mip1 alleles carrying mutations known to be sensitive to stavudine in human patients.	('human', 'Species', '9606', (175, 180))	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('toxicity', 'Disease', (78, 86))	('d4T', 'Chemical', 'MESH:D018119', (74, 77))	('mip1', 'Gene', '79109', (105, 109))	('patients', 'Species', '9606', (181, 189))	('mip1', 'Gene', (105, 109))	('mutations', 'Var', (127, 136))	('association', 'Interaction', (54, 65))	('stavudine', 'Chemical', 'MESH:D018119', (162, 171))
23711	25462018	The frequency of petite mutants was increased by d4T treatment in YLV3t3m3 carrying both wt and mutant mip1 alleles (Supplementary Table 6).	('mutant', 'Var', (96, 102))	('mip1', 'Gene', '79109', (103, 107))	('mip1', 'Gene', (103, 107))	('d4T', 'Chemical', 'MESH:D018119', (49, 52))	('increased', 'PosReg', (36, 45))	('petite mutants', 'CPA', (17, 31))
23712	25462018	The Mip1 variant corresponding to human polymorphisms G268A, L392V, R964C and E1143G rendered the strain more susceptible to d4T than wt Mip1, since the ratio of petite frequency between treated and untreated mutant strain normalized to the wt strain was higher than 1 (Fig.	('E1143G', 'Mutation', 'rs2307441', (78, 84))	('R964C', 'Var', (68, 73))	('Mip1', 'Gene', (137, 141))	('G268A', 'Var', (54, 59))	('d4T', 'Chemical', 'MESH:D018119', (125, 128))	('human', 'Species', '9606', (34, 39))	('E1143G', 'Var', (78, 84))	('L392V', 'Mutation', 'rs145289229', (61, 66))	('R964C', 'Mutation', 'rs201477273', (68, 73))	('Mip1', 'Gene', (4, 8))	('susceptible to d4T', 'MPA', (110, 128))	('petite', 'CPA', (162, 168))	('Mip1', 'Gene', '79109', (137, 141))	('G268A', 'Mutation', 'rs61752784', (54, 59))	('higher', 'PosReg', (255, 261))	('Mip1', 'Gene', '79109', (4, 8))	('L392V', 'Var', (61, 66))
23713	25462018	In particular, data related to R964C and E1143G were in agreement with what has been observed in humans.	('E1143G', 'Mutation', 'rs2307441', (41, 47))	('humans', 'Species', '9606', (97, 103))	('E1143G', 'Var', (41, 47))	('R964C', 'Mutation', 'rs201477273', (31, 36))	('R964C', 'Var', (31, 36))
23714	25462018	On the contrary, variant P241L renders Mip1 less susceptible to the NRTI (ratio of petite frequency between treated and untreated mutant strains normalized to wt strain lower than 1).	('less', 'NegReg', (44, 48))	('Mip1', 'Gene', '79109', (39, 43))	('P241L', 'Var', (25, 30))	('susceptible', 'MPA', (49, 60))	('P241L', 'Mutation', 'rs1452571273', (25, 30))	('Mip1', 'Gene', (39, 43))
23715	25462018	In the case of polymorphisms R193Q, R1142W and R1146C, the effect of stavudine and the effect of the polymorphism were additive (the ratio of petite frequency between treated and untreated mutant strains normalized to wt strain is not significantly different from 1).	('R193Q', 'Mutation', 'rs3176162', (29, 34))	('R1146C', 'Var', (47, 53))	('R193Q', 'Var', (29, 34))	('R1142W', 'Mutation', 'rs2307442', (36, 42))	('R1146C', 'Mutation', 'rs2307440', (47, 53))	('R1142W', 'Var', (36, 42))	('stavudine', 'Chemical', 'MESH:D018119', (69, 78))
23716	25462018	We further measured through qPCR the mtDNA levels after treatment with d4T.	('d4T', 'Chemical', 'MESH:D018119', (71, 74))	('d4T', 'Var', (71, 74))	('mtDNA levels', 'MPA', (37, 49))
23719	25462018	respiratory deficient cells without an intact mtDNA, of approximately 20% (Supplementary Table 6), the qPCR results clearly show that d4T treatment reduces the level of mtDNA to 50% in respiratory competent cells.	('respiratory deficient', 'Phenotype', 'HP:0002093', (0, 21))	('mtDNA', 'MPA', (169, 174))	('respiratory deficient', 'Disease', (0, 21))	('d4T', 'Var', (134, 137))	('reduces', 'NegReg', (148, 155))	('respiratory deficient', 'Disease', 'MESH:D012131', (0, 21))	('d4T', 'Chemical', 'MESH:D018119', (134, 137))
23720	25462018	Treatment with d4T in mip1 mutant strains with increased petite frequency results in decreased mtDNA levels compared to the treated wild type strain, indicating that, in presence of mip1 polymorphisms, d4T not only increased the number of respiratory deficient cells but also decreased the mtDNA levels in the whole cell population (Fig.	('mip1', 'Gene', (22, 26))	('respiratory deficient', 'Disease', (239, 260))	('decreased', 'NegReg', (85, 94))	('respiratory deficient', 'Disease', 'MESH:D012131', (239, 260))	('mutant', 'Var', (27, 33))	('d4T', 'Chemical', 'MESH:D018119', (15, 18))	('mip1', 'Gene', (182, 186))	('mtDNA levels', 'MPA', (290, 302))	('mip1', 'Gene', '79109', (182, 186))	('mtDNA levels', 'MPA', (95, 107))	('decreased', 'NegReg', (276, 285))	('increased', 'PosReg', (215, 224))	('respiratory deficient', 'Phenotype', 'HP:0002093', (239, 260))	('mip1', 'Gene', '79109', (22, 26))	('d4T', 'Chemical', 'MESH:D018119', (202, 205))	('polymorphisms', 'Var', (187, 200))
23721	25462018	Due to the low frequency of Pol gamma polymorphisms in the human population, the majority of subjects carrying these polymorphisms are heterozygous.	('Pol gamma', 'Gene', (28, 37))	('human', 'Species', '9606', (59, 64))	('polymorphisms', 'Var', (38, 51))
23724	25462018	Heteroallelic strains carrying Mip1 variants corresponding to G268A, L392V, R964C and E1143G Pol gamma polymorphisms displayed a significant increase of mitochondrial mutability, compared to the homoallelic strain, indicating that these mutations behave as dominant concerning d4T toxicity (Fig.	('toxicity', 'Disease', 'MESH:D064420', (281, 289))	('Mip1', 'Gene', '79109', (31, 35))	('toxicity', 'Disease', (281, 289))	('G268A', 'Mutation', 'rs61752784', (62, 67))	('increase', 'PosReg', (141, 149))	('L392V', 'Var', (69, 74))	('E1143G', 'Mutation', 'rs2307441', (86, 92))	('Mip1', 'Gene', (31, 35))	('G268A', 'Var', (62, 67))	('E1143G', 'Var', (86, 92))	('mitochondrial mutability', 'MPA', (153, 177))	('R964C', 'Var', (76, 81))	('R964C', 'Mutation', 'rs201477273', (76, 81))	('d4T', 'Chemical', 'MESH:D018119', (277, 280))	('Pol gamma', 'Gene', (93, 102))	('L392V', 'Mutation', 'rs145289229', (69, 74))
23725	25462018	As for haploid strains, treatment with 2 mM d4T results in decreased mtDNA copy number for G268A, L392V, R964C and E1143G Pol gamma polymorphisms in heterozygosis (Fig.	('G268A', 'Var', (91, 96))	('decreased', 'NegReg', (59, 68))	('L392V', 'Mutation', 'rs145289229', (98, 103))	('E1143G', 'Mutation', 'rs2307441', (115, 121))	('d4T', 'Chemical', 'MESH:D018119', (44, 47))	('G268A', 'Mutation', 'rs61752784', (91, 96))	('E1143G', 'Var', (115, 121))	('L392V', 'Var', (98, 103))	('R964C', 'Mutation', 'rs201477273', (105, 110))	('R964C', 'Var', (105, 110))	('mtDNA', 'Gene', (69, 74))
23727	25462018	After treatment with 1 mM d4T, the EryR mutant frequency increased in all strains, including those harboring wt MIP1 (Supplementary Table 8, columns 2 and 3).	('MIP1', 'Gene', '79109', (112, 116))	('MIP1', 'Gene', (112, 116))	('d4T', 'Chemical', 'MESH:D018119', (26, 29))	('EryR', 'Gene', (35, 39))	('increased', 'PosReg', (57, 66))	('mutant', 'Var', (40, 46))
23728	25462018	In addition, the fold increase, expressed as ratio between treated mutant strain and treated wt, is greater than 1 for most mutant strains, indicating that the simultaneous presence of a MIP1 mutator allele in and of d4T is detrimental for the fidelity of mtDNA replication (Fig.	('mutator', 'Var', (192, 199))	('mutant', 'Var', (124, 130))	('detrimental', 'NegReg', (224, 235))	('MIP1', 'Gene', '79109', (187, 191))	('d4T', 'Var', (217, 220))	('MIP1', 'Gene', (187, 191))	('d4T', 'Chemical', 'MESH:D018119', (217, 220))
23729	25462018	However, if the fold increase is further normalized with the untreated wt strain, the effect between the intrinsic mutability of mutant Mip1 and the susceptibility to d4T are synergistic only in the case of mutations R964C and E1143G (normalized fold increase higher than 1), whereas mutation P241L is less susceptible to the presence of d4T (normalized fold increase lower than 1) (Fig.	('Mip1', 'Gene', (136, 140))	('d4T', 'Chemical', 'MESH:D018119', (338, 341))	('P241L', 'Mutation', 'rs1452571273', (293, 298))	('R964C', 'Mutation', 'rs201477273', (217, 222))	('E1143G', 'Mutation', 'rs2307441', (227, 233))	('R964C', 'Var', (217, 222))	('E1143G', 'Var', (227, 233))	('Mip1', 'Gene', '79109', (136, 140))	('d4T', 'Chemical', 'MESH:D018119', (167, 170))	('mutant', 'Var', (129, 135))
23731	25462018	Strains derived from YLV3t3m3 were found insensitive to the toxicity induced by this NRTI (data not shown), probably either because hENT1 is unable to transport zalcitabine, or because HSV-TK, which is reported to phosphorylate other deoxypyrimidines, is unable to phosphorylate it, or both.	('transport zalcitabine', 'MPA', (151, 172))	('hENT1', 'Gene', (132, 137))	('toxicity', 'Disease', (60, 68))	('deoxypyrimidines', 'Chemical', '-', (234, 250))	('unable', 'NegReg', (141, 147))	('zalcitabine', 'Chemical', 'MESH:D016047', (161, 172))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('hENT1', 'Gene', '2030', (132, 137))	('YLV3t3m3', 'Var', (21, 29))
23732	25462018	In order to improve the import of ddC, hENT1 was deleted in the YLV3t3m3 strain and substituted with human CNT3 cDNA.	('ddC', 'Gene', '1644', (34, 37))	('CNT3', 'Gene', '64078', (107, 111))	('hENT1', 'Gene', (39, 44))	('deleted', 'Var', (49, 56))	('human', 'Species', '9606', (101, 106))	('ddC', 'Gene', (34, 37))	('improve', 'PosReg', (12, 19))	('CNT3', 'Gene', (107, 111))	('hENT1', 'Gene', '2030', (39, 44))
23742	25462018	6, the frequency of petite mutants increased in a dose dependent manner, indicating that: i) ddC was transported into the yeast cell, probably by aspecific transporters; ii) ddC was phosphorylated and activated to the metabolic active form by hDCK1 in yeast.	('mutants', 'Var', (27, 34))	('yeast', 'Species', '4932', (252, 257))	('yeast', 'Species', '4932', (122, 127))	('ddC', 'Gene', '1644', (93, 96))	('ddC', 'Gene', (174, 177))	('ddC', 'Gene', '1644', (174, 177))	('ddC', 'Gene', (93, 96))
23745	25462018	In order to validate the system, we took advantage of biochemical data previously obtained on human Pol gamma mutants.	('human', 'Species', '9606', (94, 99))	('Pol gamma', 'Gene', (100, 109))	('mutants', 'Var', (110, 117))
23746	25462018	It has been reported that human Pol gamma harboring E895A or Y951F mutations showed an ~ 18-fold and 2400-fold decrease respectively, in incorporation of ddCTP relative to dCTP compared to wt Pol gamma, indicating a lower susceptibility to ddC toxicity.	('Y951F', 'Mutation', 'p.Y951F', (61, 66))	('E895A', 'Mutation', 'p.E895A', (52, 57))	('Y951F', 'Var', (61, 66))	('dCTP', 'MPA', (172, 176))	('human', 'Species', '9606', (26, 31))	('ddC', 'Gene', '1644', (240, 243))	('ddC', 'Gene', (154, 157))	('toxicity', 'Disease', 'MESH:D064420', (244, 252))	('dCTP', 'Chemical', 'MESH:C024107', (172, 176))	('ddC', 'Gene', (240, 243))	('toxicity', 'Disease', (244, 252))	('dCTP', 'Chemical', 'MESH:C024107', (155, 159))	('decrease', 'NegReg', (111, 119))	('ddCTP', 'Chemical', '-', (154, 159))	('ddC', 'Gene', '1644', (154, 157))	('incorporation', 'MPA', (137, 150))	('E895A', 'Var', (52, 57))
23747	25462018	Thus, we tested whether we could observe a similar effect in the W1BCK1-10 yeast strain carrying mutations E698G and Y753F in the equivalent positions.	('yeast', 'Species', '4932', (75, 80))	('Y753F', 'Var', (117, 122))	('E698G', 'Mutation', 'p.E698G', (107, 112))	('E698G', 'Var', (107, 112))	('Y753F', 'Mutation', 'p.Y753F', (117, 122))
23748	25462018	In the haploid strain these mutations induce 100% petite; in the heteroallelic strain, both mutant mip1 alleles behaved as negative dominant, increasing the petite frequency compared to a strain harboring a copy of wt MIP1, i.e.	('MIP1', 'Gene', (218, 222))	('petite frequency', 'CPA', (157, 173))	('mip1', 'Gene', '79109', (99, 103))	('petite', 'CPA', (50, 56))	('mutant', 'Var', (92, 98))	('mutations', 'Var', (28, 37))	('mip1', 'Gene', (99, 103))	('MIP1', 'Gene', '79109', (218, 222))	('increasing', 'PosReg', (142, 152))
23750	25462018	We found that, following treatment with ddC, the petite frequency of both heteroallelic and hemiallelic strains increased (data not shown) in the case of both mutations E895G and Y951F, but the ratios of petite frequency of the heteroallelic strain to petite frequency of the hemialleic strain decreased significantly by increasing ddC concentration (Fig.	('E895G', 'Mutation', 'p.E895G', (169, 174))	('Y951F', 'Mutation', 'p.Y951F', (179, 184))	('ddC', 'Gene', (40, 43))	('Y951F', 'Var', (179, 184))	('E895G', 'Var', (169, 174))	('ddC', 'Gene', (332, 335))	('ddC', 'Gene', '1644', (40, 43))	('ddC', 'Gene', '1644', (332, 335))
23751	25462018	This result indicated that, when E895G and Y951F mutant isoforms are present, Mip1 is less susceptible to ddC toxicity, thus parallelizing with the biochemical results previously obtained in Pol gamma.	('ddC', 'Gene', '1644', (106, 109))	('Y951F', 'Var', (43, 48))	('E895G', 'Mutation', 'p.E895G', (33, 38))	('toxicity', 'Disease', 'MESH:D064420', (110, 118))	('Mip1', 'Gene', '79109', (78, 82))	('E895G', 'Var', (33, 38))	('toxicity', 'Disease', (110, 118))	('ddC', 'Gene', (106, 109))	('Mip1', 'Gene', (78, 82))	('Y951F', 'Mutation', 'p.Y951F', (43, 48))	('less', 'NegReg', (86, 90))
23752	25462018	Once we had validated the model, we tested extended and point mutability in W1BCK1-10 harboring the mip1 alleles that carry the different selected polymorphisms.	('mip1', 'Gene', '79109', (100, 104))	('point mutability', 'Var', (56, 72))	('mip1', 'Gene', (100, 104))	('tested', 'Reg', (36, 42))
23753	25462018	8A and Supplementary Table 9), only the Mip1 variants corresponding to human polymorphisms G268A and R964C were more susceptible to ddC than wt Mip1.	('ddC', 'Gene', (132, 135))	('Mip1', 'Gene', (144, 148))	('G268A', 'Var', (91, 96))	('Mip1', 'Gene', '79109', (40, 44))	('susceptible', 'MPA', (117, 128))	('ddC', 'Gene', '1644', (132, 135))	('R964C', 'Mutation', 'rs201477273', (101, 106))	('G268A', 'Mutation', 'rs61752784', (91, 96))	('R964C', 'Var', (101, 106))	('Mip1', 'Gene', (40, 44))	('Mip1', 'Gene', '79109', (144, 148))	('human', 'Species', '9606', (71, 76))
23754	25462018	Mip1 mutants harboring substitutions L392V and E1143G, which were sensitive to d4T, were not sensitive to ddC compared to the wt, as well as R193Q, R1142W and R1146C variants.	('E1143G', 'Var', (47, 53))	('ddC', 'Gene', '1644', (106, 109))	('L392V', 'Mutation', 'rs145289229', (37, 42))	('R1146C', 'Mutation', 'rs2307440', (159, 165))	('Mip1', 'Gene', (0, 4))	('R1142W', 'Mutation', 'rs2307442', (148, 154))	('R1142W', 'Var', (148, 154))	('R193Q', 'Mutation', 'rs3176162', (141, 146))	('Mip1', 'Gene', '79109', (0, 4))	('R1146C', 'Var', (159, 165))	('ddC', 'Gene', (106, 109))	('d4T', 'Chemical', 'MESH:D018119', (79, 82))	('E1143G', 'Mutation', 'rs2307441', (47, 53))	('R193Q', 'Var', (141, 146))
23757	25462018	Among the heteroallelic strains, only the strain harboring R964C showed a dominant effect in the presence of ddC (Fig.	('ddC', 'Gene', (109, 112))	('ddC', 'Gene', '1644', (109, 112))	('R964C', 'Mutation', 'rs201477273', (59, 64))	('R964C', 'Var', (59, 64))
23758	25462018	All strains showed an increase of EryR mutant frequency after treatment with ddC (Supplementary Table 11, columns 2 and 3).	('ddC', 'Gene', (77, 80))	('increase', 'PosReg', (22, 30))	('mutant', 'Var', (39, 45))	('ddC', 'Gene', '1644', (77, 80))	('EryR', 'Gene', (34, 38))
23759	25462018	The fold increase normalized with the untreated wt strain showed a synergistic effect of the intrinsic mutability of mutant Mip1 and of the susceptibility to ddC only for the G268A mutation (Fig.	('ddC', 'Gene', '1644', (158, 161))	('G268A', 'Var', (175, 180))	('mutant', 'Var', (117, 123))	('Mip1', 'Gene', (124, 128))	('ddC', 'Gene', (158, 161))	('intrinsic mutability', 'MPA', (93, 113))	('G268A', 'Mutation', 'rs61752784', (175, 180))	('susceptibility', 'MPA', (140, 154))	('Mip1', 'Gene', '79109', (124, 128))
23760	25462018	On the contrary, the P241L mutation was less susceptible to the presence of ddC, as already observed in the case of d4T.	('ddC', 'Gene', (76, 79))	('P241L', 'Var', (21, 26))	('P241L', 'Mutation', 'rs1452571273', (21, 26))	('ddC', 'Gene', '1644', (76, 79))	('d4T', 'Chemical', 'MESH:D018119', (116, 119))
23761	25462018	Thus, the use of an in vivo system with high sensitivity, such as the model organism S. cerevisiae which we are proposing, can sharpen the putative defects caused by mutations/polymorphisms, in particular on extended mitochondrial mutability or on point mutability.	('S. cerevisiae', 'Species', '4932', (85, 98))	('point', 'MPA', (248, 253))	('extended mitochondrial mutability', 'MPA', (208, 241))	('mutations/polymorphisms', 'Var', (166, 189))
23763	25462018	The two mutations in the exonuclease (exo) domain, P241L and G268A, increased the point mutability at higher levels, suggesting that mutant Pol gamma harboring these mutations, as well as other exo domain mutations lying in the protein surface, have a reduced ability to remove mismatched nucleotides.	('G268A', 'Var', (61, 66))	('point mutability at', 'MPA', (82, 101))	('Pol gamma', 'Gene', (140, 149))	('P241L', 'Var', (51, 56))	('G268A', 'Mutation', 'rs61752784', (61, 66))	('remove mismatched nucleotides', 'MPA', (271, 300))	('P241L', 'Mutation', 'rs1452571273', (51, 56))	('increased', 'PosReg', (68, 77))
23764	25462018	In addition, G268A is predicted to lie in a cluster, which comprises residues 268-277, for which a decrease in exonuclease activity is predicted if mutated.	('decrease', 'NegReg', (99, 107))	('G268A', 'Mutation', 'rs61752784', (13, 18))	('G268A', 'Var', (13, 18))	('exonuclease activity', 'MPA', (111, 131))
23765	25462018	Among them is the E1143G mutation, which has been reported to have a decreased in vitro activity at high temperatures.	('E1143G', 'Mutation', 'rs2307441', (18, 24))	('decreased', 'NegReg', (69, 78))	('E1143G', 'Var', (18, 24))
23769	25462018	found that mutant E1143G Pol gamma has a 1.4-fold higher catalytic activity than wt Pol gamma, and that this mutation can partially rescue the strong biochemical defects of the W748S mutation in cis.	('catalytic activity', 'MPA', (57, 75))	('higher', 'PosReg', (50, 56))	('W748S', 'Var', (177, 182))	('E1143G', 'Mutation', 'rs2307441', (18, 24))	('E1143G', 'Var', (18, 24))	('W748S', 'Mutation', 'rs113994097', (177, 182))
23770	25462018	On the contrary,, showed that human Pol gamma harboring the W748S mutation does not show any biochemical defects and behaves like wt Pol gamma in vivo, and that the presence in cis of the E1143G mutation does not alter the in vivo behavior of the mutant protein.	('human', 'Species', '9606', (30, 35))	('E1143G', 'Mutation', 'rs2307441', (188, 194))	('E1143G', 'Var', (188, 194))	('W748S', 'Var', (60, 65))	('W748S', 'Mutation', 'rs113994097', (60, 65))
23771	25462018	We previously showed that the presence of the E1143G-equivalent mutation in yeast decreases the mtDNA stability by 2-fold because of the A889T mutation, due to the reduced stability of the protein harboring both mutations compared to a protein harboring only the latter mutation.	('A889T', 'Var', (137, 142))	('E1143G-equivalent', 'Var', (46, 63))	('stability', 'MPA', (172, 181))	('mtDNA stability', 'CPA', (96, 111))	('E1143G', 'Mutation', 'rs2307441', (46, 52))	('decreases', 'NegReg', (82, 91))	('A889T', 'Mutation', 'rs763393580', (137, 142))	('reduced', 'NegReg', (164, 171))	('yeast', 'Species', '4932', (76, 81))
23772	25462018	In order to evaluate the possible role of the selected polymorphisms as phenotypic modifiers, we measured the petite frequency in strains harboring the A889T-equivalent mutation in cis with the polymorphism under analysis.	('petite frequency', 'CPA', (110, 126))	('A889T-equivalent', 'Var', (152, 168))	('A889T', 'Mutation', 'rs763393580', (152, 157))
23774	25462018	We showed that all the polymorphisms, except for E193Q, had negative effect, indicating that they could potentially modulate the pathological phenotype.	('negative', 'NegReg', (60, 68))	('modulate', 'Reg', (116, 124))	('E193Q', 'Mutation', 'p.E193Q', (49, 54))	('E193Q', 'Var', (49, 54))
23775	25462018	For two polymorphisms, L392V and R1146C, the effect in combination with the A889T mutation was synergistic.	('R1146C', 'Var', (33, 39))	('L392V', 'Mutation', 'rs145289229', (23, 28))	('A889T', 'Mutation', 'rs763393580', (76, 81))	('R1146C', 'Mutation', 'rs2307440', (33, 39))	('L392V', 'Var', (23, 28))
23776	25462018	A limitation to the use of yeast MIP1 to study the effects of mutations is that only conserved or semi-conserved residues can be studied.	('yeast', 'Species', '4932', (27, 32))	('MIP1', 'Gene', '79109', (33, 37))	('mutations', 'Var', (62, 71))	('MIP1', 'Gene', (33, 37))
23778	25462018	Interestingly, a comparison between the effects of four human mutations which have been studied both in the human POLG and in the MIP1 gene showed very similar results concerning mtDNA stability, mtDNA point mutability and dominance/recessivity in the two systems, indicating that the use of yeast MIP1 has a good predictive ability for conserved and semi-conserved residues.	('POLG', 'Gene', (114, 118))	('MIP1', 'Gene', '79109', (130, 134))	('MIP1', 'Gene', '79109', (298, 302))	('MIP1', 'Gene', (298, 302))	('MIP1', 'Gene', (130, 134))	('POLG', 'Gene', '5428', (114, 118))	('human', 'Species', '9606', (56, 61))	('human', 'Species', '9606', (108, 113))	('yeast', 'Species', '4932', (292, 297))	('mutations', 'Var', (62, 71))
23780	25462018	An additional point addressed in this work concerns the role of the yeast model in predicting the possible correlation between specific mutations in Mip1, corresponding to human mutations, and mtDNA mutability induced by treatment with nucleoside reverse transcriptase inhibitors (NRTI), used in the highly active antiretroviral therapy (HAART), i.e.	('nucleoside', 'Chemical', 'MESH:D009705', (236, 246))	('Mip1', 'Gene', '79109', (149, 153))	('human', 'Species', '9606', (172, 177))	('mtDNA', 'Gene', (193, 198))	('yeast', 'Species', '4932', (68, 73))	('mutations', 'Var', (136, 145))	('Mip1', 'Gene', (149, 153))
23783	25462018	Based on the "Pol gamma hypothesis" of NRTI toxicity, each mutation/SNP which changes the Pol gamma affinity for the incoming NRTI-TP, the discrimination between the NRTI-TP and the corresponding dNTP, or the NRTI excision efficiency in the mtDNA could alter the NRTI induced toxicity.	('-TP', 'Chemical', 'MESH:C011314', (170, 173))	('alter', 'Reg', (253, 258))	('Pol gamma affinity', 'MPA', (90, 108))	('mutation/SNP', 'Var', (59, 71))	('changes', 'Reg', (78, 85))	('-TP', 'Chemical', 'MESH:C011314', (130, 133))	('dNTP', 'Chemical', 'MESH:D010278', (196, 200))	('toxicity', 'Disease', 'MESH:D064420', (276, 284))	('toxicity', 'Disease', (276, 284))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
23784	25462018	To date, an association between NRTI-induced mitochondrial toxicity and SNPs/mutations in Pol gamma has been reported for two mutations, R964C and E1143G.	('mitochondrial toxicity', 'Disease', 'MESH:D028361', (45, 67))	('R964C', 'Mutation', 'rs201477273', (137, 142))	('E1143G', 'Mutation', 'rs2307441', (147, 153))	('R964C', 'Var', (137, 142))	('mitochondrial toxicity', 'Disease', (45, 67))	('E1143G', 'Var', (147, 153))	('association', 'Interaction', (12, 23))	('Pol gamma', 'Gene', (90, 99))
23785	25462018	Our previous and present results showed that mutant versions of Mip1 harboring four polymorphisms (G268A, L392V, R964C and E1143G) are more sensitive to d4T-induced mitochondrial toxicity, resulting in higher petite frequency and EryR mutant frequency, and lower mtDNA levels, than those observed in Mip1 wt strain treated with d4T.	('mitochondrial toxicity', 'Disease', 'MESH:D028361', (165, 187))	('mitochondrial toxicity', 'Disease', (165, 187))	('mtDNA levels', 'MPA', (263, 275))	('Mip1', 'Gene', (64, 68))	('EryR mutant', 'MPA', (230, 241))	('R964C', 'Mutation', 'rs201477273', (113, 118))	('E1143G', 'Mutation', 'rs2307441', (123, 129))	('lower', 'NegReg', (257, 262))	('d4T-induced', 'MPA', (153, 164))	('Mip1', 'Gene', '79109', (64, 68))	('R964C', 'Var', (113, 118))	('E1143G', 'Var', (123, 129))	('sensitive', 'MPA', (140, 149))	('d4T', 'Chemical', 'MESH:D018119', (328, 331))	('Mip1', 'Gene', (300, 304))	('higher', 'PosReg', (202, 208))	('L392V', 'Var', (106, 111))	('Mip1', 'Gene', '79109', (300, 304))	('G268A', 'Var', (99, 104))	('petite frequency', 'MPA', (209, 225))	('d4T', 'Chemical', 'MESH:D018119', (153, 156))	('L392V', 'Mutation', 'rs145289229', (106, 111))	('G268A', 'Mutation', 'rs61752784', (99, 104))
23787	25462018	a heteroallelic strain harboring a wt copy of Mip1 and a mutant copy of Mip1 showed higher petite frequency in the presence of d4T as well as a decrease in total mtDNA levels compared to a strain harboring two copies of wt Mip1.	('petite frequency', 'CPA', (91, 107))	('Mip1', 'Gene', '79109', (72, 76))	('mtDNA levels', 'MPA', (162, 174))	('Mip1', 'Gene', '79109', (46, 50))	('Mip1', 'Gene', (223, 227))	('decrease', 'NegReg', (144, 152))	('d4T', 'Var', (127, 130))	('mutant', 'Var', (57, 63))	('Mip1', 'Gene', (72, 76))	('d4T', 'Chemical', 'MESH:D018119', (127, 130))	('Mip1', 'Gene', (46, 50))	('Mip1', 'Gene', '79109', (223, 227))	('higher', 'PosReg', (84, 90))
23788	25462018	This result indicates that also heterozygous subjects, who are more frequent than homozygous ones due to the relative low frequency of these polymorphisms, are susceptible to d4T toxicity, as already observed in patients heterozygous for E1143G or R964C.	('susceptible', 'Reg', (160, 171))	('R964C', 'Mutation', 'rs201477273', (248, 253))	('toxicity', 'Disease', 'MESH:D064420', (179, 187))	('R964C', 'Var', (248, 253))	('toxicity', 'Disease', (179, 187))	('patients', 'Species', '9606', (212, 220))	('E1143G', 'Mutation', 'rs2307441', (238, 244))	('E1143G', 'Var', (238, 244))	('d4T', 'Chemical', 'MESH:D018119', (175, 178))
23789	25462018	Interestingly, Mip1 harboring a P241L mutation is less susceptible to d4T-induced extended and point mutability, suggesting that mutant polymerase either binds with a lower affinity d4T-TP or has an increased ability to remove incorporated d4T.	('d4T', 'Chemical', 'MESH:D018119', (240, 243))	('P241L', 'Mutation', 'rs1452571273', (32, 37))	('d4T', 'Chemical', 'MESH:D018119', (70, 73))	('ability', 'MPA', (209, 216))	('Mip1', 'Gene', '79109', (15, 19))	('d4T-TP', 'Chemical', 'MESH:C053197', (182, 188))	('remove incorporated d4T', 'MPA', (220, 243))	('polymerase', 'Enzyme', (136, 146))	('d4T', 'Chemical', 'MESH:D018119', (182, 185))	('Mip1', 'Gene', (15, 19))	('P241L', 'Var', (32, 37))	('increased', 'PosReg', (199, 208))	('binds', 'Interaction', (154, 159))	('mutant', 'Var', (129, 135))
23790	25462018	Additionally, P241L is part of a cluster which also includes residues 224-244 and which is predicted to decrease polymerase activity and to increase exonuclease activity if mutated.	('polymerase activity', 'MPA', (113, 132))	('P241L', 'Var', (14, 19))	('exonuclease activity', 'MPA', (149, 169))	('P241L', 'Mutation', 'rs1452571273', (14, 19))	('decrease', 'NegReg', (104, 112))	('increase', 'PosReg', (140, 148))
23791	25462018	Regarding ddC, we observed that only two polymorphisms, G268A and R964C, determined an increased sensitivity to the NRTI, and only for the latter the effects are dominant.	('increased', 'PosReg', (87, 96))	('G268A', 'Mutation', 'rs61752784', (56, 61))	('ddC', 'Gene', '1644', (10, 13))	('R964C', 'Mutation', 'rs201477273', (66, 71))	('R964C', 'Var', (66, 71))	('sensitivity', 'MPA', (97, 108))	('G268A', 'Var', (56, 61))	('ddC', 'Gene', (10, 13))
23793	25462018	Again, P241L is less sensitive to ddC toxicity.	('ddC', 'Gene', '1644', (34, 37))	('P241L', 'Var', (7, 12))	('toxicity', 'Disease', 'MESH:D064420', (38, 46))	('toxicity', 'Disease', (38, 46))	('P241L', 'Mutation', 'rs1452571273', (7, 12))	('ddC', 'Gene', (34, 37))
23794	25462018	We have previously demonstrated that extended mtDNA mutability (petite frequency) and EryR point mutability due to mutations in Mip1 are derived from different mechanisms, since for most mutations there is no correlation between increase in the former and increase in the latter.	('Mip1', 'Gene', '79109', (128, 132))	('mutations', 'Var', (115, 124))	('Mip1', 'Gene', (128, 132))
23795	25462018	Although this observation cannot exclude that the NRTI caused, as a direct effect, both an increase in petite frequency and in point mutability, the results are coherent with those of, who demonstrated that mtDNA mutations accumulated in cells from patients treated with NRTIs are not due to de novo point mutations induced by the NRTI, but might instead be caused by the clonal expansion of preexisting mutant mtDNA particles, needed to restore a proper mtDNA level in case of mtDNA depletion consequent to the NRTI treatment.	('mtDNA', 'MPA', (455, 460))	('caused by', 'Reg', (358, 367))	('patients', 'Species', '9606', (249, 257))	('mtDNA', 'Gene', (207, 212))	('mutations', 'Var', (213, 222))
23797	25462018	This study suggests that many human SNPs/mutations in POLG (i) are not neutral, (ii) could potentially behave as phenotypic modulators of pathological mutations and (iii) can increase the mitochondrial dysfunction induced by treatment with NRTIs.	('human', 'Species', '9606', (30, 35))	('POLG', 'Gene', (54, 58))	('POLG', 'Gene', '5428', (54, 58))	('increase', 'PosReg', (175, 183))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (188, 213))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (188, 213))	('mitochondrial dysfunction', 'Disease', (188, 213))	('SNPs/mutations', 'Var', (36, 50))
23798	25462018	The analysis is based on the general assumption that if an amino acid is conserved between two homologous proteins, such as Mip1 and human Pol gamma, the substitution of that amino acid in one protein can predict the effect of the mutation in the second protein.	('predict', 'Reg', (205, 212))	('Mip1', 'Gene', (124, 128))	('substitution', 'Var', (154, 166))	('human', 'Species', '9606', (133, 138))	('mutation', 'Var', (231, 239))	('Mip1', 'Gene', '79109', (124, 128))
23800	25462018	For these reasons, our results should be confirmed by studies of the polymorphisms in mammalian Pol gamma, either in the yeast model system expressing human Pol gamma or in mammalian cells or in a mammalian model system, especially in the case of substitutions of amino acids which contribute to the binding of the POLG2 subunit, absent in yeast.	('POLG2', 'Gene', (315, 320))	('substitutions', 'Var', (247, 260))	('mammalian', 'Species', '9606', (86, 95))	('yeast', 'Species', '4932', (340, 345))	('human', 'Species', '9606', (151, 156))	('binding', 'Interaction', (300, 307))	('mammalian', 'Species', '9606', (173, 182))	('POLG2', 'Gene', '11232', (315, 320))	('mammalian', 'Species', '9606', (197, 206))	('yeast', 'Species', '4932', (121, 126))
23801	25462018	From a pharmacogenetic point of view, we found that, in the presence of polymorphisms in POLG, zalcitabine should be better tolerated than stavudine since a lower number of polymorphisms determined ddC-induced toxicity and the detrimental effects are less significant in the case of ddC.	('stavudine', 'Chemical', 'MESH:D018119', (139, 148))	('zalcitabine', 'Chemical', 'MESH:D016047', (95, 106))	('toxicity', 'Disease', 'MESH:D064420', (210, 218))	('ddC', 'Gene', (283, 286))	('toxicity', 'Disease', (210, 218))	('ddC', 'Gene', (198, 201))	('POLG', 'Gene', (89, 93))	('polymorphisms', 'Var', (72, 85))	('ddC', 'Gene', '1644', (283, 286))	('POLG', 'Gene', '5428', (89, 93))	('determined', 'Reg', (187, 197))	('ddC', 'Gene', '1644', (198, 201))
23802	25462018	These results agree, in general, with clinical observations, which showed that d4T is commonly less tolerated than ddC, and in particular with the observation that there is a correlation between the presence of E1143G polymorphism and induced lipodystrophy in the case of d4T treatment, but not of ddC treatment.	('lipodystrophy', 'Disease', 'MESH:D008060', (243, 256))	('lipodystrophy', 'Disease', (243, 256))	('ddC', 'Gene', (115, 118))	('lipodystrophy', 'Phenotype', 'HP:0009125', (243, 256))	('ddC', 'Gene', (298, 301))	('ddC', 'Gene', '1644', (115, 118))	('E1143G', 'Mutation', 'rs2307441', (211, 217))	('d4T', 'Chemical', 'MESH:D018119', (79, 82))	('ddC', 'Gene', '1644', (298, 301))	('d4T', 'Chemical', 'MESH:D018119', (272, 275))	('E1143G', 'Var', (211, 217))
23803	25462018	Hence, our analysis supports the need of developing novel NRTIs which inhibit HIV reverse transcriptase but not Pol gamma, and stresses the importance of monitoring the effects of such NRTIs by biochemical and/or in vivo analysis on wt and mutant DNA polymerase gamma.	('polymerase gamma', 'Gene', (251, 267))	('mutant', 'Var', (240, 246))	('HIV reverse transcriptase', 'Enzyme', (78, 103))	('inhibit', 'NegReg', (70, 77))	('polymerase gamma', 'Gene', '5428', (251, 267))
23805	25462018	However, DNA polymerase gamma harboring R964C may lead to a higher degree of mitochondrial toxicity in the presence of Ed4T-tryphospate, as observed previously in vivo, in vitro and in this study for d4T.	('R964C', 'Mutation', 'rs201477273', (40, 45))	('R964C', 'Var', (40, 45))	('higher', 'PosReg', (60, 66))	('Ed4T-tryphospate', 'Chemical', '-', (119, 135))	('d4T', 'Chemical', 'MESH:D018119', (200, 203))	('mitochondrial toxicity', 'Disease', 'MESH:D028361', (77, 99))	('polymerase gamma', 'Gene', '5428', (13, 29))	('d4T', 'Chemical', 'MESH:D018119', (120, 123))	('mitochondrial toxicity', 'Disease', (77, 99))	('polymerase gamma', 'Gene', (13, 29))
23827	27136467	An association between high NLR and increased mortality or recurrence has been observed in various solid organ tumors, including lung, pancreatic, hepatocellular and cholangiocarcinoma.	('high', 'Var', (23, 27))	('pancreatic', 'Disease', (135, 145))	('hepatocellular', 'Disease', (147, 161))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NLR', 'Gene', (28, 31))	('cholangiocarcinoma', 'Disease', (166, 184))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('solid organ tumors', 'Disease', (99, 117))	('solid organ tumors', 'Disease', 'MESH:D009369', (99, 117))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (166, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('lung', 'Disease', (129, 133))	('pancreatic', 'Disease', 'MESH:D010195', (135, 145))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (166, 184))
23834	20478068	Epigenetic aberrations of the genome represent an alternative mechanism for cancer susceptibility; and, studies suggest that epigenetic changes that influence cancer risk can be inherited through the germline.	('cancer', 'Disease', (159, 165))	('influence', 'Reg', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('epigenetic changes', 'Var', (125, 143))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
23843	20478068	Candidate gene studies have identified two loci of interest, i.e., the Y-chromosome gr/gr deletion and the PDE11A gene, while recent GWAS analyses identified KIT-ligand, SPRY4 and BAK1).	('BAK1', 'Gene', (180, 184))	('deletion', 'Var', (90, 98))	('SPRY4', 'Gene', '81848', (170, 175))	('KIT-ligand', 'Gene', '4254', (158, 168))	('KIT-ligand', 'Gene', (158, 168))	('PDE11A', 'Gene', '50940', (107, 113))	('SPRY4', 'Gene', (170, 175))	('BAK1', 'Gene', '578', (180, 184))	('PDE11A', 'Gene', (107, 113))
23844	20478068	Epigenetic changes in the genome, such as aberrant DNA methylation, are an increasingly recognized contributor to cancer development.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('men', 'Species', '9606', (128, 131))	('aberrant', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
23847	20478068	Transgenerational epigenetic inheritance has been well studied and documented in many eukaryotic organisms (e.g., maize, yeast, Drosophila, mice), and recent human studies suggest that epigenetic aberrations that influence cancer risk can be inherited through the germline from parent to child.	('yeast', 'Species', '4932', (121, 126))	('mice', 'Species', '10090', (140, 144))	('human', 'Species', '9606', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('men', 'Species', '9606', (71, 74))	('child', 'Species', '9606', (288, 293))	('influence', 'Reg', (213, 222))	('epigenetic aberrations', 'Var', (185, 207))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('maize', 'Species', '4577', (114, 119))	('cancer', 'Disease', (223, 229))	('Drosophila', 'Species', '7227', (128, 138))
23850	20478068	Retrotransposons are thought to be resistant to epigenetic reprogramming during embryogenesis in mice, and thus may play a role in epigenetic heritability (e.g., if inserted in or near the affected gene).	('epigenetic', 'Var', (131, 141))	('mice', 'Species', '10090', (97, 101))	('role', 'Reg', (123, 127))	('play', 'Reg', (116, 120))	('Retrotransposons', 'Var', (0, 16))
23851	20478068	A recent mouse model study found that transgenerational epigenetic inheritance through the germline controls susceptibility to TGCTs.	('mouse', 'Species', '10090', (9, 14))	('transgenerational epigenetic inheritance', 'Var', (38, 78))	('TGCTs', 'Disease', (127, 132))
23857	20478068	In recent case-control studies, hypomethylation of peripheral blood DNA was found to be associated with increased risks of bladder and head/neck cancers, suggesting that global demethylation in genomic DNA is a potential biomarker of cancer susceptibility.	('cancer', 'Disease', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('bladder', 'Disease', (123, 130))	('head/neck cancers', 'Disease', (135, 152))	('hypomethylation', 'Var', (32, 47))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('associated', 'Reg', (88, 98))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('head/neck cancers', 'Disease', 'MESH:D006258', (135, 152))	('DNA', 'Gene', (68, 71))	('global demethylation', 'Var', (170, 190))
23870	20478068	Associations between lower LINE-1 methylation and TGCT risk were stronger in patients with seminoma versus non-seminomatous tumors, and in bilateral TGCT patients versus patients from multi-case families (Table 4).	('patients', 'Species', '9606', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('methylation', 'Var', (34, 45))	('lower LINE-1', 'Gene', (21, 33))	('patients', 'Species', '9606', (154, 162))	('seminoma versus non-seminomatous tumors', 'Disease', (91, 130))	('stronger', 'PosReg', (65, 73))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('seminoma versus non-seminomatous tumors', 'Disease', 'MESH:C537844', (91, 130))	('TGCT', 'Disease', (50, 54))
23871	20478068	This difference has been variably attributed to gender-related dietary differences, reduced circulating levels of folate due to female menstruation, and/or the presence of an additional X chromosome in female cells.	('reduced circulating levels of folate', 'Phenotype', 'HP:0100507', (84, 120))	('presence', 'Var', (160, 168))	('men', 'Species', '9606', (135, 138))	('folate', 'Chemical', 'MESH:D005492', (114, 120))	('reduced', 'NegReg', (84, 91))	('circulating levels of folate', 'MPA', (92, 120))
23877	20478068	This epigenetic alteration was associated with transgenerational disease states (approximately 85% frequency), including abnormalities in testis function, male infertility, and tumor development.	('abnormalities', 'Var', (121, 134))	('testis function', 'Disease', (138, 153))	('epigenetic alteration', 'Var', (5, 26))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('associated', 'Reg', (31, 41))	('male infertility', 'Phenotype', 'HP:0003251', (155, 171))	('male infertility', 'Disease', (155, 171))	('male infertility', 'Disease', 'MESH:D007248', (155, 171))	('men', 'Species', '9606', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('abnormalities in testis', 'Phenotype', 'HP:0000035', (121, 144))	('infertility', 'Phenotype', 'HP:0000789', (160, 171))	('tumor', 'Disease', (177, 182))	('transgenerational disease', 'Disease', (47, 72))
23878	20478068	This observation illustrates how an environmental exposure can epigenetically reprogram the germline and promote adult-onset defects in the germline, providing one possible mechanism by which environmental exposures may promote TGCTs.	('men', 'Species', '9606', (199, 202))	('promote', 'PosReg', (105, 112))	('TGCTs', 'Disease', (228, 233))	('promote', 'PosReg', (220, 227))	('men', 'Species', '9606', (43, 46))	('adult-onset defects in the germline', 'CPA', (113, 148))	('epigenetically', 'Var', (63, 77))
23879	20478068	Transgenerational epigenetic interactions have been shown to control susceptibility to TGCTs in mice with Dead-end homologue 1 (Dnd1) mutations.	('mice', 'Species', '10090', (96, 100))	('Dnd1', 'Gene', '213236', (128, 132))	('susceptibility', 'MPA', (69, 83))	('Dead-end homologue 1', 'Gene', (106, 126))	('control', 'Reg', (61, 68))	('mutations', 'Var', (134, 143))	('TGCTs', 'Disease', (87, 92))	('Dnd1', 'Gene', (128, 132))	('Dead-end homologue 1', 'Gene', '213236', (106, 126))	('epigenetic interactions', 'Var', (18, 41))
23881	20478068	suggested that, in humans, transgenerational epigenetics may explain the 2-3 fold risk difference in brothers and sons of TGCT affected individuals.	('epigenetics', 'Var', (45, 56))	('humans', 'Species', '9606', (19, 25))	('TGCT', 'Gene', (122, 126))
23883	20478068	Such an inherited epigenetic event could be associated either with an environmental factor or genetic susceptibility.	('associated', 'Reg', (44, 54))	('men', 'Species', '9606', (77, 80))	('epigenetic event', 'Var', (18, 34))
23885	20478068	Other studies have found that global hypomethylation in DNA from blood was associated with bladder and head/neck cancers.	('bladder', 'Disease', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('head/neck cancers', 'Disease', (103, 120))	('DNA', 'Gene', (56, 59))	('head/neck cancers', 'Disease', 'MESH:D006258', (103, 120))	('associated', 'Reg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('global hypomethylation', 'Var', (30, 52))
23886	20478068	Genomic global (LINE-1) methylation may be an independent risk factor or a phenotypic marker of cancer risk associated with genetic instability, aberrant epigenetic regulation, or other factors.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('methylation', 'Var', (24, 35))	('aberrant epigenetic regulation', 'Var', (145, 175))	('associated', 'Reg', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('genetic instability', 'Var', (124, 143))
23888	20478068	This is the first study to show that global LINE-1 methylation levels may be inherited from parent to child in humans, and that hypomethylation is associated with testicular cancer risk.	('testicular cancer', 'Phenotype', 'HP:0010788', (163, 180))	('testicular cancer', 'Disease', 'MESH:D013736', (163, 180))	('associated', 'Reg', (147, 157))	('methylation', 'MPA', (51, 62))	('child', 'Species', '9606', (102, 107))	('hypomethylation', 'Var', (128, 143))	('testicular cancer', 'Disease', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('humans', 'Species', '9606', (111, 117))
23889	20478068	The results of this study suggest that LINE-1 methylation is heritable in humans, and that transgenerational inheritance of LINE-1 methylation levels may be associated with testicular cancer risk.	('methylation', 'Var', (46, 57))	('associated', 'Reg', (157, 167))	('LINE-1', 'Gene', (124, 130))	('testicular cancer', 'Phenotype', 'HP:0010788', (173, 190))	('testicular cancer', 'Disease', 'MESH:D013736', (173, 190))	('LINE-1', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('humans', 'Species', '9606', (74, 80))	('testicular cancer', 'Disease', (173, 190))
23890	20478068	The incomplete penetrance and non-Mendelian inheritance of epigenetic variation are consistent with complex disease phenotypes, which familial testicular cancer displays, and thus it may provide some insight into the basis of this complex disease.	('Men', 'Species', '9606', (34, 37))	('familial testicular cancer', 'Disease', 'MESH:D013736', (134, 160))	('testicular cancer', 'Phenotype', 'HP:0010788', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('familial testicular cancer', 'Disease', (134, 160))	('epigenetic variation', 'Var', (59, 79))
23921	20478068	This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and by support services contracts NO2-CP-11019-50 and NO2-CP-65504-50 with Westat Inc.	('NO2-CP', 'Chemical', '-', (210, 216))	('Cancer', 'Disease', (122, 128))	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('Cancer', 'Disease', (92, 98))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('NO2-CP-11019-50', 'Var', (190, 205))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('NO2-CP', 'Chemical', '-', (190, 196))	('NO2-CP-65504-50', 'Var', (210, 225))
23927	32615943	However, subgroup analysis showed a significant association between high expressed PODXL and poor OS in the colorectal cancer, pancreatic cancer, urothelial bladder cancer, renal cell carcinoma and glioblastoma multiforme.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('PODXL', 'Gene', '5420', (83, 88))	('poor OS', 'Disease', (93, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', (127, 144))	('glioblastoma multiforme', 'Disease', (198, 221))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('PODXL', 'Gene', (83, 88))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 193))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (198, 221))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('high expressed', 'Var', (68, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('renal cell carcinoma', 'Disease', (173, 193))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (146, 171))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (173, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('colorectal cancer', 'Disease', (108, 125))	('urothelial bladder cancer', 'Disease', (146, 171))
23929	32615943	The result of meta-analysis showed that high expressed PODXL was significantly linked with poor OS in pancreatic cancer and glioblastoma multiforme, but not in gastric cancer, esophageal cancer or lung adenocarcinoma.	('high expressed', 'Var', (40, 54))	('gastric cancer', 'Disease', (160, 174))	('cancer', 'Disease', (113, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (197, 216))	('poor OS', 'Disease', (91, 98))	('cancer', 'Disease', (168, 174))	('PODXL', 'Gene', (55, 60))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (197, 216))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('glioblastoma multiforme', 'Disease', (124, 147))	('linked', 'Reg', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (124, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('cancer', 'Disease', (187, 193))	('PODXL', 'Gene', '5420', (55, 60))	('lung adenocarcinoma', 'Disease', (197, 216))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
23959	32615943	The pooled HR and 95% CI indicated that high-expressed PODXL was significantly related to poor OS in patients with various cancers (HR = 2.33, 95% CI = 1.76-3.09, P < 0.0001) with a significant heterogeneity across these studies (I2 = 63.4%, P = 0.001) (Fig.2a).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patients', 'Species', '9606', (101, 109))	('PODXL', 'Gene', '5420', (55, 60))	('poor OS', 'Disease', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('high-expressed', 'Var', (40, 54))	('PODXL', 'Gene', (55, 60))	('related', 'Reg', (79, 86))
23966	32615943	Subgroup analysis showed that, high expressed PODXL were linked with poor OS in colorectal cancer (HR = 1.79, 95% CI = 1.35-2.37, P < 0.0001), pancreatic cancer (HR = 2.98, 95% CI = 1.95-4.55, P < 0.0001), urothelial bladder cancer (HR = 2.14, 95% CI = 1.48-3.10) and other cancers (HR = 2.60, 95% CI = 1.45-4.66, P = 0.001), but not in patients with the gastric cancer (HR = 2.76, 95% CI = 0.45-15.84, P = 0.256).	('bladder cancer', 'Phenotype', 'HP:0009725', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (206, 231))	('gastric cancer', 'Disease', (355, 369))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancers', 'Disease', 'MESH:D009369', (274, 281))	('urothelial bladder cancer', 'Disease', (206, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('colorectal cancer', 'Disease', (80, 97))	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (337, 345))	('gastric cancer', 'Disease', 'MESH:D013274', (355, 369))	('PODXL', 'Gene', '5420', (46, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (355, 369))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancers', 'Disease', (274, 281))	('PODXL', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
23967	32615943	In conclusion, high expressed level of PODXL was associated with poor OS in 6 types of cancers.	('high', 'Var', (15, 19))	('cancers', 'Disease', (87, 94))	('poor OS', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('PODXL', 'Gene', '5420', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('PODXL', 'Gene', (39, 44))
23968	32615943	And regarding the analysis type, we also found that the high expression of PODXL was significantly associated with the much shorter OS, when the studies were assessed with K-M curve.	('PODXL', 'Gene', '5420', (75, 80))	('high expression', 'Var', (56, 71))	('associated', 'Reg', (99, 109))	('PODXL', 'Gene', (75, 80))
23973	32615943	As a result, these correlations indicated that the high expressed PODXL was associated with the advanced biological behavior in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PODXL', 'Gene', '5420', (66, 71))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('PODXL', 'Gene', (66, 71))	('associated', 'Reg', (76, 86))	('advanced biological behavior', 'CPA', (96, 124))	('high expressed', 'Var', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
23981	32615943	And among the 31 types of cancers, 9040 patients, the significant association between high expressed PODXL and poor OS was found in 3 types of cancers, including the glioblastoma multiforme, kidney renal papillary cell carcinoma and pancreatic adenocarcinoma (Table 5).	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PODXL', 'Gene', (101, 106))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (198, 228))	('glioblastoma multiforme', 'Disease', (166, 189))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (166, 189))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('high', 'Var', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (233, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('patients', 'Species', '9606', (40, 48))	('PODXL', 'Gene', '5420', (101, 106))	('kidney renal papillary cell carcinoma and pancreatic adenocarcinoma', 'Disease', 'MESH:C538614', (191, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cancers', 'Disease', 'MESH:D009369', (143, 150))
23993	32615943	Our meta-analysis not only indicated that high expressed PODXL was associated with poor OS, DFS or CSS in patients with cancers, but also showed that membrane expression was correlated with poor OS as well.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PODXL', 'Gene', (57, 62))	('DFS', 'Disease', (92, 95))	('CSS', 'Disease', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('high expressed', 'Var', (42, 56))	('poor OS', 'Disease', (83, 90))	('CSS', 'Chemical', '-', (99, 102))	('membrane expression', 'MPA', (150, 169))	('cancers', 'Disease', (120, 127))	('associated', 'Reg', (67, 77))	('patients', 'Species', '9606', (106, 114))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('PODXL', 'Gene', '5420', (57, 62))
24010	32615943	According to these reports, it could be deduced that high expressed PODXL promoted tumor progression by enhancing a series of cell changes such as EMT, cell migration and invasion.	('PODXL', 'Gene', '5420', (68, 73))	('promoted', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high expressed', 'Var', (53, 67))	('PODXL', 'Gene', (68, 73))	('tumor', 'Disease', (83, 88))	('invasion', 'CPA', (171, 179))	('cell changes', 'CPA', (126, 138))	('cell migration', 'CPA', (152, 166))	('enhancing', 'PosReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('EMT', 'CPA', (147, 150))
24014	32615943	Overexpressed PODXL could be detected in peripheral blood and used as a non-invasive diagnostic biomarker for the detection of pancreatic cancer.	('pancreatic cancer', 'Disease', (127, 144))	('Overexpressed', 'Var', (0, 13))	('PODXL', 'Gene', '5420', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('PODXL', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
24016	32615943	High expression of miR-509-3-5p and miR-5100 inhibited the invasion and metastasis of gastric cancers and pancreatic cancers by directly targeting PODXL, functioning as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (106, 123))	('inhibited', 'NegReg', (45, 54))	('PODXL', 'Gene', '5420', (147, 152))	('targeting', 'Reg', (137, 146))	('miR-509-3-5p', 'Var', (19, 31))	('miR-5100', 'Gene', '100847014', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (106, 124))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancers', 'Disease', 'MESH:D013274', (86, 101))	('pancreatic cancers', 'Disease', (106, 124))	('PODXL', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancers', 'Disease', (86, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (86, 101))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('pancreatic cancers', 'Disease', 'MESH:D010190', (106, 124))	('miR-5100', 'Gene', (36, 44))	('tumor', 'Disease', (171, 176))
24022	32615943	Our meta-analysis showed that PODXL plays a significant role in cancer progression, and high-expressed PODXL could be linked to aggressive biological phenotype and poor prognosis.	('PODXL', 'Gene', (30, 35))	('PODXL', 'Gene', '5420', (103, 108))	('cancer', 'Disease', (64, 70))	('linked', 'Reg', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('high-expressed', 'Var', (88, 102))	('PODXL', 'Gene', (103, 108))	('PODXL', 'Gene', '5420', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
24023	32615943	Specifically, the high expressed PODXL was correlated with poor prognosis significantly in the glioblastoma multiforme and pancreatic cancer, but not in the esophageal adenocarcinoma, gastric cancer and lung adenocarcinoma.	('high expressed', 'Var', (18, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (208, 222))	('glioblastoma multiforme', 'Disease', (95, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (168, 182))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (95, 118))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (157, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (123, 140))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('lung adenocarcinoma', 'Disease', (203, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('PODXL', 'Gene', '5420', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (203, 222))	('pancreatic cancer', 'Disease', 'MESH:D010190', (123, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('PODXL', 'Gene', (33, 38))	('gastric cancer', 'Disease', (184, 198))	('adenocarcinoma', 'Disease', (208, 222))	('pancreatic cancer', 'Disease', (123, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('adenocarcinoma', 'Disease', (168, 182))
24032	30485574	The effects of Cse1L knockdown on cell proliferation and cell cycle progression were determined by Cell Counting Kit-8 assay, flow cytometry, PH3 staining and bromodeoxyuridine incorporation assay.	('Cse1L', 'Gene', (15, 20))	('rat', 'Species', '10116', (46, 49))	('rat', 'Species', '10116', (184, 187))	('bromodeoxyuridine', 'Chemical', 'MESH:D001973', (159, 176))	('Cse1L', 'Gene', '1434', (15, 20))	('cell cycle progression', 'CPA', (57, 79))	('knockdown', 'Var', (21, 30))
24036	30485574	The knockdown of CSE1L in TCam-2 cells attenuated the cells' proliferative capacity.	('attenuated', 'NegReg', (39, 49))	('CSE1L', 'Gene', (17, 22))	('rat', 'Species', '10116', (68, 71))	('knockdown', 'Var', (4, 13))	('TCam-2', 'CellLine', 'CVCL:T012', (26, 32))
24046	30485574	We further knocked down CSE1L in a seminoma cell line TCam-2 to investigate CSE1L function in testicular cancers.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('seminoma', 'Disease', 'MESH:D018239', (35, 43))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('testicular cancers', 'Phenotype', 'HP:0010788', (94, 112))	('CSE1L', 'Gene', (24, 29))	('investigate', 'Reg', (64, 75))	('knocked down', 'Var', (11, 23))	('seminoma', 'Disease', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('testicular cancer', 'Phenotype', 'HP:0010788', (94, 111))	('TCam-2', 'CellLine', 'CVCL:T012', (54, 60))
24067	30485574	The sequence information of the primers was as follows: CSE1L-F 5'-TTTTGAGTTACCCGAAGA-3', CSE1L-R 5'-TTGTGAAGTGACTGTGCC-3', GAPDH-F 5'-GTCAGCCGCATCTTCTTTTG-3' and GAPDH-R 5'-GCGCCCAATACGACCAAATC-3'.	("CSE1L-R 5'-TTGTGAAGTGACTGTGCC-3", 'Var', (90, 121))	('GAPDH', 'Gene', '2597', (124, 129))	('GAPDH', 'Gene', '2597', (163, 168))	('GAPDH', 'Gene', (124, 129))	('GAPDH', 'Gene', (163, 168))
24106	30485574	The CSE1L protein expression in the TCam-2 cells transfected with CSE1L-KD1 and CSE1L-KD2 was also significantly diminished relative to that in the control siRNA.	('protein', 'Protein', (10, 17))	('diminished', 'NegReg', (113, 123))	('CSE1L', 'Gene', (4, 9))	('CSE1L-KD2', 'Var', (80, 89))	('CSE1L-KD1', 'Var', (66, 75))	('TCam-2', 'CellLine', 'CVCL:T012', (36, 42))
24108	30485574	Next, we inspected the effect of CSE1L deficiency on the proliferation and DNA synthesis of TCam-2 cells.	('deficiency', 'Var', (39, 49))	('DNA', 'MPA', (75, 78))	('CSE1L', 'Gene', (33, 38))	('rat', 'Species', '10116', (64, 67))	('TCam-2', 'CellLine', 'CVCL:T012', (92, 98))
24109	30485574	CCK-8 results showed that the cell numbers were significantly reduced in the CSE1L-KD1 and CSE1L-KD2 groups than in the negative control at 36, 48 and 60 hours after transfection (Figure 4C).	('reduced', 'NegReg', (62, 69))	('cell numbers', 'CPA', (30, 42))	('CCK-8', 'Chemical', '-', (0, 5))	('CSE1L-KD1', 'Var', (77, 86))
24111	30485574	As shown in Figure 4D, the percentage of cells was significantly increased in the G0/G1 phase and decreased in the S phase in the CSE1L-KD1 and CSE1L-KD2 groups, whereas a moderate rise in cell numbers was noted in the G2/M phase in the CSE1L-KD2 group.	('increased', 'PosReg', (65, 74))	('rat', 'Species', '10116', (176, 179))	('CSE1L-KD2', 'Var', (144, 153))	('CSE1L-KD1', 'Var', (130, 139))	('decreased', 'NegReg', (98, 107))
24112	30485574	These results indicate that CSE1L deficiency can induce G1/G0 arrest and delay the G2/M phase of TCam-2 cells.	('G1/G0 arrest', 'CPA', (56, 68))	('deficiency', 'Var', (34, 44))	('CSE1L', 'Gene', (28, 33))	('TCam-2', 'CellLine', 'CVCL:T012', (97, 103))	('induce', 'PosReg', (49, 55))	('delay', 'NegReg', (73, 78))	('G2/M phase of TCam-2 cells', 'CPA', (83, 109))
24113	30485574	To verify this result, we continued to evaluate the influence of CSE1L knockdown on the DNA synthesis of TCam-2 cells by using the BrdU incorporation assay.	('DNA synthesis', 'MPA', (88, 101))	('knockdown', 'Var', (71, 80))	('rat', 'Species', '10116', (143, 146))	('CSE1L', 'Gene', (65, 70))	('BrdU', 'Chemical', 'MESH:D001973', (131, 135))	('TCam-2', 'CellLine', 'CVCL:T012', (105, 111))
24115	30485574	As shown in Figure 4E,G, the percentage of BrdU-positive cells in the CSE1L-KD1 and CSE1L-KD2 groups were obviously decreased relative to that in the control group.	('BrdU', 'Chemical', 'MESH:D001973', (43, 47))	('BrdU-positive', 'MPA', (43, 56))	('CSE1L-KD1', 'Var', (70, 79))	('CSE1L-KD2', 'Var', (84, 93))	('decreased', 'NegReg', (116, 125))
24119	30485574	To confirm our hypothesis, we performed immunostainings of alpha-tubulin and CSE1L in TCam-2 cells after Cse1l knockdown.	('alpha-tubulin', 'Gene', (59, 72))	('knockdown', 'Var', (111, 120))	('Cse1l', 'Gene', '1434', (105, 110))	('alpha-tubulin', 'Gene', '10376', (59, 72))	('CSE1L', 'Gene', (77, 82))	('Cse1l', 'Gene', (105, 110))	('TCam-2', 'CellLine', 'CVCL:T012', (86, 92))
24120	30485574	We found a significant number of mitotic cells with abnormal spindle geometry in the CSE1L-KD1 and CSE1L-KD2 groups compared with those in the TCam-2 cells transfected with control siRNA.	('TCam-2', 'CellLine', 'CVCL:T012', (143, 149))	('CSE1L-KD1', 'Var', (85, 94))	('mitotic cells', 'CPA', (33, 46))
24121	30485574	By calculating for the normal and abnormal spindle numbers in the dividing TCam-2 cells of the NC, CSE1L-KD1 and CSE1L-KD2 groups, we found a rise in the ratio of the dividing cells with abnormal spindles.	('TCam-2', 'CellLine', 'CVCL:T012', (75, 81))	('rat', 'Species', '10116', (154, 157))	('CSE1L-KD2', 'Var', (113, 122))	('rise', 'PosReg', (142, 146))
24122	30485574	Statistical data revealed that after CSE1L knockdown, the ratio of centrosome number to dividing cell number was higher than that of the normal dividing cells containing two centrosomes (Figure 5D).	('CSE1L', 'Gene', (37, 42))	('rat', 'Species', '10116', (58, 61))	('knockdown', 'Var', (43, 52))	('higher', 'PosReg', (113, 119))
24123	30485574	Overall, these data demonstrated that CSE1L can facilitate the completion of normal cell mitosis in TCam-2 cells.	('facilitate', 'PosReg', (48, 58))	('completion', 'CPA', (63, 73))	('TCam-2', 'CellLine', 'CVCL:T012', (100, 106))	('CSE1L', 'Var', (38, 43))	('rat', 'Species', '10116', (27, 30))
24129	30485574	Studies in colorectal cancer cell lines (HCT116, SW480, HT29 and RKO) found that cell proliferation limited by the RNAi of CSE1L and CSE1L-deficient cells seemed to arrest the G0/G1 phase.35, 36 The depletion of CSE1L by RNAi in primary papillary thyroid carcinoma cell line B-CPAP led to reduced cell proliferation; this phenotype was confirmed by the significantly reduced BrdU incorporation in CSE1L knockdown groups.24 To investigate the functional significance of CSE1L in osteosarcoma, authors performed the RNAi of CSE1L in the two osteosarcoma cell lines MNNG/HOS and U2OS, and cell growth was significantly inhibited.	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('osteosarcoma', 'Disease', (539, 551))	('osteosarcoma', 'Disease', 'MESH:D012516', (539, 551))	('papillary thyroid carcinoma', 'Disease', 'MESH:C536915', (237, 264))	('osteosarcoma', 'Phenotype', 'HP:0002669', (478, 490))	('colorectal cancer', 'Disease', (11, 28))	('rat', 'Species', '10116', (309, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('RNAi', 'Var', (514, 518))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (237, 264))	('HCT116', 'CellLine', 'CVCL:0291', (41, 47))	('BrdU', 'Chemical', 'MESH:D001973', (375, 379))	('rat', 'Species', '10116', (387, 390))	('papillary thyroid carcinoma', 'Disease', (237, 264))	('rat', 'Species', '10116', (93, 96))	('MNNG/HOS', 'CellLine', 'CVCL:0439', (563, 571))	('osteosarcoma', 'Phenotype', 'HP:0002669', (539, 551))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('osteosarcoma', 'Disease', (478, 490))	('CSE1L', 'Gene', (522, 527))	('osteosarcoma', 'Disease', 'MESH:D012516', (478, 490))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cell growth', 'CPA', (586, 597))	('U2OS', 'CellLine', 'CVCL:0042', (576, 580))	('HT29', 'CellLine', 'CVCL:0320', (56, 60))	('SW480', 'CellLine', 'CVCL:0546', (49, 54))	('inhibited', 'NegReg', (616, 625))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (247, 264))
24131	30485574	The BrdU incorporation in the CSE1L-KD1 and CSE1L-KD2 groups was significantly reduced relative to those in the control groups.	('reduced', 'NegReg', (79, 86))	('rat', 'Species', '10116', (16, 19))	('BrdU', 'Chemical', 'MESH:D001973', (4, 8))	('CSE1L-KD1', 'Var', (30, 39))	('BrdU incorporation', 'CPA', (4, 22))	('CSE1L-KD2', 'Var', (44, 53))
24137	30485574	When CSE1L expression was disrupted in TCam-2 cells, spindle formation was seriously influenced, and the chromosome exhibited a disordered alignment.	('spindle formation', 'CPA', (53, 70))	('CSE1L', 'Gene', (5, 10))	('disordered alignment', 'CPA', (128, 148))	('TCam-2', 'CellLine', 'CVCL:T012', (39, 45))	('disrupted', 'Var', (26, 35))	('influenced', 'Reg', (85, 95))	('exhibited', 'Reg', (116, 125))
24138	30485574	By cell cycle assay, the cell ratio in the G2/M phase also exhibited a moderately increasing trend in CSE1L-deficient cells, and PH3 immunostaining verified an increase in M phase cells by CSE1L knockdown.	('rat', 'Species', '10116', (75, 78))	('increase', 'PosReg', (160, 168))	('cell ratio', 'CPA', (25, 35))	('G2/M phase', 'CPA', (43, 53))	('increasing', 'PosReg', (82, 92))	('rat', 'Species', '10116', (30, 33))	('knockdown', 'Var', (195, 204))	('CSE1L-deficient', 'Gene', (102, 117))	('M phase cells', 'CPA', (172, 185))
24140	30485574	The RNAi of BuGZ in several human cell lines resulted in chromosomal misalignment and mitotic block in the M phase.39 KIFC3 and KIF3b, members of the human kinesin family, have been reported to be highly expressed in seminoma tissues; the proteins also bind along the spindle and affect spindle formation in Hela cells.40, 41 Given these data, we conclude that CSE1L is essential to proper cell division and the disrupted CSE1L expression in TCam-2 cells led to M phase delay.	('human', 'Species', '9606', (150, 155))	('KIFC3', 'Gene', '3801', (118, 123))	('TCam-2', 'CellLine', 'CVCL:T012', (442, 448))	('M phase delay', 'CPA', (462, 475))	('BuGZ', 'Gene', (12, 16))	('human', 'Species', '9606', (28, 33))	('seminoma', 'Disease', 'MESH:D018239', (217, 225))	('CSE1L', 'Gene', (422, 427))	('BuGZ', 'Gene', '7756', (12, 16))	('Hela cells', 'CellLine', 'CVCL:0030', (308, 318))	('seminoma', 'Disease', (217, 225))	('KIF3b', 'Gene', '9371', (128, 133))	('KIF3b', 'Gene', (128, 133))	('disrupted', 'Var', (412, 421))	('KIFC3', 'Gene', (118, 123))
24165	22496838	Although the actual physiological ligand of GPER remains unknown, we considered that it could be a good candidate for mediating the proliferative effect of E2-BSA and of some xeno-oestrogens such as bisphenol A, which are able in vitro to stimulate seminoma cell proliferation.	('E2', 'Chemical', 'MESH:D004958', (156, 158))	('seminoma', 'Disease', (249, 257))	('bisphenol A', 'Chemical', 'MESH:C006780', (199, 210))	('E2-BSA', 'Var', (156, 162))	('proliferative', 'MPA', (132, 145))	('rat', 'Species', '10116', (139, 142))	('rat', 'Species', '10116', (270, 273))	('seminoma', 'Disease', 'MESH:D018239', (249, 257))	('stimulate', 'PosReg', (239, 248))
24197	22496838	NM_001039966 and NM_001101, respectively), were as follows: 5'-TCTAAACTGCGGTCAGATGTGGCT-3' (gper forward) and 5'-TGTGAAGAGTGCAAGGTGACCAGT-3' (gper reverse) and 5'-TTGCTGATCCACATCTGCTG-3' (beta-actin forward) and 5'-GACAGGATGCAGAAGGAGAT-3' (beta-actin reverse), respectively.	('gper', 'Gene', '2852', (92, 96))	('gper', 'Gene', (92, 96))	('gper', 'Gene', '2852', (142, 146))	('beta-actin', 'Gene', '728378', (188, 198))	('NM_001101', 'Var', (17, 26))	('beta-actin', 'Gene', (188, 198))	('beta-actin', 'Gene', (240, 250))	('beta-actin', 'Gene', '728378', (240, 250))	('gper', 'Gene', (142, 146))
24212	22496838	As we previously reported that this E2-BSA specific effect was not inhibited by ICI-182,780, a pure ER antagonist, but was reversed by Pertussis toxin, a G protein inhibitor, we hypothesize that E2-BSA directly interacted with GPER to induce JKT-1 cell proliferation.	('E2', 'Chemical', 'MESH:D004958', (36, 38))	('E2', 'Chemical', 'MESH:D004958', (195, 197))	('rat', 'Species', '10116', (260, 263))	('E2-BSA', 'Var', (195, 201))	('JKT-1 cell proliferation', 'CPA', (242, 266))	('interacted', 'Interaction', (211, 221))	('JKT-1', 'CellLine', 'CVCL:T011', (242, 247))	('induce', 'PosReg', (235, 241))
24215	22496838	Whereas transfection with control siRNA had no effect on JKT-1 cell proliferation after incubation with E2 and E2-BSA (data not shown), GPER silencing had no effect on proliferation of the JKT-1 cells incubated with E2 but it completely neutralized the E2-BSA-induced proliferative effect, similar to co-incubation with G15, confirming that GPER mediated the effects of E2-BSA on JKT-1 cell proliferation (Figure 5).	('proliferative', 'CPA', (268, 281))	('neutralized', 'NegReg', (237, 248))	('silencing', 'Var', (141, 150))	('JKT-1', 'CellLine', 'CVCL:T011', (189, 194))	('E2', 'Chemical', 'MESH:D004958', (370, 372))	('JKT-1', 'CellLine', 'CVCL:T011', (57, 62))	('E2', 'Chemical', 'MESH:D004958', (253, 255))	('rat', 'Species', '10116', (75, 78))	('E2', 'Chemical', 'MESH:D004958', (216, 218))	('rat', 'Species', '10116', (175, 178))	('E2', 'Chemical', 'MESH:D004958', (104, 106))	('rat', 'Species', '10116', (398, 401))	('E2', 'Chemical', 'MESH:D004958', (111, 113))	('JKT-1', 'CellLine', 'CVCL:T011', (380, 385))	('rat', 'Species', '10116', (275, 278))
24227	22496838	One explanation could be the different antibodies used, which triggered different epitopes (intra- or extracytoplasmic) and/or cell trafficking of the protein, which is described as highly unusual in human embryonic kidney HEK-293 cells with an accumulation in the peri-nuclear space after endocytosis from the plasma membrane.	('HEK-293', 'CellLine', 'CVCL:0045', (223, 230))	('embryonic kidney', 'Disease', (206, 222))	('cell trafficking', 'CPA', (127, 143))	('epitopes', 'MPA', (82, 90))	('embryonic kidney', 'Disease', 'MESH:D007674', (206, 222))	('human', 'Species', '9606', (200, 205))	('antibodies', 'Var', (39, 49))
24229	22496838	Moreover, membrane localization of GPER was supported by its co-localization with E2-BSA-FITC, which does not cross the membrane, and its ability to trigger a very rapid signal transduction induced by E2-BSA, a membrane impermeable estrogen.	('E2-BSA', 'Var', (201, 207))	('E2', 'Chemical', 'MESH:D004958', (82, 84))	('FITC', 'Chemical', 'MESH:D016650', (89, 93))	('trigger', 'Reg', (149, 156))	('E2', 'Chemical', 'MESH:D004958', (201, 203))
24239	22496838	Another explanation for GPER overexpression could be hypomethylation of the GPER gene promoter region considering that such epigenetic modifications are now largely described in cancer.	('overexpression', 'PosReg', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('hypomethylation', 'Var', (53, 68))	('GPER', 'Gene', (76, 80))
24244	22496838	In contrast, G1, a selective GPER agonist, which had a low affinity for ERbeta but a high affinity for GPER, and E2-BSA, induced JKT-1 cell proliferation.	('ERbeta', 'Gene', (72, 78))	('E2', 'Chemical', 'MESH:D004958', (113, 115))	('GPER', 'MPA', (103, 107))	('E2-BSA', 'Var', (113, 119))	('rat', 'Species', '10116', (147, 150))	('ERbeta', 'Gene', '2100', (72, 78))	('JKT-1', 'CellLine', 'CVCL:T011', (129, 134))	('JKT-1 cell proliferation', 'CPA', (129, 153))	('induced', 'Reg', (121, 128))
24250	22496838	Using RNAi silencing and G15, a selective GPER antagonist, we definitively demonstrated the involvement of GPER in E2-BSA-induced JKT-1 cell proliferation, similar to that shown recently by our laboratory for bisphenol A, a plasticizer widely present in the environment and considered as a xeno-oestrogen.	('rat', 'Species', '10116', (148, 151))	('men', 'Species', '9606', (265, 268))	('E2', 'Chemical', 'MESH:D004958', (115, 117))	('involvement', 'Reg', (92, 103))	('rat', 'Species', '10116', (198, 201))	('rat', 'Species', '10116', (82, 85))	('E2-BSA-induced', 'Var', (115, 129))	('men', 'Species', '9606', (99, 102))	('JKT-1', 'CellLine', 'CVCL:T011', (130, 135))	('GPER', 'Protein', (107, 111))	('bisphenol A', 'Chemical', 'MESH:C006780', (209, 220))
24264	19940282	Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group.	('to 9', 'Species', '1214577', (56, 60))	('Hearing impairment', 'Phenotype', 'HP:0000365', (0, 18))	('Hearing impairment', 'Disease', (0, 18))	('dose-intensive chemotherapy', 'Var', (142, 169))	('tinnitus', 'Disease', (68, 76))	('tinnitus', 'Disease', 'MESH:D014012', (68, 76))	('Hearing impairment', 'Disease', 'MESH:D034381', (0, 18))	('tinnitus', 'Phenotype', 'HP:0000360', (68, 76))
24266	19940282	Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Raynaud-like', 'Disease', (165, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (23, 40))	('testicular cancer', 'Disease', 'MESH:D013736', (23, 40))	('men', 'Species', '9606', (183, 186))	('cisplatin-based', 'Var', (63, 78))	('Raynaud-like phenomena', 'Phenotype', 'HP:0030880', (165, 187))	('testicular cancer', 'Disease', (23, 40))	('troubled', 'Reg', (108, 116))
24369	19940282	High education level was associated with statistically significantly lower odds for all symptoms compared with low education level, whereas marital status was statistically significantly associated only with Raynaud-like phenomena.	('High education', 'Var', (0, 14))	('men', 'Species', '9606', (226, 229))	('low education', 'Phenotype', 'HP:0001249', (111, 124))	('lower', 'NegReg', (69, 74))	('Raynaud-like phenomena', 'Phenotype', 'HP:0030880', (208, 230))
24372	19940282	The odds regarding Raynaud-like phenomena were also statistically significantly higher for the dose-intensive chemotherapy group than for the one to four chemotherapy cycles group (P = .002 [hands], P = .02 [feet]).	('Raynaud-like phenomena', 'Phenotype', 'HP:0030880', (19, 41))	('Raynaud-like phenomena', 'Disease', (19, 41))	('men', 'Species', '9606', (37, 40))	('dose-intensive chemotherapy', 'Var', (95, 122))	('higher', 'PosReg', (80, 86))
24376	19940282	Men who received one to four cycles of cisplatin-based chemotherapy were statistically significantly more inclined to report increased severity of hearing impairment (OR = 1.5, 95% CI = 1.2 to 2.0) and tinnitus (OR = 1.8, 95% CI = 1.4 to 2.4) than those who did not receive chemotherapy (Table 4).	('tinnitus', 'Disease', 'MESH:D014012', (202, 210))	('cisplatin-based', 'Var', (39, 54))	('tinnitus', 'Phenotype', 'HP:0000360', (202, 210))	('hearing impairment', 'Disease', (147, 165))	('hearing impairment', 'Disease', 'MESH:D034381', (147, 165))	('hearing impairment', 'Phenotype', 'HP:0000365', (147, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('tinnitus', 'Disease', (202, 210))	('increased severity of hearing impairment', 'Phenotype', 'HP:0012714', (125, 165))	('Men', 'Species', '9606', (0, 3))
24380	19940282	All ototoxicity measures were statistically significantly more severe in the dose-intensive chemotherapy group than in the one to four chemotherapy cycles group (P < .001).	('ototoxicity', 'Disease', (4, 15))	('ototoxicity', 'Disease', 'MESH:D006311', (4, 15))	('dose-intensive', 'Var', (77, 91))
24412	19940282	Chemotherapy-induced ototoxicity is mainly ascribed to cisplatin, which causes loss of outer hair cells in the organ of Corti, leading to tinnitus and hearing impairment.	('tinnitus', 'Disease', (138, 146))	('loss', 'NegReg', (79, 83))	('outer hair', 'Protein', (87, 97))	('hearing impairment', 'Disease', 'MESH:D034381', (151, 169))	('tinnitus', 'Disease', 'MESH:D014012', (138, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('ototoxicity', 'Disease', (21, 32))	('ototoxicity', 'Disease', 'MESH:D006311', (21, 32))	('hearing impairment', 'Disease', (151, 169))	('tinnitus', 'Phenotype', 'HP:0000360', (138, 146))	('hearing impairment', 'Phenotype', 'HP:0000365', (151, 169))	('leading to', 'Reg', (127, 137))	('cisplatin', 'Var', (55, 64))
24462	23316184	In addition, it is thought the abnormality high temperature may also impair apoptosis of remaining gonocytes, allowing some to persist to become the possible source of carcinoma in situ and malignancy after puberty.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('abnormality high temperature', 'Var', (31, 59))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (168, 185))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('impair', 'NegReg', (69, 75))	('rat', 'Species', '10116', (53, 56))	('carcinoma in situ', 'Disease', 'MESH:D002278', (168, 185))	('malignancy', 'Disease', (190, 200))	('apoptosis', 'CPA', (76, 85))	('carcinoma in situ', 'Disease', (168, 185))
24513	23316184	Inhibition of PDGFR-beta tyrosine kinase activity in the first week postnatally in a mouse causes a severe reduction in the proliferation of gonocytes and increases their apoptosis.	('reduction', 'NegReg', (107, 116))	('rat', 'Species', '10116', (131, 134))	('mouse', 'Species', '10090', (85, 90))	('increases', 'PosReg', (155, 164))	('proliferation', 'CPA', (124, 137))	('apoptosis', 'CPA', (171, 180))	('PDGFR-beta', 'Gene', '5159', (14, 24))	('Inhibition', 'Var', (0, 10))	('PDGFR-beta', 'Gene', (14, 24))	('activity', 'MPA', (41, 49))
24561	23316184	In the context of the proposal, that early germ cell development is the key, these long-term results are consistent with either no effect of age at all, or with the suggestion that lack of neonatal gonocyte transformation and impaired apoptosis predisposes to malignancy.	('apoptosis', 'CPA', (235, 244))	('predisposes', 'Reg', (245, 256))	('lack', 'Var', (181, 185))	('men', 'Species', '9606', (60, 63))	('impaired', 'NegReg', (226, 234))	('malignancy', 'Disease', 'MESH:D009369', (260, 270))	('malignancy', 'Disease', (260, 270))
24611	17448228	It is known that endocrine disruptors such as phthalates can lead to both reduced Leydig cell function and to cryptorchidism.	('cryptorchidism', 'Disease', (110, 124))	('phthalates', 'Var', (46, 56))	('phthalates', 'Chemical', 'MESH:C032279', (46, 56))	('cryptorchidism', 'Phenotype', 'HP:0000028', (110, 124))	('reduced', 'NegReg', (74, 81))	('Leydig cell function', 'CPA', (82, 102))
24613	17448228	For example, in the jsd/jsd mouse, which has impaired spermatogenesis due to a mutation in the mUtp14b gene, retention of the testis in the abdomen actually rescues the arrest of spermatogonial differentiation, thus partly restoring spermatogenesis.	('restoring', 'PosReg', (223, 232))	('men', 'Species', '9606', (144, 147))	('arrest', 'MPA', (169, 175))	('rescues', 'PosReg', (157, 164))	('spermatogenesis', 'CPA', (233, 248))	('mouse', 'Species', '10090', (28, 33))	('mUtp14b', 'Gene', '195434', (95, 102))	('jsd', 'Gene', (20, 23))	('jsd', 'Gene', (24, 27))	('jsd', 'Gene', '195434', (20, 23))	('retention of the testis', 'Phenotype', 'HP:0012870', (109, 132))	('jsd', 'Gene', '195434', (24, 27))	('mutation', 'Var', (79, 87))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (45, 69))	('mUtp14b', 'Gene', (95, 102))
24614	17448228	However, more extensive studies show that the higher temperature is actually causing a subtle androgen-control system to be down-regulated, and that the activated androgen receptor is mediating the arrest of spermatogenesis in this mutant.	('arrest of spermatogenesis', 'Phenotype', 'HP:0031038', (198, 223))	('androgen receptor', 'Gene', (163, 180))	('subtle androgen-control system', 'MPA', (87, 117))	('spermatogenesis', 'CPA', (208, 223))	('down-regulated', 'NegReg', (124, 138))	('androgen receptor', 'Gene', '367', (163, 180))	('mutant', 'Var', (232, 238))
24650	17448228	There are indeed a number of mutations in fertility genes in the human, which are considered important in other species, suggesting that humans as a species are essentially subfertile, and thus more predisposed to subtle negative environmental influences.	('human', 'Species', '9606', (137, 142))	('human', 'Species', '9606', (65, 70))	('mutations', 'Var', (29, 38))	('fertility genes', 'Gene', (42, 57))	('humans', 'Species', '9606', (137, 143))	('men', 'Species', '9606', (237, 240))
24807	27577987	Novel association of familial testicular germ cell tumor and autosomal dominant polycystic kidney disease with PKD1 mutation Adolescent brothers were diagnosed with testicular germ cell tumors within the same month.	('testicular germ cell tumor', 'Disease', (30, 56))	('cell tumors', 'Disease', (181, 192))	('mutation', 'Var', (116, 124))	('testicular germ cell tumor', 'Disease', 'MESH:C563236', (30, 56))	('germ cell tumors', 'Phenotype', 'HP:0100728', (176, 192))	('tumor', 'Disease', (186, 191))	('cell tumors', 'Disease', 'MESH:D005935', (181, 192))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (61, 105))	('germ cell tumor', 'Phenotype', 'HP:0100728', (41, 56))	('tumor', 'Disease', (51, 56))	('association', 'Interaction', (6, 17))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('PKD1', 'Gene', (111, 115))	('germ cell tumor', 'Phenotype', 'HP:0100728', (176, 191))	('polycystic kidney', 'Phenotype', 'HP:0000113', (80, 97))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('kidney disease', 'Phenotype', 'HP:0000112', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('autosomal dominant polycystic kidney disease', 'Disease', (61, 105))	('PKD1', 'Gene', '5310', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('testicular germ cell tumor', 'Disease', (165, 191))	('testicular germ cell tumor', 'Disease', 'MESH:C563236', (165, 191))
24809	27577987	The proband, his brother, and their mother, were all found to have a novel splice variant in intron 8 of the PKD1 gene by clinical exome sequencing.	('PKD1', 'Gene', (109, 113))	('splice variant in', 'Var', (75, 92))	('PKD1', 'Gene', '5310', (109, 113))
24810	27577987	This is the second family ever reported with both FTGCT and ADPKD, and the first described association of FTGCT with a splice variant in PKD1.	('PKD1', 'Gene', (137, 141))	('PKD1', 'Gene', '5310', (137, 141))	('association', 'Reg', (91, 102))	('splice variant', 'Var', (119, 133))
24811	27577987	We suggest this novel variant in PKD1 may convey increased risk for FTGCT in addition to causing ADPKD.	('PKD1', 'Gene', (33, 37))	('variant', 'Var', (22, 29))	('PKD1', 'Gene', '5310', (33, 37))	('risk', 'Reg', (59, 63))	('ADPKD', 'Disease', (97, 102))	('FTGCT', 'Disease', (68, 73))	('causing', 'Reg', (89, 96))
24813	27577987	Autosomal dominant polycystic kidney disease (ADPKD) is well known to be caused by pathogenic variants in PKD1 and PKD2 mutations.	('kidney disease', 'Phenotype', 'HP:0000112', (30, 44))	('PKD1', 'Gene', (106, 110))	('PKD2', 'Gene', '5311', (115, 119))	('caused', 'Reg', (73, 79))	('PKD1', 'Gene', '5310', (106, 110))	('Autosomal dominant polycystic kidney disease', 'Disease', (0, 44))	('Autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (0, 44))	('PKD2', 'Gene', (115, 119))	('variants', 'Var', (94, 102))	('polycystic kidney', 'Phenotype', 'HP:0000113', (19, 36))
24816	27577987	We describe two brothers with FTGCT and ADPKD likely due to a PKD1 mutation identified using clinical exome sequencing (CES).	('CES', 'Disease', 'MESH:C535918', (120, 123))	('mutation', 'Var', (67, 75))	('CES', 'Disease', (120, 123))	('PKD1', 'Gene', (62, 66))	('due to', 'Reg', (53, 59))	('PKD1', 'Gene', '5310', (62, 66))
24827	27577987	CES identified, in both brothers, a maternally inherited NM_001009944.2:c.1723-1G>A variant predicted to disrupt the canonical splice acceptor site in intron 8 of the PKD1 gene (Figure 2).	('c.1723-1G>A', 'Var', (72, 83))	('PKD1', 'Gene', '5310', (167, 171))	('CES', 'Disease', (0, 3))	('disrupt', 'NegReg', (105, 112))	('NM_001009944.2:c.1723-1G>A', 'Mutation', 'c.1723-1G>A', (57, 83))	('PKD1', 'Gene', (167, 171))	('CES', 'Disease', 'MESH:C535918', (0, 3))
24828	27577987	Variants in the PKD1 gene are already known to be associated with autosomal dominant polycystic kidney disease (ADPKD).	('Variants', 'Var', (0, 8))	('polycystic kidney', 'Phenotype', 'HP:0000113', (85, 102))	('kidney disease', 'Phenotype', 'HP:0000112', (96, 110))	('PKD1', 'Gene', '5310', (16, 20))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (66, 110))	('associated', 'Reg', (50, 60))	('PKD1', 'Gene', (16, 20))	('autosomal dominant polycystic kidney disease', 'Disease', (66, 110))
24831	27577987	Interestingly, a survey of PKD1 mutations in COSMIC (Catalogue of Somatic Mutations in Cancer) reveals overabundance of specific missense and truncating variants in a number of tumors, including testicular germ cell tumors, suggesting a potential role for somatic PKD1 variants in oncogenesis.	('testicular germ cell tumor', 'Disease', (195, 221))	('tumors', 'Disease', (216, 222))	('PKD1', 'Gene', (264, 268))	('testicular germ cell tumor', 'Disease', 'MESH:C563236', (195, 221))	('PKD1', 'Gene', '5310', (27, 31))	('cell tumors', 'Disease', (211, 222))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('missense', 'Var', (129, 137))	('cell tumors', 'Disease', 'MESH:D005935', (211, 222))	('germ cell tumors', 'Phenotype', 'HP:0100728', (206, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('mutations', 'Var', (32, 41))	('variants', 'Var', (153, 161))	('PKD1', 'Gene', '5310', (264, 268))	('truncating', 'MPA', (142, 152))	('germ cell tumor', 'Phenotype', 'HP:0100728', (206, 221))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('PKD1', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('variants', 'Var', (269, 277))	('Cancer', 'Disease', (87, 93))	('tumors', 'Disease', (177, 183))
24834	27577987	We report a family with two brothers affected with both FTGCT and ADPKD, in which we identified a maternally inherited PKD1 mutation.	('PKD1', 'Gene', (119, 123))	('mutation', 'Var', (124, 132))	('PKD1', 'Gene', '5310', (119, 123))
24838	27577987	Specifically, a variant in the same splice acceptor we identified, c.1723-2A>C, has been previously reported as a cause of ADPKD, supporting this newly identified variant is also pathogenic.	('cause', 'Reg', (114, 119))	('ADPKD', 'Disease', (123, 128))	('c.1723-2A>C', 'Var', (67, 78))	('c.1723-2A>C', 'Mutation', 'c.1723-2A>C', (67, 78))
24842	27577987	Alternatively, in those patients with ADPKD, if they are found to have the identified PKD1 c.1723-1G>A variant, an increased risk for FTGCT should be considered.	('PKD1', 'Gene', '5310', (86, 90))	('c.1723-1G>A', 'Mutation', 'c.1723-1G>A', (91, 102))	('PKD1', 'Gene', (86, 90))	('FTGCT', 'Disease', (134, 139))	('c.1723-1G>A', 'Var', (91, 102))	('patients', 'Species', '9606', (24, 32))
24908	29141221	To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation.	('mouse', 'Species', '10090', (55, 60))	('Kras', 'Protein', (101, 105))	('inactivation', 'Var', (126, 138))	('activation', 'PosReg', (106, 116))
24930	29141221	One explanation for why somatic cancers are resistant to genotoxic chemotherapy is that they accumulate mutations in DNA damage response (DDR) pathways, most notoriously in the p53 gene.	('somatic cancers', 'Disease', (24, 39))	('mutations', 'Var', (104, 113))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('p53', 'Gene', (177, 180))	('somatic cancers', 'Disease', 'MESH:D009369', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('p53', 'Gene', '22060', (177, 180))
24932	29141221	This DDR activation can act as a tumorigenesis barrier by slowing or halting cell cycle progression in the presence of oncogene-induced DNA damage, but may also create selective pressure to mutate the genes involved in maintaining that barrier, thus facilitating continued tumorigenesis despite genomic instability.	('mutate', 'Var', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('facilitating', 'Reg', (250, 262))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (273, 278))	('cell cycle progression', 'CPA', (77, 99))	('halting', 'NegReg', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('slowing', 'NegReg', (58, 65))	('genes', 'Gene', (201, 206))
24933	29141221	Once DDR genes have been mutated, cells no longer respond appropriately to DNA damage, including damage induced by chemotherapy drugs like cisplatin.	('DDR genes', 'Gene', (5, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('mutated', 'Var', (25, 32))
24934	29141221	Depending on the particular genes affected and the tissue context, DDR mutations can either enable avoidance of DNA damage-induced apoptotic signals, conferring chemoresistance, or render cancer cells susceptible to particular genotoxins or to inhibition of residual DDR function, approaches that are now being evaluated for clinical efficacy.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('avoidance', 'MPA', (99, 108))	('render', 'Reg', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('mutations', 'Var', (71, 80))	('chemoresistance', 'CPA', (161, 176))	('cancer', 'Disease', (188, 194))	('DDR', 'Gene', (67, 70))	('DNA damage-induced apoptotic signals', 'MPA', (112, 148))
24938	29141221	These mouse teratoma models include conditional knockout of the Pten tumor suppressor targeted to primordial germ cells as well as 129-Dnd1Ter/Ter mice, which are homozygous for a mutation in the Dead end gene.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (147, 151))	('teratoma', 'Phenotype', 'HP:0009792', (12, 20))	('tumor', 'Disease', (69, 74))	('Pten', 'Gene', (64, 68))	('teratoma', 'Disease', 'MESH:D013724', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('mutation', 'Var', (180, 188))	('teratoma', 'Disease', (12, 20))	('mouse', 'Species', '10090', (6, 11))
24939	29141221	Interestingly, the 129 strain background is permissive for testicular teratoma formation in mice; on other strain backgrounds the Dnd1Ter/Ter mutation leads to BAX-mediated germ cell apoptosis rather than tumorigenesis.	('BAX', 'Gene', '12028', (160, 163))	('leads to', 'Reg', (151, 159))	('teratoma', 'Phenotype', 'HP:0009792', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('testicular teratoma', 'Phenotype', 'HP:0100616', (59, 78))	('testicular teratoma', 'Disease', 'MESH:C562472', (59, 78))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('Dnd1Ter/Ter', 'Gene', (130, 141))	('mutation', 'Var', (142, 150))	('mice', 'Species', '10090', (92, 96))	('testicular teratoma', 'Disease', (59, 78))	('BAX', 'Gene', (160, 163))
24942	29141221	Inactivating PTEN mutations in humans specifically mark the transition from TGCT precursor lesions to invasive germ cell tumors.	('germ cell tumors', 'Disease', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('germ cell tumor', 'Phenotype', 'HP:0100728', (111, 126))	('Inactivating', 'Var', (0, 12))	('germ cell tumors', 'Phenotype', 'HP:0100728', (111, 127))	('TGCT', 'Disease', (76, 80))	('germ cell tumors', 'Disease', 'MESH:D009373', (111, 127))	('PTEN', 'Gene', (13, 17))	('humans', 'Species', '9606', (31, 37))	('mutations', 'Var', (18, 27))
24943	29141221	The most common chromosomal aberration in human TGCTs is isochromosome 12p, an additional copy of a region from the small arm of Chromosome 12 which contains the KRAS oncogene (KRAS2) as well as several stem cell-related genes (NANOG, STELLA, and others).	('KRAS', 'Gene', (162, 166))	('KRAS', 'Gene', '16653', (162, 166))	('STELLA', 'Gene', (235, 241))	('human', 'Species', '9606', (42, 47))	('STELLA', 'Gene', '359787', (235, 241))	('KRAS', 'Gene', '16653', (177, 181))	('KRAS2', 'Gene', '3845', (177, 182))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (16, 38))	('KRAS', 'Gene', (177, 181))	('isochromosome', 'Var', (57, 70))	('small arm', 'Phenotype', 'HP:0009824', (116, 125))	('KRAS2', 'Gene', (177, 182))
24947	29141221	This was accomplished using mice carrying a G12D activating mutation in the first exon of the endogenous Kras gene, preceded by a conditional LoxP-Stop-LoxP cassette (LSL-KrasG12D), as well as a conditional allele of Pten (Ptenflox/flox) in which the critical exon 5 is flanked by LoxP sites.	('Kras', 'Gene', (105, 109))	('mice', 'Species', '10090', (28, 32))	('G12D', 'Var', (44, 48))	('activating', 'PosReg', (49, 59))	('G12D', 'Mutation', 'rs121913529', (44, 48))	('G12D', 'Mutation', 'rs121913529', (175, 179))
24948	29141221	Recombination between adjacent LoxP sites, which enables KrasG12D expression and inactivates Pten, was mediated by the CRE recombinase under control of a portion of the Stra8 promoter (Stra8-Cre), which is active primarily in mitotic spermatogonia in early postnatal life and continuing throughout adulthood.	('Stra8', 'Gene', '20899', (169, 174))	('Stra8', 'Gene', (185, 190))	('inactivates', 'NegReg', (81, 92))	('expression', 'MPA', (66, 76))	('Stra8', 'Gene', '20899', (185, 190))	('Stra8', 'Gene', (169, 174))	('KrasG12D', 'Var', (57, 65))	('Pten', 'Gene', (93, 97))
24949	29141221	Double mutant experimental animals, which we refer to as gPAK mice for germ cell-specific Pten and Kras mutant mice, harbored one conditional and one null allele of Pten (Ptenflox/-), one copy of the conditional LSL-KrasG12D allele (Kras+/LSL), and the Stra8-Cre transgene (Stra8-CreTg) on a mixed strain background.	('Stra8', 'Gene', (274, 279))	('Stra8', 'Gene', '20899', (253, 258))	('Kras+/LSL', 'Gene', '16653', (233, 242))	('mutant', 'Var', (104, 110))	('Kras+/LSL', 'Gene', (233, 242))	('mice', 'Species', '10090', (62, 66))	('Stra8', 'Gene', '20899', (274, 279))	('mice', 'Species', '10090', (111, 115))	('Stra8', 'Gene', (253, 258))	('Pten', 'Gene', (90, 94))	('men', 'Species', '9606', (20, 23))
24951	29141221	While Kras activation or Pten inactivation individually rarely resulted in TGCT formation, combined Kras activation and Pten inactivation in gPAK mice led to rapid germ cell tumorigenesis, with 75% of gPAK mice succumbing to large bilateral or unilateral TGCTs with a median tumor-free survival of 24.5 days (Fig.	('tumor', 'Disease', (174, 179))	('germ cell tumor', 'Phenotype', 'HP:0100728', (164, 179))	('succumbing', 'CPA', (211, 221))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('mice', 'Species', '10090', (206, 210))	('activation', 'PosReg', (105, 115))	('Pten', 'Gene', (120, 124))	('Kras', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('inactivation', 'Var', (125, 137))	('mice', 'Species', '10090', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
24952	29141221	The reduction in tumor-free survival in gPAK mice as compared to controls was highly significant (p=1.560x10-6), and no control mice developed tumors within the same time period.	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (45, 49))	('tumor', 'Disease', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduction', 'NegReg', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('gPAK', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
24973	29141221	The OCT4+ population formed teratocarcinoma in secondary hosts whereas OCT4- cells did not, confirming that the OCT4+ EC cells have tumor-propagating activity and function as CSCs.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('teratocarcinoma', 'Disease', 'MESH:D018243', (28, 43))	('OCT4+', 'Var', (112, 117))	('EC', 'Phenotype', 'HP:0002898', (118, 120))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('teratocarcinoma', 'Disease', (28, 43))	('tumor', 'Disease', (132, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
24994	29141221	No significant differences in germ cell numbers were detected at P3 in any of the tumor-free single or double mutants (Fig.	('double mutants', 'Var', (103, 117))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
25000	29141221	Pten single mutants showed increased vacuolization and degenerative changes at P180 (Fig.	('increased', 'PosReg', (27, 36))	('single mutants', 'Var', (5, 19))	('P180', 'Gene', '81910', (79, 83))	('degenerative changes', 'Phenotype', 'HP:0002180', (55, 75))	('Pten', 'Gene', (0, 4))	('vacuolization', 'CPA', (37, 50))	('P180', 'Gene', (79, 83))	('degenerative changes', 'CPA', (55, 75))
25010	29141221	S5A and Table S2, gPAK tumors harbored recurrent copy number gains and losses across the six tumors analyzed, including events on Chromosomes 1, 7, 9, 12, 14, 17, and X.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('losses', 'NegReg', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('gains', 'PosReg', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('copy number', 'Var', (49, 60))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
25013	29141221	129-Dnd1Ter/Ter teratomas additionally harbored recurrent copy number changes on Chromosomes 4, 6, 11, and 20 that were not identified in gPAK tumors (Table S3).	('teratomas', 'Disease', 'MESH:D013724', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (143, 149))	('teratoma', 'Phenotype', 'HP:0009792', (16, 24))	('129-Dnd1Ter/Ter', 'Var', (0, 15))	('copy number changes', 'Var', (58, 77))	('teratomas', 'Phenotype', 'HP:0009792', (16, 25))	('teratomas', 'Disease', (16, 25))
25014	29141221	Recent genomic analyses of human TGCT revealed a high frequency of copy-neutral reciprocal loss-of-heterozygosity events, but unfortunately aCGH cannot be used to detect such events.	('copy-neutral', 'Var', (67, 79))	('loss-of-heterozygosity', 'NegReg', (91, 113))	('human', 'Species', '9606', (27, 32))
25024	29141221	Strikingly, the percentage of OCT4+ cells was significantly reduced in the gPAK mice treated with either cisplatin alone or BEP (Fig.	('BEP', 'Chemical', '-', (124, 127))	('reduced', 'NegReg', (60, 67))	('mice', 'Species', '10090', (80, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('BEP', 'Var', (124, 127))
25046	29141221	Consistent with this, we were able to detect Stra8-Cre-mediated recombination in a few small clusters of testicular germ cells at E12.5 and subsequently observed only 1-2 neoplasms per testis.	('E12.5', 'Var', (130, 135))	('Stra8', 'Gene', (45, 50))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('Stra8', 'Gene', '20899', (45, 50))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('neoplasms', 'Disease', (171, 180))
25050	29141221	Notably, teratoma formation in DndTer mice is associated with a failure of embryonic germ cells to undergo proper mitotic arrest, suggesting that G0 arrest and downregulation of pluripotency gene expression at E12.5 to E15.5 may mark the end of the period during which germ cells are particularly susceptible to malignant transformation.	('downregulation', 'NegReg', (160, 174))	('mice', 'Species', '10090', (38, 42))	('teratoma', 'Phenotype', 'HP:0009792', (9, 17))	('teratoma', 'Disease', 'MESH:D013724', (9, 17))	('mitotic arrest', 'Disease', (114, 128))	('pluripotency', 'Protein', (178, 190))	('E12.5', 'Var', (210, 215))	('mitotic arrest', 'Disease', 'MESH:D006323', (114, 128))	('teratoma', 'Disease', (9, 17))
25054	29141221	Interestingly, loss of the pro-apoptotic gene Bax causes testis hypercellularity soon after birth, followed by massive cell death at P25, suggesting the existence of mechanisms to eliminate excess germ cells from adult testes.	('Bax', 'Gene', (46, 49))	('testis', 'Disease', (57, 63))	('Bax', 'Gene', '12028', (46, 49))	('loss', 'Var', (15, 19))	('P25', 'Gene', '12569', (133, 136))	('P25', 'Gene', (133, 136))	('causes', 'Reg', (50, 56))
25055	29141221	It is unclear why Kras activation or Pten inactivation alone is insufficient to cause germ cell tumorigenesis in the majority of cases.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Pten', 'Gene', (37, 41))	('germ cell tumor', 'Phenotype', 'HP:0100728', (86, 101))	('tumor', 'Disease', (96, 101))	('inactivation', 'Var', (42, 54))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cause', 'Reg', (80, 85))	('Kras', 'Protein', (18, 22))
25056	29141221	It has been reported previously that Stra8-Cre-driven Pten loss does not induce TGCTs or affect fertility, although in our studies we did see infrequent TGCTs as well as germ cell loss with Pten deletion alone, perhaps reflecting differences in mouse strain background in these studies.	('Pten', 'Gene', (190, 194))	('Pten', 'Gene', (54, 58))	('loss', 'NegReg', (59, 63))	('Stra8', 'Gene', '20899', (37, 42))	('affect fertility', 'Phenotype', 'HP:0000144', (89, 105))	('loss', 'NegReg', (180, 184))	('mouse', 'Species', '10090', (245, 250))	('germ cell', 'CPA', (170, 179))	('deletion', 'Var', (195, 203))	('TGCTs', 'CPA', (153, 158))	('Stra8', 'Gene', (37, 42))
25059	29141221	Mice expressing activated oncogenic Kras in somatic tissues primarily develop lung cancers as well as oral, gastric, and skin papillomas and thymic lymphomas, but rarely neoplasms of other tissue origins (Guerra et al.).	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lymphomas', 'Phenotype', 'HP:0002665', (148, 157))	('oral', 'Disease', (102, 106))	('Mice', 'Species', '10090', (0, 4))	('neoplasms', 'Phenotype', 'HP:0002664', (170, 179))	('develop', 'PosReg', (70, 77))	('lung cancers', 'Disease', 'MESH:D008175', (78, 90))	('papillomas', 'Phenotype', 'HP:0012740', (126, 136))	('thymic lymphomas', 'Disease', 'MESH:D013953', (141, 157))	('neoplasms', 'Disease', 'MESH:D009369', (170, 179))	('lung cancers', 'Disease', (78, 90))	('skin papillomas', 'Disease', (121, 136))	('gastric', 'Disease', (108, 115))	('neoplasms', 'Disease', (170, 179))	('lung cancers', 'Phenotype', 'HP:0100526', (78, 90))	('thymic lymphomas', 'Disease', (141, 157))	('skin papillomas', 'Disease', 'MESH:D010212', (121, 136))	('Kras', 'Var', (36, 40))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
25061	29141221	Pten inactivation in oocytes promotes premature activation of the entire primordial follicle pool, causing an initial surge of follicle maturation that leads to premature ovarian failure.	('follicle', 'MPA', (127, 135))	('premature ovarian failure', 'Disease', (161, 186))	('premature ovarian failure', 'Disease', 'MESH:D016649', (161, 186))	('leads to', 'Reg', (152, 160))	('activation', 'PosReg', (48, 58))	('Pten', 'Gene', (0, 4))	('premature ovarian failure', 'Phenotype', 'HP:0008209', (161, 186))	('inactivation', 'Var', (5, 17))
25063	29141221	It is possible that the combined Pten inactivation and Kras activation in our model promotes premature cell division of SSC precursors concomitant with activation of excessive self-renewal signals, leading to development of germ cell-derived tumors containing OCT4+ malignant stem cells (EC cells).	('men', 'Species', '9606', (216, 219))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('leading to', 'Reg', (198, 208))	('Pten', 'Gene', (33, 37))	('premature cell division', 'CPA', (93, 116))	('inactivation', 'Var', (38, 50))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('EC', 'Phenotype', 'HP:0002898', (288, 290))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('activation', 'PosReg', (60, 70))	('excessive self', 'Phenotype', 'HP:0100716', (166, 180))	('Kras', 'Gene', (55, 59))	('tumors', 'Disease', (242, 248))	('promotes', 'PosReg', (84, 92))
25072	29141221	The following strains, with strain backgrounds in parentheses, were used: Stra8-Cre (129S6); LSL-KrasG12D (129S6); Ptenflox (mixed C57BL/6J, 129S6, FVB); Tg(Pou5f1-EGFP)2Mnn (mixed C57BL/6J, 129S6); Gt(ROSA)26Sortm1Sor (C57BL/6J); Gt(ROSA)26Sortm9(CAG-tdTomato)Hze (C57BL/6J); Dnd1Ter (129X1).	('G12D', 'Mutation', 'rs121913529', (101, 105))	('Pou5f1', 'Gene', (157, 163))	('Pou5f1', 'Gene', '18999', (157, 163))	('Stra8', 'Gene', (74, 79))	('C57BL/6J', 'Var', (266, 274))	('Stra8', 'Gene', '20899', (74, 79))
25078	29141221	Validation of 7qA3 deletion in gPAK and 129-Dnd1Ter/Ter tumors was performed by qPCR.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ter tumors', 'Disease', (52, 62))	('deletion', 'Var', (19, 27))	('7qA3', 'Gene', (14, 18))	('Ter tumors', 'Disease', 'MESH:C537274', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
25104	22348147	In addition, defects in the same genes, kit-ligand (KITL) and Dmrt1, dramatically increase the incidence of teratoma in mice and are associated with or predispose humans to the adult TGCTs.	('Dmrt1', 'Gene', '50796', (62, 67))	('Dmrt1', 'Gene', (62, 67))	('adult TGCTs', 'CPA', (177, 188))	('KITL', 'Gene', (52, 56))	('humans', 'Species', '9606', (163, 169))	('teratoma', 'Disease', 'MESH:D013724', (108, 116))	('mice', 'Species', '10090', (120, 124))	('kit-ligand', 'Gene', '17311', (40, 50))	('teratoma', 'Phenotype', 'HP:0009792', (108, 116))	('KITL', 'Gene', '17311', (52, 56))	('predispose', 'Reg', (152, 162))	('teratoma', 'Disease', (108, 116))	('increase', 'PosReg', (82, 90))	('defects', 'Var', (13, 20))	('kit-ligand', 'Gene', (40, 50))	('associated', 'Reg', (133, 143))
25127	22348147	In the present study we unequivocally demonstrated that fetal radiation exposure during E10.5-E11.5 induces testicular germ cell cancers, most of which show the multiple dermal origins typical of teratomas, in a genetically susceptible mouse model.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('testicular', 'Disease', (108, 118))	('teratomas', 'Phenotype', 'HP:0009792', (196, 205))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('teratomas', 'Disease', (196, 205))	('teratomas', 'Disease', 'MESH:D013724', (196, 205))	('induces', 'Reg', (100, 107))	('teratoma', 'Phenotype', 'HP:0009792', (196, 204))	('E10.5-E11.5', 'Var', (88, 99))	('mouse', 'Species', '10090', (236, 241))
25133	22348147	Between days E10.5 & 11.5 they undergo epigenetic changes that include both global DNA demethylation which involves single-strand breaks (SSBs) and activation of the base-excision repair pathway with chromatin localization of the proteins involved, as well as chromatin remodeling involving loss and replacement of histones and changes in their modifications.	('and', 'PosReg', (144, 147))	('men', 'Species', '9606', (307, 310))	('the base-excision repair', 'Pathway', (162, 186))	('involving', 'NegReg', (281, 290))	('both global DNA', 'MPA', (71, 86))	('involves single-strand', 'MPA', (107, 129))	('and', 'Var', (296, 299))	('and', 'Reg', (324, 327))	('SSBs', 'Chemical', '-', (138, 142))	('their', 'MPA', (339, 344))
25135	22348147	This radiation-induced damage might perturb signaling pathways involving endogenous SSBs and base-excision repair regulating this epigenetic transformation and allow the cells to retain pluripotency as embryonic stem-like cells that subsequently form the TGCTs.	('damage', 'Var', (23, 29))	('signaling pathways', 'Pathway', (44, 62))	('pluripotency', 'Disease', (186, 198))	('pluripotency', 'Disease', 'None', (186, 198))	('perturb', 'Reg', (36, 43))	('allow', 'Reg', (160, 165))	('SSBs', 'Chemical', '-', (84, 88))
25136	22348147	Previously genetic alterations in germ cells, including the ter mutation in the Dnd1 gene, loss of Dmrt1 , or loss of Pten  produced a high incidence of TGCTs (particularly teratomas) in mice.	('Dnd1', 'Gene', (80, 84))	('Dnd1', 'Gene', '213236', (80, 84))	('TGCTs', 'Disease', (153, 158))	('loss', 'Var', (110, 114))	('Pten', 'Gene', (118, 122))	('Pten', 'Gene', '19211', (118, 122))	('teratoma', 'Phenotype', 'HP:0009792', (173, 181))	('ter mutation', 'Var', (60, 72))	('mice', 'Species', '10090', (187, 191))	('teratomas', 'Disease', 'MESH:D013724', (173, 182))	('loss', 'Var', (91, 95))	('Dmrt1', 'Gene', '50796', (99, 104))	('teratomas', 'Phenotype', 'HP:0009792', (173, 182))	('Dmrt1', 'Gene', (99, 104))	('teratomas', 'Disease', (173, 182))
25181	21168769	After cell cycle arrest, the Pt lesions are either removed by nucleotide excision repair (NER) or apoptosis is triggered.	('Pt', 'Chemical', 'MESH:D010984', (29, 31))	('apoptosis', 'CPA', (98, 107))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (6, 23))	('nucleotide excision repair', 'Var', (62, 88))
25187	21168769	Core particle DNA containing a site-specific cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link enforces a characteristic rotational orientation of the DNA strand on the nucleosome, such that the Pt adduct faces inward toward the histone core.	('GpTpG', 'Chemical', '-', (75, 80))	('enforces', 'Reg', (105, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cross-link', 'Var', (94, 104))	('1,3-d', 'Chemical', 'MESH:C023891', (69, 74))	('1,2-d', 'Chemical', '-', (55, 60))	('GpG', 'Chemical', 'MESH:C018309', (61, 64))	('Pt', 'Chemical', 'MESH:D010984', (205, 207))	('rotational orientation', 'MPA', (131, 153))
25202	21168769	These data suggest a mechanism whereby cisplatin-DNA adducts may inhibit transcription by denying RNA polymerase elongation complexes access to nucleosomal DNA, but more research is necessary to test the validity of this hypothesis.	('transcription', 'MPA', (73, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('nucleosomal', 'Chemical', '-', (144, 155))	('inhibit', 'NegReg', (65, 72))	('denying', 'NegReg', (90, 97))	('adducts', 'Var', (53, 60))
25203	21168769	Another study revealed cisplatin inhibition of both chromatin remodeling events and transcription, but no mechanistic connections were drawn between the two observations.	('cisplatin', 'Var', (23, 32))	('inhibition', 'NegReg', (33, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('transcription', 'MPA', (84, 97))	('chromatin remodeling events', 'MPA', (52, 79))
25204	21168769	In the present report we describe experiments performed to explore (i) how a single 1,2-cis-{Pt(NH3)2}2+-d(GpG) or 1,3-cis-{Pt(NH3)2}2+-d(GpTpG) intrastrand cross-link affects the structure of nucleosome core particles; (ii) whether these Pt-DNA adducts inhibit DNA translocation and twist propagation; and (iii) how elongation complexes of T7 RNAP navigate nucleosomes modified with site-specific cisplatin intrastrand lesions on either the template or coding strands.	('-{Pt(NH3)2', 'Chemical', '-', (91, 101))	('lesions', 'Var', (420, 427))	('Pt', 'Chemical', 'MESH:D010984', (239, 241))	('-{Pt(NH3)2', 'Chemical', '-', (122, 132))	('structure of nucleosome core particles', 'MPA', (180, 218))	('GpG', 'Chemical', 'MESH:C018309', (107, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (398, 407))	('1,3-cis-{Pt(NH3)2}2+-d', 'Chemical', '-', (115, 137))	('Pt', 'Chemical', 'MESH:D010984', (93, 95))	('DNA translocation', 'CPA', (262, 279))	('Pt', 'Chemical', 'MESH:D010984', (124, 126))	('affects', 'Reg', (168, 175))	('GpTpG', 'Chemical', '-', (138, 143))	('inhibit', 'NegReg', (254, 261))	('twist propagation', 'CPA', (284, 301))	('modified', 'Reg', (370, 378))	('cisplatin', 'Gene', (398, 407))
25210	21168769	These results provided the first insight into the mechanism of transcription inhibition by Pt-DNA adducts in a nucleosome-containing environment.	('transcription', 'MPA', (63, 76))	('Pt', 'Chemical', 'MESH:D010984', (91, 93))	('adducts', 'Var', (98, 105))	('Pt-DNA', 'Gene', (91, 97))
25236	21168769	NCPs modified with a 1,2-Pt(GpG) intrastrand adduct still contained ~10% of nucleosomes at the off-centered translational position after 3 h of heat equilibration, demonstrating that 1,2-Pt(GpG) intrastrand cross-links are better able to inhibit nucleosome mobility than their 1,3-Pt(GpTpG) counterpart.	('inhibit', 'NegReg', (238, 245))	('GpTpG', 'Chemical', '-', (284, 289))	('cross-links', 'Var', (207, 218))	('GpG', 'Chemical', 'MESH:C018309', (28, 31))	('nucleosome mobility', 'MPA', (246, 265))	('1,2-Pt', 'Chemical', '-', (183, 189))	('1,3-Pt', 'Chemical', '-', (277, 283))	('GpG', 'Chemical', 'MESH:C018309', (190, 193))	('1,2-Pt', 'Chemical', '-', (21, 27))
25237	21168769	At 50  C all nucleosome samples were completely equilibrated within 30 min (data not shown), indicating that the mechanism by which Pt-DNA cross-links inhibit the process does not involve covalent interactions between the platinum lesion and the protein core, nor any other irreversible phenomenon.	('platinum', 'Chemical', 'MESH:D010984', (222, 230))	('inhibit', 'NegReg', (151, 158))	('Pt', 'Chemical', 'MESH:D010984', (132, 134))	('cross-links', 'Var', (139, 150))
25239	21168769	Similarities between the abilities of cisplatin-DNA intrastrand cross-links and DNA minor groove-binding polyamide ligands to inhibit nucleosome sliding fuel the hypothesis that, like pyrrole-imidazole complexes, Pt-DNA adducts may block RNA synthesis by denying polymerase access to nucleosomal DNA and stalling the elongation complex at the histone octamer barrier.	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('Pt', 'Chemical', 'MESH:D010984', (213, 215))	('polyamide', 'Chemical', 'MESH:D009757', (105, 114))	('RNA synthesis', 'MPA', (238, 251))	('nucleosome sliding', 'MPA', (134, 152))	('adducts', 'Var', (220, 227))	('inhibit', 'NegReg', (126, 133))	('polymerase', 'Enzyme', (263, 273))	('nucleosomal', 'Chemical', '-', (284, 295))	('denying', 'NegReg', (255, 262))	('block', 'NegReg', (232, 237))	('elongation', 'MPA', (317, 327))	('stalling', 'NegReg', (304, 312))	('pyrrole-imidazole', 'Chemical', '-', (184, 201))
25261	21168769	Superhelical DNA in the nucleosome is highly distorted, and the data presented here indicate that Pt-DNA adducts alter the DNA position in the nucleosome such that the bend induced by a platinum 1,3-intrastrand cross-link is congruent with the bend caused by wrapping of DNA around the histone core.	('adducts', 'Var', (105, 112))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('Pt', 'Chemical', 'MESH:D010984', (98, 100))	('alter', 'Reg', (113, 118))
25271	21168769	Polyamides block transcription of nucleosomal but not linear DNA, leading to the hypothesis that these adducts lock the nucleosome in place and prevent DNA sliding.	('Polyamides', 'Var', (0, 10))	('block', 'NegReg', (11, 16))	('transcription', 'MPA', (17, 30))	('prevent', 'NegReg', (144, 151))	('Polyamides', 'Chemical', 'MESH:D009757', (0, 10))	('nucleosomal', 'Chemical', '-', (34, 45))	('DNA sliding', 'MPA', (152, 163))
25274	21168769	The cisplatin 1,2-d(GpG) cross-links cause a more dramatic bend angle than 1,3-d(GpTpG) cross-links, and are a slightly stronger inhibitor of DNA sliding.	('GpG', 'Chemical', 'MESH:C018309', (20, 23))	('GpTpG', 'Chemical', '-', (81, 86))	('1,3-d', 'Chemical', 'MESH:C023891', (75, 80))	('1,2-d', 'Chemical', '-', (14, 19))	('cross-links', 'Var', (25, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('bend angle', 'CPA', (59, 69))
25276	21168769	We therefore cannot conclude from these data alone that a single Pt cross-link will inhibit transcription by this mechanism analogously to polyamide ligands.	('cross-link', 'Var', (68, 78))	('Pt', 'Chemical', 'MESH:D010984', (65, 67))	('inhibit', 'NegReg', (84, 91))	('polyamide', 'Chemical', 'MESH:D009757', (139, 148))	('transcription', 'MPA', (92, 105))
25277	21168769	Of the three current hypotheses presented in the introduction describing how platinum intrastrand cross-links may inhibit transcription in cancer cells, the results of our in vitro transcription experiments argue against disruption of nucleosome dynamics as a potential mechanism.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('transcription', 'MPA', (122, 135))	('inhibit', 'NegReg', (114, 121))	('intrastrand', 'Var', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cross-links', 'Var', (98, 109))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('cancer', 'Disease', (139, 145))
25278	21168769	Although a single {Pt(NH3)2}2+ intrastrand cross-link reduces the rate of nucleosome mobility to some degree, this effect appears to be insufficient to prevent the histone translocation that occurs during transcription of nucleosomes by T7 RNA polymerase, or, by analogy, RNA polymerase III.	('Pt', 'Chemical', 'MESH:D010984', (19, 21))	('insufficient', 'Disease', 'MESH:D000309', (136, 148))	('cross-link', 'Var', (43, 53))	('insufficient', 'Disease', (136, 148))	('rate', 'MPA', (66, 70))	('histone translocation', 'MPA', (164, 185))	('NH3)', 'Chemical', 'MESH:D000641', (22, 26))	('reduces', 'NegReg', (54, 61))
25280	21168769	An interesting side-product of transcription reactions on templates containing platinum cross-links on the DNA coding strand of either free or nucleosomal templates is a transcript longer than the run-off product, ~204 nucleotides in length.	('platinum', 'Chemical', 'MESH:D010984', (79, 87))	('transcript', 'MPA', (170, 180))	('platinum cross-links', 'Var', (79, 99))	('cross-links', 'Var', (88, 99))	('nucleosomal', 'Chemical', '-', (143, 154))
25314	21168769	Pt-DNA adducts retard ATP-independent nucleosome mobility.	('retard', 'NegReg', (15, 21))	('Pt', 'Chemical', 'MESH:D010984', (0, 2))	('ATP-independent nucleosome mobility', 'MPA', (22, 57))	('adducts', 'Var', (7, 14))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))
25335	19835738	Abnormalities in the differentiation and migration of these cells lead to the variety of presentations of germ cell tumors.	('germ cell tumors', 'Phenotype', 'HP:0100728', (106, 122))	('migration', 'CPA', (41, 50))	('germ cell tumors', 'Disease', 'MESH:D009373', (106, 122))	('Abnormalities', 'Var', (0, 13))	('germ cell tumor', 'Phenotype', 'HP:0100728', (106, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lead to', 'Reg', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('germ cell tumors', 'Disease', (106, 122))	('differentiation', 'CPA', (21, 36))
25343	19835738	Progression from precursor lesions to invasive germ cell tumor among pubertal and post-pubertal males is often associated with acquisition of excess genetic material from the short arm of chromosome 12, including isochromosome 12p.	('germ cell tumor', 'Phenotype', 'HP:0100728', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('short arm', 'Phenotype', 'HP:0009824', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('isochromosome 12p', 'Var', (213, 230))	('tumor', 'Disease', (57, 62))
25391	19835738	Cisplatin causes both renal glomerular and tubular dysfunction with decreases in glomerular filtration rate and wasting of magnesium, which fortunately is often subclinical.	('wasting of magnesium', 'MPA', (112, 132))	('tubular dysfunction', 'Phenotype', 'HP:0000124', (43, 62))	('decreases in glomerular filtration rate', 'Phenotype', 'HP:0012213', (68, 107))	('glomerular filtration rate', 'MPA', (81, 107))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Cisplatin', 'Var', (0, 9))	('magnesium', 'Chemical', 'MESH:D008274', (123, 132))	('renal glomerular and tubular dysfunction', 'Disease', 'MESH:D007674', (22, 62))	('decreases', 'NegReg', (68, 77))
25392	19835738	Cisplatin is also associated with a dose-related high-frequency hearing loss among 20-40% of patients, which is permanent, and peripheral neuropathy, which often improves over time.	('hearing loss', 'Phenotype', 'HP:0000365', (64, 76))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (127, 148))	('hearing loss', 'Disease', (64, 76))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (127, 148))	('peripheral neuropathy', 'Disease', (127, 148))	('high-frequency hearing loss', 'Phenotype', 'HP:0005101', (49, 76))	('Cisplatin', 'Var', (0, 9))	('hearing loss', 'Disease', 'MESH:D034381', (64, 76))	('patients', 'Species', '9606', (93, 101))
25405	19835738	Therapy-associated risks include carcinomas in prior radiation fields or myelodysplasia and leukemia, often associated with etoposide dose and characterized by abnormalities in the MLL gene.	('leukemia', 'Disease', (92, 100))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('leukemia', 'Disease', 'MESH:D007938', (92, 100))	('myelodysplasia', 'Disease', (73, 87))	('etoposide', 'Chemical', 'MESH:D005047', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('MLL', 'Gene', '4297', (181, 184))	('abnormalities', 'Var', (160, 173))	('myelodysplasia', 'Phenotype', 'HP:0002863', (73, 87))	('MLL', 'Gene', (181, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('associated', 'Reg', (108, 118))	('carcinomas', 'Disease', (33, 43))	('carcinomas', 'Disease', 'MESH:D002277', (33, 43))	('myelodysplasia', 'Disease', 'MESH:D009190', (73, 87))
25480	31024927	has also revealed that the shift from androgen to estrogen causes inguinal hernia in male mice, and this effect could be entirely prevented by an aromatase inhibitor.	('inguinal hernia', 'Phenotype', 'HP:0000023', (66, 81))	('inguinal hernia', 'Disease', (66, 81))	('inguinal hernia', 'Disease', 'MESH:D006552', (66, 81))	('mice', 'Species', '10090', (90, 94))	('shift', 'Var', (27, 32))	('hernia', 'Phenotype', 'HP:0100790', (75, 81))
25495	31024927	Genetic studies from China revealed that DNA sequence variants (DSVs) might contribute to inguinal hernia development by changing the transcriptional activities of TBX1, TBX2, TBX3, Sirtuin 1, and GATA transcription factor 6 (GATA6) gene promoters.	('TBX1', 'Gene', '6899', (164, 168))	('GATA transcription factor 6', 'Gene', '2627', (197, 224))	('hernia', 'Phenotype', 'HP:0100790', (99, 105))	('TBX2', 'Gene', '6909', (170, 174))	('men', 'Species', '9606', (113, 116))	('TBX3', 'Gene', '6926', (176, 180))	('contribute', 'Reg', (76, 86))	('transcriptional activities', 'MPA', (134, 160))	('inguinal hernia', 'Disease', (90, 105))	('Sirtuin 1', 'Gene', (182, 191))	('GATA6', 'Gene', '2627', (226, 231))	('GATA transcription factor 6', 'Gene', (197, 224))	('TBX3', 'Gene', (176, 180))	('changing', 'Reg', (121, 129))	('inguinal hernia', 'Disease', 'MESH:D006552', (90, 105))	('variants', 'Var', (54, 62))	('TBX1', 'Gene', (164, 168))	('inguinal hernia', 'Phenotype', 'HP:0000023', (90, 105))	('GATA6', 'Gene', (226, 231))	('TBX2', 'Gene', (170, 174))	('Sirtuin 1', 'Gene', '23411', (182, 191))
25496	31024927	Some of these genetic alterations may also play a role as etiologic or prognostic factors in human cancers.	('genetic alterations', 'Var', (14, 33))	('play', 'Reg', (43, 47))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('rat', 'Species', '10116', (26, 29))	('human', 'Species', '9606', (93, 98))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
25513	31024927	A recent experimental study with a mouse model revealed that advanced glycation end product Nepsilon-carboxymethyllysine could promote progression of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('promote', 'PosReg', (127, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('men', 'Species', '9606', (15, 18))	('mouse', 'Species', '10090', (35, 40))	('carboxymethyllysine', 'Chemical', 'MESH:C048496', (101, 120))	('Nepsilon-carboxymethyllysine', 'Var', (92, 120))	('pancreatic cancer', 'Disease', (150, 167))
25531	31024927	Inhibition of alphavbeta3 with antibody results in a decrease in the migration of these cells and angiogenesis.	('rat', 'Species', '10116', (72, 75))	('decrease', 'NegReg', (53, 61))	('alphavbeta3', 'Protein', (14, 25))	('angiogenesis', 'CPA', (98, 110))	('migration of these cells', 'CPA', (69, 93))	('Inhibition', 'Var', (0, 10))
25534	31024927	Moreover, the blockade with DisBa-01 may be preventive against incisional hernia development.	('hernia', 'Phenotype', 'HP:0100790', (74, 80))	('DisBa-01', 'Chemical', '-', (28, 36))	('blockade', 'Var', (14, 22))	('men', 'Species', '9606', (88, 91))	('hernia', 'Disease', (74, 80))	('DisBa-01', 'Gene', (28, 36))	('hernia', 'Disease', 'MESH:D006547', (74, 80))	('incisional hernia', 'Phenotype', 'HP:0004872', (63, 80))
25535	31024927	A recent animal study from Brazil demonstrated that DisBa-01 increased the number of macrophages and fibroblasts and no subject treated with this recombinant disintegrin developed incisional hernia.	('incisional hernia', 'Phenotype', 'HP:0004872', (180, 197))	('DisBa-01', 'Chemical', '-', (52, 60))	('hernia', 'Disease', (191, 197))	('increased', 'PosReg', (61, 70))	('rat', 'Species', '10116', (41, 44))	('hernia', 'Phenotype', 'HP:0100790', (191, 197))	('hernia', 'Disease', 'MESH:D006547', (191, 197))	('DisBa-01', 'Var', (52, 60))
25584	31024927	CRS + HIPEC do not increase the risk of incisional hernia as measured within 12 months postoperatively, but when developed, incisional hernia adversely affected health-related quality of life.	('rat', 'Species', '10116', (94, 97))	('hernia', 'Disease', (51, 57))	('hernia', 'Disease', (135, 141))	('incisional hernia', 'Phenotype', 'HP:0004872', (40, 57))	('hernia', 'Phenotype', 'HP:0100790', (51, 57))	('hernia', 'Disease', 'MESH:D006547', (51, 57))	('hernia', 'Disease', 'MESH:D006547', (135, 141))	('hernia', 'Phenotype', 'HP:0100790', (135, 141))	('CRS + HIPEC', 'Var', (0, 11))	('health-related quality of life', 'CPA', (161, 191))	('affected', 'Reg', (152, 160))	('incisional hernia', 'Phenotype', 'HP:0004872', (124, 141))
25662	31024927	The only evidence of a relationship between cancer and polypropylene meshes has been obtained from animal studies and the risk of carcinogenesis in humans has not been confirmed.	('humans', 'Species', '9606', (148, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carcinogenesis', 'Disease', (130, 144))	('polypropylene', 'Chemical', 'MESH:D011126', (55, 68))	('polypropylene', 'Var', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
25666	31024927	To date, no study has addressed the same subject in the women, but polypropylene meshes used for gynecologic procedures have been implicated as a potential risk factor for cancer development in women.	('polypropylene', 'Var', (67, 80))	('men', 'Species', '9606', (196, 199))	('women', 'Species', '9606', (56, 61))	('polypropylene', 'Chemical', 'MESH:D011126', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('women', 'Species', '9606', (194, 199))	('men', 'Species', '9606', (186, 189))	('risk factor', 'Reg', (156, 167))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('men', 'Species', '9606', (58, 61))
25689	26694252	However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors.	('germ cell tumors', 'Disease', 'MESH:D009373', (116, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('germ cell tumors', 'Phenotype', 'HP:0100728', (116, 132))	('testicular cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('epigenetic alterations', 'Var', (32, 54))	('testicular cancer', 'Disease', 'MESH:D013736', (58, 75))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('testicular cancer', 'Phenotype', 'HP:0010788', (58, 75))	('germ cell tumors', 'Disease', (116, 132))	('platinum', 'Chemical', 'MESH:D010984', (96, 104))
25691	26694252	Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors.	('chemotherapy resistance', 'CPA', (126, 149))	('contribute', 'Reg', (112, 122))	('germ cell tumors', 'Disease', (191, 207))	('DNA', 'MPA', (86, 89))	('germ cell tumors', 'Phenotype', 'HP:0100728', (191, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('germ cell tumors', 'Disease', 'MESH:D009373', (191, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('men', 'Species', '9606', (33, 36))	('epigenetic aberrations', 'Var', (51, 73))
25693	26694252	Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting.	('drug resistance', 'Phenotype', 'HP:0020174', (171, 186))	('DNA', 'Gene', (62, 65))	('testicular cancer', 'Disease', 'MESH:D013736', (190, 207))	('acquired drug resistance', 'MPA', (162, 186))	('testicular cancer', 'Disease', (190, 207))	('methylation', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('testicular cancer', 'Phenotype', 'HP:0010788', (190, 207))
25712	26694252	Epigenetic features of neoplasms are being explored as possible novel therapeutic options.	('neoplasms', 'Phenotype', 'HP:0002664', (23, 32))	('neoplasms', 'Disease', 'MESH:D009369', (23, 32))	('neoplasms', 'Disease', (23, 32))	('Epigenetic features', 'Var', (0, 19))
25713	26694252	This can include DNA methylation, histone modification, nucleosome repositioning, and posttranscriptional gene regulation by micro-RNA (miRNA).	('histone', 'MPA', (34, 41))	('posttranscriptional gene regulation', 'MPA', (86, 121))	('miR', 'Gene', (136, 139))	('micro-RNA', 'Var', (125, 134))	('miR', 'Gene', '22877', (136, 139))
25716	26694252	Hypermethylation represses transcription of CpG-rich promoter regions of tumor suppressor genes leading to gene silencing.	('gene', 'MPA', (107, 111))	('represses', 'NegReg', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('transcription', 'MPA', (27, 40))	('silencing', 'NegReg', (112, 121))	('tumor', 'Disease', (73, 78))
25718	26694252	A unique feature of GCTs that may explain their exquisite sensitivity to platinum therapies compared to other solid somatic tumors is global CpG hypomethylation.	('platinum', 'Chemical', 'MESH:D010984', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('hypomethylation', 'Var', (145, 160))	('somatic tumors', 'Disease', 'MESH:C563610', (116, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('GCTs', 'Phenotype', 'HP:0100728', (20, 24))	('somatic tumors', 'Disease', (116, 130))
25722	26694252	The hypo-methylation of seminomas correlates with hypersensitivity to chemotherapy.	('seminomas', 'Disease', (24, 33))	('hypo-methylation', 'Var', (4, 20))	('hypersensitivity', 'Disease', 'MESH:D004342', (50, 66))	('hypersensitivity', 'Disease', (50, 66))	('seminomas', 'Disease', 'MESH:D018239', (24, 33))
25724	26694252	More recently discovered epigenetic changes in cancer involve miRNA.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('miR', 'Gene', (62, 65))	('cancer', 'Disease', (47, 53))	('epigenetic changes', 'Var', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('miR', 'Gene', '22877', (62, 65))
25727	26694252	A variety of miRNAs have been found to be elevated in GCT patient serum including miR-302a-3p, 302b-3p, 302c-3p, 367-3p, 371a-3p, 372-3p and 373-3p.	('372-3p', 'Var', (130, 136))	('371a-3p', 'Var', (121, 128))	('miR', 'Gene', (82, 85))	('miR', 'Gene', (13, 16))	('302c-3p', 'Var', (104, 111))	('patient', 'Species', '9606', (58, 65))	('373-3p', 'Var', (141, 147))	('367-3p', 'Var', (113, 119))	('miR', 'Gene', '22877', (13, 16))	('miR', 'Gene', '22877', (82, 85))	('elevated', 'PosReg', (42, 50))	('302b-3p', 'Var', (95, 102))
25732	26694252	These studies show that epigenetic features of GCTs such as miRNAs could provide future biomarkers for this disease.	('GCTs', 'Phenotype', 'HP:0100728', (47, 51))	('miR', 'Gene', '22877', (60, 63))	('epigenetic features', 'Var', (24, 43))	('miR', 'Gene', (60, 63))
25733	26694252	Epigenetic silencing, such as hypermethylation, may play a role in resistance to platinum in refractory GCTs.	('platinum', 'Chemical', 'MESH:D010984', (81, 89))	('hypermethylation', 'Var', (30, 46))	('GCTs', 'Phenotype', 'HP:0100728', (104, 108))	('play', 'Reg', (52, 56))
25735	26694252	Hypomethylated DNA is generally thought to be more active, or "open", allowing for easier integration of platinum into DNA leading to more cellular damage and apoptosis.	('Hypomethylated', 'Var', (0, 14))	('cellular damage', 'CPA', (139, 154))	('platinum', 'Chemical', 'MESH:D010984', (105, 113))	('more', 'PosReg', (134, 138))	('integration', 'Interaction', (90, 101))	('apoptosis', 'CPA', (159, 168))
25737	26694252	Platinum refractory GCTs have been associated with hypermethylation in the promoter regions of tumor suppressor genes.	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('Platinum refractory GCTs', 'Disease', (0, 24))	('hypermethylation', 'Var', (51, 67))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('GCTs', 'Phenotype', 'HP:0100728', (20, 24))	('tumor', 'Disease', (95, 100))
25738	26694252	Hypermethylation of RASSF1A and H1C1, was found to be associated with resistance in GCTs.	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (20, 27))	('GCTs', 'Phenotype', 'HP:0100728', (84, 88))	('resistance in GCTs', 'Disease', (70, 88))	('RASSF1A', 'Gene', '11186', (20, 27))	('H1C1', 'Gene', (32, 36))	('associated', 'Reg', (54, 64))
25742	26694252	Epigenetic silencing through methylation has been demonstrated to have similar effects to DNA mutations in tumorigenesis and chemotherapy resistance and has led to studies designed to reverse this potential mechanism in platinum refractory tumors.	('methylation', 'Var', (29, 40))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (94, 103))	('platinum', 'Chemical', 'MESH:D010984', (220, 228))	('chemotherapy resistance', 'CPA', (125, 148))	('effects', 'Reg', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('DNA', 'Gene', (90, 93))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
25751	26694252	Studies have shown that DNMTIs hit multiple targets including the tumor suppressor gene p53.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DNMTIs', 'Chemical', '-', (24, 30))	('tumor', 'Disease', (66, 71))	('p53', 'Gene', (88, 91))	('DNMTIs', 'Var', (24, 30))	('p53', 'Gene', '7157', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
25759	26694252	Knockdown of DNMT3B resulted in resistance to decitabine, suggesting that decitabine sensitivity in EC is mechanistically linked to, and dependent on, high levels of DNMT3B.	('resistance to decitabine', 'MPA', (32, 56))	('Knockdown', 'Var', (0, 9))	('DNMT3B', 'Gene', (166, 172))	('DNMT3B', 'Gene', '1789', (166, 172))	('decitabine', 'Chemical', 'MESH:D000077209', (46, 56))	('resulted in', 'Reg', (20, 31))	('DNMT3B', 'Gene', (13, 19))	('decitabine', 'Chemical', 'MESH:D000077209', (74, 84))	('DNMT3B', 'Gene', '1789', (13, 19))	('EC', 'Phenotype', 'HP:0002898', (100, 102))
25765	26694252	Two recent phase I/II studies showed that low dose DNMTI treatment could restore sensitivity to carboplatin in patients with heavily pretreated ovarian cancer and resistance to cisplatin was correlated with hypermethylation of ovarian tumor DNA.	('men', 'Species', '9606', (62, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('ovarian tumor', 'Disease', 'MESH:D010051', (227, 240))	('sensitivity to carboplatin', 'MPA', (81, 107))	('DNMTI', 'Chemical', '-', (51, 56))	('pretreated ovarian cancer', 'Phenotype', 'HP:0008209', (133, 158))	('hypermethylation', 'Var', (207, 223))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('correlated', 'Reg', (191, 201))	('restore', 'PosReg', (73, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('carboplatin', 'Chemical', 'MESH:D016190', (96, 107))	('ovarian tumor', 'Disease', (227, 240))	('ovarian cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ovarian tumor', 'Phenotype', 'HP:0100615', (227, 240))	('patients', 'Species', '9606', (111, 119))
25775	26694252	Interestingly, tumors biopsied after treatment found that patients who had PFS of more than 6 months had a greater number of demethylated genes involved in cancer pathways than patients who had PFS of less than 6 months.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('men', 'Species', '9606', (42, 45))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('demethylate', 'Chemical', '-', (125, 136))	('patients', 'Species', '9606', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('demethylated genes', 'MPA', (125, 143))	('patients', 'Species', '9606', (58, 66))	('PFS', 'Var', (75, 78))	('tumors', 'Disease', (15, 21))
25777	26694252	showed similar findings in the same patient population with a DNMTI and carboplatin used in succession with a 13.8% overall response rate, as well as a disease control rate (partial response rate plus stable disease) of 45%.	('DNMTI', 'Var', (62, 67))	('carboplatin', 'Chemical', 'MESH:D016190', (72, 83))	('disease control', 'CPA', (152, 167))	('patient', 'Species', '9606', (36, 43))	('DNMTI', 'Chemical', '-', (62, 67))
25812	26694252	Clinical trials in ovarian cancer have demonstrated safety of DNMTI and platinum combination therapy which is currently being further investigated in phase II trials.	('ovarian cancer', 'Disease', 'MESH:D010051', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('platinum', 'Chemical', 'MESH:D010984', (72, 80))	('DNMTI', 'Var', (62, 67))	('ovarian cancer', 'Disease', (19, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('DNMTI', 'Chemical', '-', (62, 67))
26063	25587109	In the subgroup analysis of never-tobacco smokers, marijuana use was associated with an increased risk of prostate cancer and cervical cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('marijuana', 'Species', '3483', (51, 60))	('marijuana', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cervical cancer', 'Disease', (126, 141))	('prostate cancer', 'Disease', (106, 121))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('tobacco', 'Species', '4097', (34, 41))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
26104	25587109	Seventh, immunohistochemical assessment of these biopsies has shown significantly increased expression of molecular markers of pre-tumor progression, including EGRF (epidermal growth factor receptor) and Ki-67 (a nuclear proliferation protein) compared to nonsmokers.	('men', 'Species', '9606', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Ki-67', 'Var', (204, 209))	('tumor', 'Disease', (131, 136))	('EGRF', 'Protein', (160, 164))	('increased', 'PosReg', (82, 91))	('expression', 'MPA', (92, 102))
26151	25587109	It is of importance to developand validate marijuana smoking related exposure markers including DNA adducts; exposure related early biological responses such as specific somatic mutations of tumor suppressor gene; genetic polymorphisms of metabolic, inflammation and DNA repair genes; and epigenetic markers including DNA methylation, microRNA, etc.	('polymorphisms', 'Var', (222, 235))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('inflammation', 'Disease', 'MESH:D007249', (250, 262))	('inflammation', 'Disease', (250, 262))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('mutations', 'Var', (178, 187))	('marijuana', 'Species', '3483', (43, 52))
26155	24386123	Further oxidation and activation of the base excision repair mechanism leads to replacement of a modified cytosine by an unmodified one.	('cytosine', 'Chemical', 'MESH:D003596', (106, 114))	('base excision repair mechanism', 'Pathway', (40, 70))	('modified', 'Var', (97, 105))	('replacement', 'MPA', (80, 91))
26158	24386123	We demonstrate that all carcinoma in situ and the majority of seminomas are hypomethylated and hypohydroxymethylated compared to non-seminomas.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (24, 41))	('hypomethylated', 'Var', (76, 90))	('seminomas', 'Disease', (62, 71))	('seminomas', 'Disease', 'MESH:D018239', (62, 71))	('non-seminomas', 'Disease', 'MESH:D018239', (129, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('seminomas', 'Disease', 'MESH:D018239', (133, 142))	('carcinoma in situ', 'Disease', 'MESH:D002278', (24, 41))	('non-seminomas', 'Disease', (129, 142))	('seminomas', 'Disease', (133, 142))	('hypohydroxymethylated', 'Var', (95, 116))	('carcinoma in situ', 'Disease', (24, 41))
26163	24386123	Finally, mutations of IDH1 (IDH1 R132) and IDH2 (IDH2 R172) leading to production of the TET inhibiting oncometabolite 2-hydroxyglutarate in germ cell cancer cell lines were not detected.	('IDH2', 'Gene', '3418', (49, 53))	('IDH1', 'Gene', '3417', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('TET', 'Chemical', '-', (89, 92))	('germ cell cancer', 'Phenotype', 'HP:0100728', (141, 157))	('IDH2', 'Gene', (43, 47))	('mutations', 'Var', (9, 18))	('TET inhibiting oncometabolite 2-hydroxyglutarate', 'MPA', (89, 137))	('IDH1', 'Gene', (22, 26))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('IDH2', 'Gene', '3418', (43, 47))	('IDH1', 'Gene', '3417', (22, 26))	('IDH2', 'Gene', (49, 53))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (119, 137))	('IDH1', 'Gene', (28, 32))
26164	24386123	In general, methylation of cytosines within CpG dinucleotides of promoter regions leads to epigenetic gene silencing.	('epigenetic gene silencing', 'MPA', (91, 116))	('methylation', 'Var', (12, 23))	('cytosines', 'Chemical', 'MESH:D003596', (27, 36))	('leads to', 'Reg', (82, 90))
26167	24386123	The DNMTs 3A and 3B are able to methylate DNA de novo in cooperation with the cofactor DNMT3L.	('DNMT', 'Gene', (87, 91))	('methylate', 'Var', (32, 41))	('DNMT3L', 'Gene', '29947', (87, 93))	('DNMT3L', 'Gene', (87, 93))	('DNMT', 'Gene', '1786', (4, 8))	('DNMT', 'Gene', '1786', (87, 91))	('DNMT', 'Gene', (4, 8))
26177	24386123	Tet1 knock-down resulted in an increase in global and Nanog promotor specific DNA methylation, while 5hmC levels become reduced.	('5hmC', 'Chemical', 'MESH:C011865', (101, 105))	('knock-down', 'Var', (5, 15))	('Nanog', 'Gene', '79923', (54, 59))	('5hmC levels', 'MPA', (101, 112))	('Nanog', 'Gene', (54, 59))	('Tet1', 'Gene', (0, 4))	('increase', 'PosReg', (31, 39))
26184	24386123	Recently, it has been demonstrated that mutations of the isocitrate dehydrogenases (IDH) 1 and 2 genes (IDH1 R132, IDH2R172) in glioblastomas, diffuse astrocytic and oligodendroglial tumors are associated with the production of the oncometabolite 2-hydroxyglutarate and decreased levels of alpha-ketoglutarate, leading to inhibition of alpha-ketoglutarate-dependent oxygenases, which are involved in DNA and histone tail demethylation    .	('glioblastomas', 'Disease', (128, 141))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('isocitrate dehydrogenases (IDH) 1 and 2', 'Gene', '3417;3418', (57, 96))	('levels of alpha-ketoglutarate', 'MPA', (280, 309))	('IDH2R172', 'Gene', (115, 123))	('IDH1', 'Gene', '3417', (104, 108))	('glioblastomas', 'Disease', 'MESH:D005909', (128, 141))	('decreased levels of alpha-ketoglutarate', 'Phenotype', 'HP:0012403', (270, 309))	('inhibition', 'NegReg', (322, 332))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (290, 309))	('mutations', 'Var', (40, 49))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (247, 265))	('decreased', 'NegReg', (270, 279))	('oligodendroglial tumors', 'Disease', (166, 189))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (336, 355))	('glioblastomas', 'Phenotype', 'HP:0012174', (128, 141))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('oxygen', 'Chemical', 'MESH:D010100', (366, 372))	('oligodendroglial tumors', 'Disease', 'MESH:D009369', (166, 189))	('alpha-ketoglutarate-dependent oxygenases', 'Enzyme', (336, 376))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('IDH2R172', 'Gene', '3418', (115, 123))	('IDH1', 'Gene', (104, 108))
26185	24386123	Additionally, mutations of the IDH genes are associated with increased DNA methylation at CpG islands.	('DNA methylation', 'MPA', (71, 86))	('IDH', 'Gene', (31, 34))	('IDH', 'Gene', '3417', (31, 34))	('increased', 'PosReg', (61, 70))	('mutations', 'Var', (14, 23))
26186	24386123	Since TET enzymes require alpha-ketoglutarate and oxygen, mutations of IDH1 and IDH2 might have an impact on ADD processes in GCCs.	('mutations', 'Var', (58, 67))	('IDH2', 'Gene', '3418', (80, 84))	('impact', 'Reg', (99, 105))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (26, 45))	('IDH1', 'Gene', (71, 75))	('TET', 'Chemical', '-', (6, 9))	('ADD processes', 'MPA', (109, 122))	('GCCs', 'Disease', (126, 130))	('IDH1', 'Gene', '3417', (71, 75))	('oxygen', 'Chemical', 'MESH:D010100', (50, 56))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('IDH2', 'Gene', (80, 84))
26191	24386123	By extending our analysis to human type II GCCs, we found the majority of CIS and seminoma cells to be hypomethylated and hypohydroxymethylated, while non-seminomas displayed high 5mC and 5hmC levels, demonstrating correlation between 5mC and 5hmC.	('seminoma', 'Disease', 'MESH:D018239', (82, 90))	('S', 'Chemical', 'MESH:D013455', (76, 77))	('seminoma', 'Disease', 'MESH:D018239', (155, 163))	('5mC', 'Chemical', 'MESH:D044503', (180, 183))	('seminoma', 'Disease', (82, 90))	('non-seminomas', 'Disease', (151, 164))	('CIS', 'Disease', (74, 77))	('5mC', 'Chemical', 'MESH:D044503', (235, 238))	('5hmC', 'Chemical', 'MESH:C011865', (243, 247))	('5hmC', 'Chemical', 'MESH:C011865', (188, 192))	('non-seminomas', 'Disease', 'MESH:D018239', (151, 164))	('human', 'Species', '9606', (29, 34))	('seminoma', 'Disease', (155, 163))	('hypomethylated', 'Var', (103, 117))	('hypohydroxymethylated', 'MPA', (122, 143))
26238	24386123	Somatic sequence alterations of the codon R132 (IDH1; HGNC, Acc: 5382) and R172 (IDH2; HGNC, Acc: 5383) were investigated by pyrosequencing as recently described.	('IDH1', 'Gene', '3417', (48, 52))	('R172', 'Var', (75, 79))	('IDH2', 'Gene', (81, 85))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1', 'Gene', (48, 52))	('S', 'Chemical', 'MESH:D013455', (0, 1))
26243	24386123	As positive control glioblastoma samples with confirmed IDH1/IDH2 mutations were included.	('mutations', 'Var', (66, 75))	('glioblastoma', 'Disease', (20, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('IDH2', 'Gene', (61, 65))	('IDH1', 'Gene', '3417', (56, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('IDH2', 'Gene', '3418', (61, 65))	('IDH1', 'Gene', (56, 60))
26249	24386123	Since murine PGCs are able to actively demethylate their genome during their migration to the genital ridges, we asked if adult human gonocytes and germ cells of different developmental stages also display ADD.	('human', 'Species', '9606', (128, 133))	('PGC', 'Gene', '5225', (13, 16))	('murine', 'Species', '10090', (6, 12))	('demethylate', 'Var', (39, 50))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('PGC', 'Gene', (13, 16))
26291	24386123	It has been demonstrated that mutations of the IDH1 and IDH2 gene (IDH1 R132, IDH2R172) in glioblastomas are associated with the production of the TET inhibiting oncometabolite 2-hydroxyglutarate   .	('IDH2', 'Gene', '3418', (56, 60))	('production', 'MPA', (129, 139))	('IDH2', 'Gene', (78, 82))	('IDH2', 'Gene', '3418', (78, 82))	('IDH1', 'Gene', '3417', (67, 71))	('glioblastomas', 'Phenotype', 'HP:0012174', (91, 104))	('IDH1', 'Gene', (47, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (91, 103))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (177, 195))	('TET inhibiting oncometabolite 2-hydroxyglutarate', 'MPA', (147, 195))	('IDH2R172', 'Gene', '3418', (78, 86))	('associated', 'Reg', (109, 119))	('mutations', 'Var', (30, 39))	('glioblastomas', 'Disease', (91, 104))	('IDH1', 'Gene', '3417', (47, 51))	('IDH2R172', 'Gene', (78, 86))	('IDH1', 'Gene', (67, 71))	('glioblastomas', 'Disease', 'MESH:D005909', (91, 104))	('TET', 'Chemical', '-', (147, 150))	('IDH2', 'Gene', (56, 60))
26293	24386123	We screened all analyzed GCC cell lines for mutations in the IDH1 (IDH1R132) and IDH2 (IDH2 R172) by pyrosequencing, but did not detect any mutations (Data S1, example given in Fig.	('IDH1', 'Gene', (67, 71))	('IDH2', 'Gene', (81, 85))	('IDH2', 'Gene', '3418', (81, 85))	('IDH1', 'Gene', (61, 65))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('IDH1', 'Gene', '3417', (67, 71))	('mutations', 'Var', (44, 53))	('IDH2', 'Gene', (87, 91))	('IDH1R132', 'Gene', (67, 75))	('IDH1', 'Gene', '3417', (61, 65))	('IDH1R132', 'Gene', '3417', (67, 75))	('IDH2', 'Gene', '3418', (87, 91))
26294	24386123	Glioblastoma samples with confirmed mutations of the IDH1 or IDH2 gene was used as positive controls.	('Glioblastoma', 'Disease', (0, 12))	('IDH1', 'Gene', (53, 57))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('IDH2', 'Gene', (61, 65))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', '3417', (53, 57))	('IDH2', 'Gene', '3418', (61, 65))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))
26307	24386123	Furthermore, the choriocarcinoma cell lines JEG-3 and JAR are strongly positive for DNMT3B, while the seminoma cell line TCam-2 and seminoma tissues displayed only very low expression levels, suggesting that seminomas posses only weak de novo DNA methylation activity, but are able to maintain DNA methylation patterns during replication by the maintenance DNA methyltransferase DNMT1.	('DNMT1', 'Gene', (379, 384))	('positive', 'Reg', (71, 79))	('choriocarcinoma', 'Disease', (17, 32))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (17, 32))	('DNMT1', 'Gene', '1786', (379, 384))	('seminoma', 'Disease', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('seminoma', 'Disease', 'MESH:D018239', (132, 140))	('choriocarcinoma', 'Disease', 'MESH:D002822', (17, 32))	('seminomas', 'Disease', 'MESH:D018239', (208, 217))	('seminomas', 'Disease', (208, 217))	('seminoma', 'Disease', 'MESH:D018239', (208, 216))	('DNA methylation patterns', 'MPA', (294, 318))	('DNMT3B', 'Var', (84, 90))	('seminoma', 'Disease', 'MESH:D018239', (102, 110))	('JAR', 'CellLine', 'CVCL:0360', (54, 57))	('seminoma', 'Disease', (132, 140))	('seminoma', 'Disease', (208, 216))
26341	24386123	We found the majority of CIS and seminoma tissues to be hypomethylated and hypohydroxymethylated compared to EC tissues.	('hypomethylated', 'Var', (56, 70))	('S', 'Chemical', 'MESH:D013455', (27, 28))	('seminoma', 'Disease', (33, 41))	('seminoma', 'Disease', 'MESH:D018239', (33, 41))	('hypohydroxymethylated', 'Var', (75, 96))	('CIS', 'Disease', (25, 28))
26349	24386123	Since our study reveals that 29% of seminomas are hypermethylated compared to CIS and the other seminoma samples analyzed (Fig.	('seminoma', 'Disease', (36, 44))	('seminoma', 'Disease', 'MESH:D018239', (96, 104))	('hypermethylated', 'Var', (50, 65))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('seminoma', 'Disease', (96, 104))	('seminoma', 'Disease', 'MESH:D018239', (36, 44))	('seminomas', 'Disease', 'MESH:D018239', (36, 45))	('seminomas', 'Disease', (36, 45))	('S', 'Chemical', 'MESH:D013455', (0, 1))
26361	24386123	In non-seminoma tissues and cell lines, maintenance- and de novo- methylation seem to occur in parallel, indicated by expression of DNMT1, DNMT3B and DNMT3L.	('DNMT1', 'Gene', (132, 137))	('DNMT3L', 'Gene', '29947', (150, 156))	('non-seminoma', 'Disease', (3, 15))	('DNMT1', 'Gene', '1786', (132, 137))	('non-seminoma', 'Disease', 'MESH:D018239', (3, 15))	('DNMT3B', 'Var', (139, 145))	('DNMT3L', 'Gene', (150, 156))
26370	24386123	A mutation in IDH1 (IDH1R132) or IDH2 (IDH2R172) causes the production of the TET inhibiting oncometabolite 2-hydroxyglutarate  .	('IDH1', 'Gene', '3417', (20, 24))	('production', 'MPA', (60, 70))	('IDH1R132', 'Gene', (20, 28))	('mutation', 'Var', (2, 10))	('IDH2', 'Gene', (33, 37))	('IDH2', 'Gene', (39, 43))	('TET', 'Chemical', '-', (78, 81))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (108, 126))	('IDH1R132', 'Gene', '3417', (20, 28))	('TET inhibiting oncometabolite 2-hydroxyglutarate', 'MPA', (78, 126))	('IDH2', 'Gene', '3418', (33, 37))	('IDH2', 'Gene', '3418', (39, 43))	('causes', 'Reg', (49, 55))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', (20, 24))	('IDH2R172', 'Gene', '3418', (39, 47))	('IDH2R172', 'Gene', (39, 47))	('IDH1', 'Gene', '3417', (14, 18))
26381	24386123	We hypothesize that genes important for a PGC-/CIS-/seminoma-like cell fate are silenced by de novo methylation, while EC associated genes become actively demethylated.	('PGC', 'Gene', '5225', (42, 45))	('PGC', 'Gene', (42, 45))	('silenced', 'NegReg', (80, 88))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('seminoma', 'Disease', 'MESH:D018239', (52, 60))	('methylation', 'Var', (100, 111))	('seminoma', 'Disease', (52, 60))
26388	31673449	Furthermore, TQ and Cis-platinum had apoptotic effects on both ACHN and GP-293 cell lines.	('Cis-platinum', 'Var', (20, 32))	('Cis-platinum', 'Chemical', 'MESH:D002945', (20, 32))	('apoptotic effects', 'CPA', (37, 54))	('TQ', 'Chemical', 'MESH:C003466', (13, 15))
26390	31673449	Additionally, Cis-platinum was more effective on ACHN cell line than on GP-293 cell line.	('Cis-platinum', 'Chemical', 'MESH:D002945', (14, 26))	('ACHN', 'Disease', (49, 53))	('Cis-platinum', 'Var', (14, 26))
26396	31673449	Several risk factors are involved in the RCC including obesity, smoking, Western-style diet and gene polymorphisms of antioxidant enzymes.	('obesity', 'Phenotype', 'HP:0001513', (55, 62))	('gene polymorphisms', 'Var', (96, 114))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('obesity', 'Disease', 'MESH:D009765', (55, 62))	('RCC', 'Disease', 'MESH:D002292', (41, 44))	('RCC', 'Disease', (41, 44))	('obesity', 'Disease', (55, 62))
26398	31673449	However, enormous side effects of Cis-Platinum especially nephrotoxicity, limit its therapeutic usefulness.	('Cis-Platinum', 'Chemical', 'MESH:D002945', (34, 46))	('Cis-Platinum', 'Var', (34, 46))	('limit', 'NegReg', (74, 79))	('nephrotoxicity', 'Disease', 'MESH:D007674', (58, 72))	('nephrotoxicity', 'Disease', (58, 72))
26431	31673449	4 shows GP-293 and ACHN cell viability results for TQ concentrations after 24, 48 and 72 h. In GP-293 cells, cell viability was significant during all of the time periods of exposures to TQ from 5 mug/mL concentration in comparison to the control wells.	('TQ', 'Chemical', 'MESH:C003466', (51, 53))	('GP-293', 'Var', (95, 101))	('TQ', 'Chemical', 'MESH:C003466', (187, 189))	('cell viability', 'CPA', (109, 123))
26434	31673449	In GP-293 cells, after 24 h of exposure to Cis-platinum, decreased cell viability was recorded at the 1 mug/mL concentration compared to the control wells; however, the reduction was significant at the 6 mug/mL concentration.	('cell viability', 'CPA', (67, 81))	('decreased', 'NegReg', (57, 66))	('Cis-platinum', 'Var', (43, 55))	('Cis-platinum', 'Chemical', 'MESH:D002945', (43, 55))
26441	31673449	It was indicated that at the 0.5 mug/mL concentration and higher, Cis-platinum induced apoptosis in ACHN cells.	('apoptosis', 'CPA', (87, 96))	('Cis-platinum', 'Var', (66, 78))	('Cis-platinum', 'Chemical', 'MESH:D002945', (66, 78))
26454	31673449	Hela (human cervical carcinoma), M059K and M059J (human glioblastoma) ]24[.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('carcinoma', 'Disease', 'MESH:D002277', (21, 30))	('human', 'Species', '9606', (6, 11))	('carcinoma', 'Disease', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('glioblastoma', 'Disease', (56, 68))	('M059J', 'Var', (43, 48))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('human', 'Species', '9606', (50, 55))
26456	31673449	The findings also revealed that Cis-platinum induced morphological changes in both the cell lines, but these changes were stronger in ACHN cell lines than in GP-293 cell lines.	('Cis-platinum', 'Var', (32, 44))	('Cis-platinum', 'Chemical', 'MESH:D002945', (32, 44))	('morphological changes', 'CPA', (53, 74))	('stronger', 'PosReg', (122, 130))
26461	31673449	Moreover, in our study, results revealed that Cis-platinum inhibited proliferation of ACHN and GP-293 cell lines, and ACHN cell lines displayed increased sensitivity towards Cis-platinum compared to GP-293 cells lines.	('Cis-platinum', 'Chemical', 'MESH:D002945', (46, 58))	('sensitivity', 'MPA', (154, 165))	('proliferation', 'CPA', (69, 82))	('Cis-platinum', 'Var', (46, 58))	('Cis-platinum', 'Chemical', 'MESH:D002945', (174, 186))	('inhibited', 'NegReg', (59, 68))	('increased', 'PosReg', (144, 153))
26467	31673449	In this study, Cis-platinum had a selective effect on apoptosis induction in ACHN cell lines compared to GP-293 cell lines.	('apoptosis', 'CPA', (54, 63))	('Cis-platinum', 'Chemical', 'MESH:D002945', (15, 27))	('Cis-platinum', 'Var', (15, 27))
26468	31673449	Moreover, Cis-platinum increased the percentage of apoptosis in ACHN cell lines at lower concentrations whereas reduced it at higher concentrations.	('apoptosis', 'CPA', (51, 60))	('Cis-platinum', 'Var', (10, 22))	('Cis-platinum', 'Chemical', 'MESH:D002945', (10, 22))
26475	31673449	Interestingly, based on our results, Cis-platinum was more promising in reducing cell viability and inducing apoptosis in ACHN cell lines compared to GP-293 cell lines.	('Cis-platinum', 'Chemical', 'MESH:D002945', (37, 49))	('inducing', 'Reg', (100, 108))	('apoptosis', 'CPA', (109, 118))	('reducing', 'NegReg', (72, 80))	('Cis-platinum', 'Var', (37, 49))	('cell viability', 'CPA', (81, 95))
26477	31673449	Based on previous studies, which compared the effect of Cis-platinum, TQ and total extract of N. sativa and its fractions on ACHN, GP-293 and L929 cell lines, it was shown that total extract of N. sativa and Cis-platinum more selectively caused cytotoxicity in ACHN cell lines.	('Cis-platinum', 'Chemical', 'MESH:D002945', (208, 220))	('N. sativa', 'Species', '555479', (94, 103))	('N. sativa', 'Species', '555479', (194, 203))	('cytotoxicity', 'Disease', 'MESH:D064420', (245, 257))	('Cis-platinum', 'Var', (208, 220))	('TQ', 'Chemical', 'MESH:C003466', (70, 72))	('Cis-platinum', 'Chemical', 'MESH:D002945', (56, 68))	('cytotoxicity', 'Disease', (245, 257))
26480	31673449	In addition, Cis-platinum was more effective on ACHN cell line than GP-293 cell lines.	('Cis-platinum', 'Chemical', 'MESH:D002945', (13, 25))	('ACHN', 'Disease', (48, 52))	('Cis-platinum', 'Var', (13, 25))
26488	30914949	Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV).	('patients', 'Species', '9606', (46, 54))	('lymphocytopenia', 'Disease', 'MESH:D008231', (271, 286))	('alopecia', 'Phenotype', 'HP:0001596', (143, 151))	('rs13181', 'Mutation', 'rs13181', (66, 73))	('rs238406 C/C', 'Var', (173, 185))	('ERCC2', 'Gene', '2068', (60, 65))	('develop', 'PosReg', (263, 270))	('ERCC2', 'Gene', (167, 172))	('develop', 'PosReg', (199, 206))	('rs2740574 A/G', 'Var', (92, 105))	('develop', 'PosReg', (135, 142))	('ERCC2', 'Gene', '2068', (167, 172))	('leukopenia', 'Disease', 'MESH:D007970', (207, 217))	('rs2740574', 'Mutation', 'rs2740574', (92, 101))	('alopecia', 'Disease', (143, 151))	('leukopenia', 'Phenotype', 'HP:0001882', (207, 217))	('lymphocytopenia', 'Disease', (271, 286))	('CYP3A4', 'Gene', '1576', (85, 91))	('leukopenia', 'Disease', (207, 217))	('GSTT1', 'Gene', '2952', (237, 242))	('CYP3A4', 'Gene', (85, 91))	('patients', 'Species', '9606', (153, 161))	('rs238406', 'Mutation', 'rs238406', (173, 181))	('rs13181 T/G', 'Var', (66, 77))	('lymphocytopenia', 'Phenotype', 'HP:0001888', (271, 286))	('GSTT1', 'Gene', (237, 242))	('patients', 'Species', '9606', (223, 231))	('ERCC2', 'Gene', (60, 65))
26489	30914949	Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia.	('anemia', 'Phenotype', 'HP:0001903', (68, 74))	('ERCC2', 'Gene', (14, 19))	('rs1799793', 'Mutation', 'rs1799793', (20, 29))	('anemia', 'Disease', (68, 74))	('Patients', 'Species', '9606', (0, 8))	('anemia', 'Disease', 'MESH:D000740', (68, 74))	('rs1799793 A/A', 'Var', (20, 33))	('ERCC2', 'Gene', '2068', (14, 19))
26490	30914949	The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05).	('rs1050565', 'Mutation', 'rs1050565', (9, 18))	('associated', 'Reg', (48, 58))	('GSTP1', 'Gene', '2950', (78, 83))	('pain', 'Phenotype', 'HP:0012531', (64, 68))	('linked infection', 'Disease', (101, 117))	('linked infection', 'Disease', 'MESH:C564433', (101, 117))	('BLMH', 'Gene', (4, 8))	('pain', 'Disease', 'MESH:D010146', (64, 68))	('pain', 'Disease', (64, 68))	('BLMH', 'Gene', '642', (4, 8))	('rs1050565 G/G', 'Var', (9, 22))	('GSTP1', 'Gene', (78, 83))
26491	30914949	Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia.	('leukopenia', 'Phenotype', 'HP:0001882', (142, 152))	('genotypes', 'Var', (69, 78))	('BEP', 'Chemical', '-', (102, 105))	('leukopenia', 'Disease', (142, 152))	('ERCC1/2', 'Gene', (61, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (168, 179))	('leukopenia', 'Disease', 'MESH:D007970', (142, 152))	('severe', 'Disease', (135, 141))	('ERCC1/2', 'Gene', '2067;2068', (61, 68))	('febrile neutropenia', 'Disease', (160, 179))	('febrile neutropenia', 'Disease', 'MESH:D009503', (160, 179))
26504	30914949	Most of the chemotherapeutic drugs are metabolized by phase I polymorphic Cytochrome P450 enzymes, whose variant alleles commonly affect drug effectiveness and toxicity.	('variant', 'Var', (105, 112))	('Cytochrome P450', 'Gene', (74, 89))	('affect', 'Reg', (130, 136))	('toxicity', 'Disease', 'MESH:D064420', (160, 168))	('toxicity', 'Disease', (160, 168))	('drug effectiveness', 'CPA', (137, 155))	('Cytochrome P450', 'Gene', '4051', (74, 89))
26506	30914949	The CYP3A4*1B rs2740574 genotype is associated with an increased risk of leukemia following treatment with etoposide and teniposide.	('etoposide', 'Chemical', 'MESH:D005047', (107, 116))	('rs2740574', 'Mutation', 'rs2740574', (14, 23))	('men', 'Species', '9606', (97, 100))	('CYP3A4', 'Gene', (4, 10))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('leukemia', 'Disease', (73, 81))	('CYP3A4', 'Gene', '1576', (4, 10))	('teniposide', 'Chemical', 'MESH:D013713', (121, 131))	('rs2740574', 'Var', (14, 23))
26509	30914949	On the other hand, polymorphisms in phase II enzymes have been reported to affect the resistance and adverse reactions to several chemotherapy regimens.	('polymorphisms', 'Var', (19, 32))	('phase II enzymes', 'Enzyme', (36, 52))	('adverse reactions to several chemotherapy regimens', 'CPA', (101, 151))	('resistance', 'CPA', (86, 96))	('affect', 'Reg', (75, 81))	('men', 'Species', '9606', (147, 150))
26513	30914949	Besides, the GSTP1 Ile105Val polymorphism has been strongly associated with progression-free survival.	('GSTP1', 'Gene', (13, 18))	('Ile105Val', 'Var', (19, 28))	('progression-free survival', 'CPA', (76, 101))	('GSTP1', 'Gene', '2950', (13, 18))	('Ile105Val', 'Mutation', 'rs1695', (19, 28))	('associated', 'Reg', (60, 70))
26514	30914949	The T/T genotype of the -69 C > T GSTA1 polymorphism correlates with overall survival.	('GSTA1', 'Gene', '2938', (34, 39))	('overall survival', 'CPA', (69, 85))	('T/T', 'Var', (4, 7))	('GSTA1', 'Gene', (34, 39))	('-69 C > T', 'Mutation', 'rs3957357', (24, 33))
26516	30914949	Moreover, the presence of UDP-Glucuronosyl-transferase Family 1 Member A1 (UGT1A1) polymorphic variants has also been associated with chemotherapy response and Gilbert Syndrome after chemotherapy.	('UGT1A1', 'Gene', (75, 81))	('presence', 'Var', (14, 22))	('chemotherapy response', 'CPA', (134, 155))	('polymorphic variants', 'Var', (83, 103))	('UDP-Glucuronosyl-transferase Family 1 Member A1', 'Gene', (26, 73))	('Gilbert Syndrome', 'Disease', (160, 176))	('UDP-Glucuronosyl-transferase Family 1 Member A1', 'Gene', '54658', (26, 73))	('UGT1A1', 'Gene', '54658', (75, 81))	('associated with', 'Reg', (118, 133))
26518	30914949	In line with this evidence, the FDA recommended tests to detect the presence of UGT1A1*28, to predict patients at risk of irinotecan poisoning1.	('irinotecan', 'Chemical', 'MESH:D000077146', (122, 132))	('patients', 'Species', '9606', (102, 110))	('UGT1A1', 'Gene', '54658', (80, 86))	('presence', 'Var', (68, 76))	('UGT1A1', 'Gene', (80, 86))	('irinotecan poisoning1', 'Disease', (122, 143))	('men', 'Species', '9606', (41, 44))
26520	30914949	P-glycoprotein 1 (P-gp1), also known as multidrug resistance protein 1 (MDR1) or ATP- binding cassette sub-family B member 1, is highly polymorphic and several studies have reported that carriers of the T-allele for the genetic variation C3435T (rs1045642) have an increased risk of colon, breast, and renal cancer.	('colon', 'Disease', (283, 288))	('P-glycoprotein 1', 'Gene', (0, 16))	('C3435T', 'Mutation', 'rs1045642', (238, 244))	('renal cancer', 'Disease', 'MESH:D007680', (302, 314))	('MDR1', 'Gene', '5243', (72, 76))	('P-glycoprotein 1', 'Gene', '5243', (0, 16))	('P-gp1', 'Gene', (18, 23))	('multidrug resistance protein 1', 'Gene', (40, 70))	('breast', 'Disease', (290, 296))	('ATP- binding cassette sub-family B member 1', 'Gene', '5243', (81, 124))	('P-gp1', 'Gene', '5243', (18, 23))	('ATP- binding cassette sub-family B member 1', 'Gene', (81, 124))	('MDR1', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('C3435T', 'Var', (238, 244))	('renal cancer', 'Disease', (302, 314))	('rs1045642', 'Mutation', 'rs1045642', (246, 255))	('renal cancer', 'Phenotype', 'HP:0009726', (302, 314))	('multidrug resistance protein 1', 'Gene', '5243', (40, 70))
26521	30914949	However,, found no significant differences in hematological toxicities in the groups with the MDR1 C3435T polymorphism in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('MDR1', 'Gene', '5243', (94, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('hematological toxicities', 'Disease', (46, 70))	('C3435T', 'Mutation', 'rs1045642', (99, 105))	('hematological toxicities', 'Disease', 'MESH:D006402', (46, 70))	('C3435T', 'Var', (99, 105))	('MDR1', 'Gene', (94, 98))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
26529	30914949	Mutations abolishing the enzymatic function of the ERCC2 protein are manifested clinically in combinations of three severe syndromes, including Xeroderma pigmentosum.	('ERCC2', 'Gene', '2068', (51, 56))	('ERCC2', 'Gene', (51, 56))	('Mutations', 'Var', (0, 9))	('Xeroderma pigmentosum', 'Disease', (144, 165))	('abolishing', 'NegReg', (10, 20))	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (144, 165))	('protein', 'Protein', (57, 64))	('enzymatic function', 'MPA', (25, 43))
26530	30914949	Polymorphisms in these enzymes further affect DNA repair and are involved in resistance to chemotherapy, survival, and cancer manifestation.	('DNA repair', 'MPA', (46, 56))	('Polymorphisms', 'Var', (0, 13))	('affect', 'Reg', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('involved', 'Reg', (65, 73))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
26531	30914949	Based on the accumulated scientific evidence about BEP chemotherapy, we here focused on functionally significant gene polymorphisms in proteins that control metabolism, uptake, and response to BEP drugs (2).	('uptake', 'MPA', (169, 175))	('proteins', 'Protein', (135, 143))	('BEP', 'Chemical', '-', (51, 54))	('BEP', 'Chemical', '-', (193, 196))	('polymorphisms', 'Var', (118, 131))	('metabolism', 'MPA', (157, 167))
26532	30914949	Mainly, the allelic variants of CYP3A4 rs2740574 (*1B), CYP3A4 rs35599367 (*22), CYP3A5 rs776746 (*3), GSTM1-null, GSTP1 rs1695, GSTT1- null, UGT1A1 rs8175347 (*28), BLMH rs1050565, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs13181, ERCC2 rs1799793, ERCC2 rs238406, and MDR1 rs1045642 were analyzed with non-genetic factors to validate their association with ADRs in testicular cancer patients treated with BEP schedule.	('BLMH', 'Gene', '642', (166, 170))	('GSTP1', 'Gene', '2950', (115, 120))	('rs1799793', 'Var', (235, 244))	('GSTT1', 'Gene', '2952', (129, 134))	('ADR', 'Gene', '231', (355, 358))	('rs3212986', 'Mutation', 'rs3212986', (203, 212))	('GSTP1', 'Gene', (115, 120))	('rs1050565', 'Mutation', 'rs1050565', (171, 180))	('UGT1A1', 'Gene', (142, 148))	('GSTM1', 'Gene', '2944', (103, 108))	('rs2740574', 'Var', (39, 48))	('rs2740574', 'Mutation', 'rs2740574', (39, 48))	('rs776746', 'Mutation', 'rs776746', (88, 96))	('CYP3A4', 'Gene', '1576', (56, 62))	('rs35599367', 'Mutation', 'rs35599367', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('GSTT1', 'Gene', (129, 134))	('CYP3A4', 'Gene', '1576', (32, 38))	('testicular cancer', 'Disease', 'MESH:D013736', (363, 380))	('CYP3A4', 'Gene', (56, 62))	('UGT1A1', 'Gene', '54658', (142, 148))	('ERCC2', 'Gene', (246, 251))	('ERCC2', 'Gene', (229, 234))	('rs1050565', 'Var', (171, 180))	('rs11615', 'Mutation', 'rs11615', (188, 195))	('ERCC2', 'Gene', (214, 219))	('CYP3A4', 'Gene', (32, 38))	('rs776746', 'Var', (88, 96))	('MDR1', 'Gene', '5243', (266, 270))	('BLMH', 'Gene', (166, 170))	('CYP3A5', 'Gene', '1577', (81, 87))	('ERCC2', 'Gene', '2068', (229, 234))	('ERCC2', 'Gene', '2068', (246, 251))	('ERCC1', 'Gene', '2067', (182, 187))	('ERCC2', 'Gene', '2068', (214, 219))	('CYP3A5', 'Gene', (81, 87))	('testicular cancer', 'Disease', (363, 380))	('rs1695', 'Mutation', 'rs1695', (121, 127))	('rs1045642', 'Mutation', 'rs1045642', (271, 280))	('rs35599367', 'Var', (63, 73))	('GSTM1', 'Gene', (103, 108))	('ERCC1', 'Gene', '2067', (197, 202))	('testicular cancer', 'Phenotype', 'HP:0010788', (363, 380))	('rs13181', 'Mutation', 'rs13181', (220, 227))	('ERCC1', 'Gene', (182, 187))	('rs8175347', 'Mutation', 'rs8175347', (149, 158))	('rs238406', 'Mutation', 'rs238406', (252, 260))	('ADR', 'Gene', (355, 358))	('patients', 'Species', '9606', (381, 389))	('BEP', 'Chemical', '-', (403, 406))	('ADRs', 'Phenotype', 'HP:0020172', (355, 359))	('rs3212986', 'Var', (203, 212))	('ERCC1', 'Gene', (197, 202))	('rs238406', 'Var', (252, 260))	('rs1799793', 'Mutation', 'rs1799793', (235, 244))	('MDR1', 'Gene', (266, 270))
26563	30914949	These results show that ERCC2 rs1799793 A/A genotype was associated with anemia in a recessive model of inheritance, ERCC2 rs13181 T/G and CYP3A4 rs2740574 A/G genotypes were associated with alopecia in a codominant model of inheritance, and ERCC2 rs238406 A/A genotype was associated with leukopenia, both in codominant and recessive models of inheritance.	('associated', 'Reg', (175, 185))	('rs13181', 'Mutation', 'rs13181', (123, 130))	('rs1799793', 'Mutation', 'rs1799793', (30, 39))	('leukopenia', 'Phenotype', 'HP:0001882', (290, 300))	('ERCC2', 'Gene', '2068', (242, 247))	('anemia', 'Phenotype', 'HP:0001903', (73, 79))	('leukopenia', 'Disease', (290, 300))	('rs238406', 'Mutation', 'rs238406', (248, 256))	('anemia', 'Disease', (73, 79))	('ERCC2', 'Gene', (24, 29))	('alopecia', 'Disease', (191, 199))	('rs238406 A/A', 'Var', (248, 260))	('ERCC2', 'Gene', '2068', (24, 29))	('rs2740574 A/G', 'Var', (146, 159))	('rs2740574', 'Mutation', 'rs2740574', (146, 155))	('ERCC2', 'Gene', (117, 122))	('rs1799793 A/A', 'Var', (30, 43))	('CYP3A4', 'Gene', '1576', (139, 145))	('associated', 'Reg', (274, 284))	('ERCC2', 'Gene', '2068', (117, 122))	('anemia', 'Disease', 'MESH:D000740', (73, 79))	('rs13181 T/G', 'Var', (123, 134))	('CYP3A4', 'Gene', (139, 145))	('alopecia', 'Phenotype', 'HP:0001596', (191, 199))	('ERCC2', 'Gene', (242, 247))	('leukopenia', 'Disease', 'MESH:D007970', (290, 300))	('associated', 'Reg', (57, 67))
26564	30914949	GSTT1-null genotype was associated with lymphocytopenia, BLMH rs1050565 G/G genotype was linked with pain in a recessive model of inheritance and GSTP1 rs1695 G/G genotype was associated with infections in a recessive model of inheritance.	('rs1050565', 'Mutation', 'rs1050565', (62, 71))	('associated', 'Reg', (24, 34))	('rs1695', 'Mutation', 'rs1695', (152, 158))	('lymphocytopenia', 'Phenotype', 'HP:0001888', (40, 55))	('pain', 'Disease', 'MESH:D010146', (101, 105))	('infections', 'Disease', 'MESH:D007239', (192, 202))	('GSTP1', 'Gene', (146, 151))	('lymphocytopenia', 'Disease', 'MESH:D008231', (40, 55))	('infections', 'Disease', (192, 202))	('linked', 'Reg', (89, 95))	('BLMH', 'Gene', (57, 61))	('GSTT1', 'Gene', '2952', (0, 5))	('pain', 'Disease', (101, 105))	('GSTT1', 'Gene', (0, 5))	('lymphocytopenia', 'Disease', (40, 55))	('pain', 'Phenotype', 'HP:0012531', (101, 105))	('BLMH', 'Gene', '642', (57, 61))	('rs1050565 G/G', 'Var', (62, 75))	('GSTP1', 'Gene', '2950', (146, 151))
26578	30914949	In the univariate analyses (Table 3), we found interesting association between BLMH rs1050565 G/G genotype and severe pain in patients (OR = 16.73, CI = 1.78-157.15, p-value = 0.014).	('rs1050565', 'Mutation', 'rs1050565', (84, 93))	('pain', 'Phenotype', 'HP:0012531', (118, 122))	('pain', 'Disease', 'MESH:D010146', (118, 122))	('pain', 'Disease', (118, 122))	('BLMH', 'Gene', (79, 83))	('patients', 'Species', '9606', (126, 134))	('BLMH', 'Gene', '642', (79, 83))	('rs1050565 G/G', 'Var', (84, 97))
26580	30914949	Considering that G allele of BLMH leads to the incorporation of 443Val in the enzyme, reducing its biochemical activity, this association supports our finding and high bleomycin plasma levels in patients can be expected.	('high bleomycin plasma levels', 'MPA', (163, 191))	('BLMH', 'Gene', (29, 33))	('443Val', 'Var', (64, 70))	('BLMH', 'Gene', '642', (29, 33))	('bleomycin', 'Chemical', 'MESH:D001761', (168, 177))	('reducing', 'NegReg', (86, 94))	('patients', 'Species', '9606', (195, 203))	('biochemical activity', 'MPA', (99, 119))	('incorporation', 'Var', (47, 60))
26581	30914949	On the other hand, patients with CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia (OR = 6.87, CI = 1.02-46.06, p-value = 0.047).	('patients', 'Species', '9606', (19, 27))	('develop', 'PosReg', (83, 90))	('alopecia', 'Disease', (91, 99))	('CYP3A4', 'Gene', (33, 39))	('rs2740574 A/G', 'Var', (40, 53))	('alopecia', 'Phenotype', 'HP:0001596', (91, 99))	('rs2740574', 'Mutation', 'rs2740574', (40, 49))	('CYP3A4', 'Gene', '1576', (33, 39))
26584	30914949	Cisplatin mainly reacts with N-7 of guanine and adenine to form adducts with the DNA resulting in the formation of intra and inter strands crosslinks, causing potential errors in DNA repair, resulting in accumulation of damaged DNA, and activation of apoptotic pathway in neoplastic and normal cells.	('adducts', 'Interaction', (64, 71))	('apoptotic pathway', 'Pathway', (251, 268))	('DNA repair', 'MPA', (179, 189))	('damaged DNA', 'MPA', (220, 231))	('adenine', 'Chemical', 'MESH:D000225', (48, 55))	('intra', 'Protein', (115, 120))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('N-7', 'Chemical', 'MESH:C106144', (29, 32))	('errors', 'Var', (169, 175))	('guanine', 'Chemical', 'MESH:D006147', (36, 43))	('accumulation', 'PosReg', (204, 216))	('activation', 'PosReg', (237, 247))
26586	30914949	We observed that GSTT1-null genotype is associated with lymphocytopenia (OR = 17.67, CI = 1.23-252.73, p-value = 0.034) and GSTP1 rs1695 G/G genotype is associated with increased infections (OR = 12.25, CI = 1.05-143.09, p-value = 0.046).	('lymphocytopenia', 'Phenotype', 'HP:0001888', (56, 71))	('GSTP1', 'Gene', '2950', (124, 129))	('increased infections', 'Disease', 'MESH:D019586', (169, 189))	('rs1695 G/G', 'Var', (130, 140))	('rs1695', 'Mutation', 'rs1695', (130, 136))	('lymphocytopenia', 'Disease', 'MESH:D008231', (56, 71))	('lymphocytopenia', 'Disease', (56, 71))	('GSTT1', 'Gene', '2952', (17, 22))	('GSTP1', 'Gene', (124, 129))	('GSTT1', 'Gene', (17, 22))	('increased infections', 'Disease', (169, 189))	('increased infections', 'Phenotype', 'HP:0002719', (169, 189))
26587	30914949	Similarly, ERCC2 rs1799793 A/A genotype showed association with anemia (OR = 27.00, CI = 1.68-434.44, p-value = 0.020), ERCC2 rs238406 A/A genotype was associated with leukopenia (OR = 5.5, CI = 1.26-24.10, p-value = 0.024) and ERCC2 rs13181 T/G genotype was linked with alopecia (OR = 10.86, CI = 1.16-101.35, p-value = 0.036), indicating that defects in the metabolism and/or the response to cisplatin could lead to the specific severe ADRs (Table 3).	('ERCC2', 'Gene', (11, 16))	('defects', 'Var', (345, 352))	('rs13181', 'Mutation', 'rs13181', (234, 241))	('ERCC2', 'Gene', '2068', (11, 16))	('metabolism', 'MPA', (360, 370))	('anemia', 'Phenotype', 'HP:0001903', (64, 70))	('ERCC2', 'Gene', (120, 125))	('leukopenia', 'Disease', 'MESH:D007970', (168, 178))	('lead to', 'Reg', (410, 417))	('anemia', 'Disease', (64, 70))	('leukopenia', 'Phenotype', 'HP:0001882', (168, 178))	('ADR', 'Gene', (438, 441))	('ERCC2', 'Gene', '2068', (120, 125))	('leukopenia', 'Disease', (168, 178))	('ADRs', 'Phenotype', 'HP:0020172', (438, 442))	('ADR', 'Gene', '231', (438, 441))	('rs1799793', 'Mutation', 'rs1799793', (17, 26))	('ERCC2', 'Gene', (228, 233))	('rs238406', 'Mutation', 'rs238406', (126, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (394, 403))	('alopecia', 'Phenotype', 'HP:0001596', (271, 279))	('ERCC2', 'Gene', '2068', (228, 233))	('rs238406 A/A', 'Var', (126, 138))	('anemia', 'Disease', 'MESH:D000740', (64, 70))
26588	30914949	This is in agreement with studies that report that G allele of GSTP1 rs1695 has been associated with an increased risk of myelosuppression, polyneuropathy, and toxicity.	('rs1695', 'Mutation', 'rs1695', (69, 75))	('polyneuropathy', 'Disease', 'MESH:D011115', (140, 154))	('GSTP1', 'Gene', (63, 68))	('myelosuppression', 'Disease', 'MESH:D001855', (122, 138))	('polyneuropathy', 'Disease', (140, 154))	('neuropathy', 'Phenotype', 'HP:0009830', (144, 154))	('polyneuropathy', 'Phenotype', 'HP:0001271', (140, 154))	('GSTP1', 'Gene', '2950', (63, 68))	('men', 'Species', '9606', (16, 19))	('myelosuppression', 'Disease', (122, 138))	('rs1695', 'Var', (69, 75))	('toxicity', 'Disease', 'MESH:D064420', (160, 168))	('toxicity', 'Disease', (160, 168))	('associated', 'Reg', (85, 95))
26590	30914949	Studies on GSTM1 and GSTT1 have shown that high expression levels of both enzymes result in a low response to chemotherapy, and deletion of these genes shows high degrees of toxicity.	('GSTM1', 'Gene', (11, 16))	('expression levels', 'MPA', (48, 65))	('toxicity', 'Disease', (174, 182))	('toxicity', 'Disease', 'MESH:D064420', (174, 182))	('GSTT1', 'Gene', (21, 26))	('low response to chemotherapy', 'MPA', (94, 122))	('GSTT1', 'Gene', '2952', (21, 26))	('GSTM1', 'Gene', '2944', (11, 16))	('deletion', 'Var', (128, 136))
26591	30914949	In ovarian cancer patients, severe emesis grades III-IV were associated with GSTT1-null genotype.	('genotype', 'Var', (88, 96))	('GSTT1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('GSTT1', 'Gene', '2952', (77, 82))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('patients', 'Species', '9606', (18, 26))	('emesis', 'Phenotype', 'HP:0002013', (35, 41))	('emesis', 'Disease', 'MESH:D014839', (35, 41))	('emesis', 'Disease', (35, 41))
26592	30914949	In contrast, in patients with GSTM1-null genotype the risk of thrombocytopenia and anemia was lower.	('thrombocytopenia', 'Disease', 'MESH:D013921', (62, 78))	('anemia', 'Disease', 'MESH:D000740', (83, 89))	('anemia', 'Phenotype', 'HP:0001903', (83, 89))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (62, 78))	('patients', 'Species', '9606', (16, 24))	('GSTM1', 'Gene', '2944', (30, 35))	('genotype', 'Var', (41, 49))	('GSTM1', 'Gene', (30, 35))	('lower', 'NegReg', (94, 99))	('thrombocytopenia', 'Disease', (62, 78))	('anemia', 'Disease', (83, 89))
26593	30914949	For GSTP1, the G/G genotype seems to decrease the susceptibility to grade III neuropathy when compared to that in patients with A/G and/or A/A genotypes (recessive model of inheritance) in ovarian cancer.	('decrease', 'NegReg', (37, 45))	('neuropathy', 'Phenotype', 'HP:0009830', (78, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (189, 203))	('GSTP1', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian cancer', 'Disease', 'MESH:D010051', (189, 203))	('III neuropathy', 'Disease', 'MESH:D009422', (74, 88))	('G/G', 'Var', (15, 18))	('III neuropathy', 'Disease', (74, 88))	('patients', 'Species', '9606', (114, 122))	('ovarian cancer', 'Disease', (189, 203))	('GSTP1', 'Gene', '2950', (4, 9))
26610	30914949	Our findings from the univariate analyses suggest that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop grades III-IV alopecia; patients with ERCC2 rs238406 C/C genotype may develop severe leukopenia; and patients with GSTT1-null genotype could develop lymphocytopenia.	('GSTT1', 'Gene', (267, 272))	('lymphocytopenia', 'Phenotype', 'HP:0001888', (301, 316))	('patients', 'Species', '9606', (253, 261))	('alopecia', 'Phenotype', 'HP:0001596', (166, 174))	('lymphocytopenia', 'Disease', 'MESH:D008231', (301, 316))	('develop', 'PosReg', (144, 151))	('rs2740574 A/G', 'Var', (101, 114))	('grades III-IV alopecia', 'Disease', (152, 174))	('rs2740574', 'Mutation', 'rs2740574', (101, 110))	('ERCC2', 'Gene', (190, 195))	('CYP3A4', 'Gene', '1576', (94, 100))	('develop', 'PosReg', (222, 229))	('leukopenia', 'Disease', 'MESH:D007970', (237, 247))	('ERCC2', 'Gene', '2068', (190, 195))	('ERCC2', 'Gene', (69, 74))	('rs238406', 'Mutation', 'rs238406', (196, 204))	('leukopenia', 'Phenotype', 'HP:0001882', (237, 247))	('CYP3A4', 'Gene', (94, 100))	('lymphocytopenia', 'Disease', (301, 316))	('ERCC2', 'Gene', '2068', (69, 74))	('rs13181 T/G', 'Var', (75, 86))	('leukopenia', 'Disease', (237, 247))	('patients', 'Species', '9606', (176, 184))	('GSTT1', 'Gene', '2952', (267, 272))	('rs238406 C/C', 'Var', (196, 208))	('patients', 'Species', '9606', (55, 63))	('rs13181', 'Mutation', 'rs13181', (75, 82))
26611	30914949	Patients with ERCC2 rs1799793 A/A genotype were at higher risk of developing anemia.	('ERCC2', 'Gene', (14, 19))	('anemia', 'Disease', (77, 83))	('rs1799793', 'Mutation', 'rs1799793', (20, 29))	('anemia', 'Disease', 'MESH:D000740', (77, 83))	('Patients', 'Species', '9606', (0, 8))	('rs1799793 A/A', 'Var', (20, 33))	('ERCC2', 'Gene', '2068', (14, 19))	('anemia', 'Phenotype', 'HP:0001903', (77, 83))
26612	30914949	Patients with BLMH rs1050565 G/G genotype experienced severe pain, and patients with GSTP1 G/G genotype were susceptible to severe infections.	('rs1050565 G/G', 'Var', (19, 32))	('susceptible', 'Reg', (109, 120))	('infections', 'Disease', (131, 141))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('severe infections', 'Phenotype', 'HP:0032169', (124, 141))	('GSTP1', 'Gene', (85, 90))	('patients', 'Species', '9606', (71, 79))	('rs1050565', 'Mutation', 'rs1050565', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('GSTP1', 'Gene', '2950', (85, 90))	('BLMH', 'Gene', (14, 18))	('BLMH', 'Gene', '642', (14, 18))	('infections', 'Disease', 'MESH:D007239', (131, 141))	('pain', 'Disease', 'MESH:D010146', (61, 65))	('pain', 'Disease', (61, 65))
26614	30914949	The multivariate analyses showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia.	('ERCC1/2', 'Gene', '2067;2068', (65, 72))	('febrile neutropenia', 'Disease', (164, 183))	('genotypes', 'Var', (73, 82))	('febrile neutropenia', 'Disease', 'MESH:D009503', (164, 183))	('BEP', 'Chemical', '-', (106, 109))	('neutropenia', 'Phenotype', 'HP:0001875', (172, 183))	('leukopenia', 'Phenotype', 'HP:0001882', (146, 156))	('leukopenia', 'Disease', 'MESH:D007970', (146, 156))	('leukopenia', 'Disease', (146, 156))	('ERCC1/2', 'Gene', (65, 72))	('severe', 'Disease', (139, 145))
26798	25756204	Seminoma testicular cancer was defined as ICD-O morphology codes: 9060/3, 9061/3, 9062/3 and 9063/3.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Seminoma testicular cancer', 'Disease', 'MESH:D018239', (0, 26))	('Seminoma testicular cancer', 'Disease', (0, 26))	('9063/3', 'Var', (93, 99))	('testicular cancer', 'Phenotype', 'HP:0010788', (9, 26))
26845	24922532	Prior mutation screening of USP26 demonstrated an association with human male infertility and low testosterone production, but protein localization and expression in the human testis has not been characterized previously.	('testosterone', 'Chemical', 'MESH:D013739', (98, 110))	('association', 'Reg', (50, 61))	('testosterone production', 'MPA', (98, 121))	('mutation', 'Var', (6, 14))	('infertility', 'Phenotype', 'HP:0000789', (78, 89))	('male infertility', 'Disease', 'MESH:D007248', (73, 89))	('low', 'NegReg', (94, 97))	('male infertility', 'Disease', (73, 89))	('human', 'Species', '9606', (170, 175))	('male infertility', 'Phenotype', 'HP:0003251', (73, 89))	('human', 'Species', '9606', (67, 72))	('USP26', 'Gene', (28, 33))	('low testosterone', 'Phenotype', 'HP:0040171', (94, 110))
26859	24922532	Our group and others have described specific mutations in USP26 which are associated with male infertility; however the mechanism of how such mutations modulate testicular function is unknown.	('mutations', 'Var', (45, 54))	('modulate', 'Reg', (152, 160))	('male infertility', 'Disease', 'MESH:D007248', (90, 106))	('infertility', 'Phenotype', 'HP:0000789', (95, 106))	('male infertility', 'Phenotype', 'HP:0003251', (90, 106))	('male infertility', 'Disease', (90, 106))	('USP26', 'Gene', (58, 63))	('associated', 'Reg', (74, 84))
26860	24922532	In one of the most comprehensive single nucleotide polymorphism (SNP) studies based on a genome wide association study and published male infertility genes, 147 SNPs were evaluated and 14 had significant association with male infertility including USP26 (rs35397110).	('infertility', 'Phenotype', 'HP:0000789', (226, 237))	('rs35397110', 'Var', (255, 265))	('male infertility', 'Phenotype', 'HP:0003251', (133, 149))	('male infertility', 'Disease', 'MESH:D007248', (133, 149))	('infertility', 'Phenotype', 'HP:0000789', (138, 149))	('male infertility', 'Disease', (133, 149))	('rs35397110', 'Mutation', 'rs35397110', (255, 265))	('male infertility', 'Phenotype', 'HP:0003251', (221, 237))	('male infertility', 'Disease', (221, 237))	('male infertility', 'Disease', 'MESH:D007248', (221, 237))
26861	24922532	Based on mutational screening-phenotype analysis we hypothesize that USP26 plays a critical role in the regulation of early stages of maturation including mitotic divisions of spermatogonia or migration of primordial germ cells, as mutations in USP26 occur in patients with Sertoli cell only syndrome and early maturation arrest.	('Sertoli cell', 'Phenotype', 'HP:0100619', (274, 286))	('USP26', 'Gene', (245, 250))	('occur', 'Reg', (251, 256))	('Sertoli cell only syndrome', 'Phenotype', 'HP:0100619', (274, 300))	('patients', 'Species', '9606', (260, 268))	('Sertoli cell only syndrome', 'Disease', 'MESH:D054331', (274, 300))	('mutations', 'Var', (232, 241))	('Sertoli cell only syndrome', 'Disease', (274, 300))
26870	24922532	This research study including human and animal tissue, has been approved by Weill Cornell Medical College IRB (IRB 1209013045 and IRB 1202012193 and IRB 0102004794) in accordance with principles of the Declaration of Helsinki.	('human', 'Species', '9606', (30, 35))	('IRB 1209013045', 'Var', (111, 125))	('IRB 1202012193', 'Var', (130, 144))	('IRB 0102004794', 'Var', (149, 163))
26887	24922532	Each 20 ul reaction mixture contained 1x Lightcycler 480 Probes Master Mix (Roche Diagnostics), 1 microL cDNA, UPL probe (200 nmol/l), TBP probe (100 nmol/l), and forward and reverse primers for USP26#79 and TBP or AR#14 and TBP (Roche Diagnostics).	('USP26', 'Var', (195, 200))	('Mix', 'Gene', (71, 74))	('AR', 'Gene', '367', (215, 217))	('TBP', 'Gene', (225, 228))	('TBP', 'Gene', '6908', (225, 228))	('Mix', 'Gene', '83881', (71, 74))	('TBP', 'Gene', (135, 138))	('TBP', 'Gene', (208, 211))	('TBP', 'Gene', '6908', (135, 138))	('TBP', 'Gene', '6908', (208, 211))
26933	24922532	Within human testis, USP26 was expressed in Leydig cells and early spermatogonia, as expected from our previously published mutational analysis showing USP26 mutations associated with infertility and low testosterone in men (Figures 3 and 4) and our murine studies (not shown).	('USP26', 'Gene', (152, 157))	('low', 'NegReg', (200, 203))	('murine', 'Species', '10090', (250, 256))	('associated with', 'Reg', (168, 183))	('human', 'Species', '9606', (7, 12))	('infertility', 'Phenotype', 'HP:0000789', (184, 195))	('infertility', 'Disease', 'MESH:D007247', (184, 195))	('infertility', 'Disease', (184, 195))	('testosterone', 'MPA', (204, 216))	('mutations', 'Var', (158, 167))	('testosterone', 'Chemical', 'MESH:D013739', (204, 216))	('men', 'Species', '9606', (220, 223))	('low testosterone', 'Phenotype', 'HP:0040171', (200, 216))
26947	24922532	For the first time, to our knowledge, colocalization with androgen receptor in human testis has been confirmed in Leydig cells, and early cells of spermatogenesis, as well as in follicular cells of benign and malignant thyroid tissue.	('androgen receptor', 'Gene', '367', (58, 75))	('human', 'Species', '9606', (79, 84))	('androgen receptor', 'Gene', (58, 75))	('colocalization', 'Var', (38, 52))
26949	24922532	Our mutation screening revealed that USP26 mutation is associated with infertility and low testosterone levels.	('mutation', 'Var', (43, 51))	('USP26', 'Gene', (37, 42))	('associated', 'Reg', (55, 65))	('infertility', 'Disease', 'MESH:D007247', (71, 82))	('infertility', 'Phenotype', 'HP:0000789', (71, 82))	('low testosterone', 'Phenotype', 'HP:0040171', (87, 103))	('infertility', 'Disease', (71, 82))	('low', 'NegReg', (87, 90))	('testosterone', 'Chemical', 'MESH:D013739', (91, 103))
26950	24922532	We hypothesize that hypogonadism is secondary and subsequent to aberrations in Leydig cell function and spermatogenesis.	('Leydig cell function', 'CPA', (79, 99))	('spermatogenesis', 'CPA', (104, 119))	('hypogonadism', 'Disease', 'MESH:D007006', (20, 32))	('hypogonadism', 'Phenotype', 'HP:0000135', (20, 32))	('aberrations', 'Var', (64, 75))	('aberrations in Leydig cell', 'Phenotype', 'HP:0010789', (64, 90))	('hypogonadism', 'Disease', (20, 32))
26953	24922532	In prior work by our group, sequence alterations in the USP26 gene were identified in approximately 11% of patients with severe oligospermia and non-obstructive azoospermia but were not identified in fertile controls.	('identified', 'Reg', (72, 82))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (145, 172))	('sequence alterations', 'Var', (28, 48))	('oligospermia', 'Disease', (128, 140))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (145, 172))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (149, 172))	('azoospermia', 'Phenotype', 'HP:0000027', (161, 172))	('non-obstructive azoospermia', 'Disease', (145, 172))	('patients', 'Species', '9606', (107, 115))	('USP26', 'Gene', (56, 61))	('oligospermia', 'Disease', 'MESH:D009845', (128, 140))	('oligospermia', 'Phenotype', 'HP:0000798', (128, 140))
26954	24922532	Patients with USP26 mutations had statistically significant lower testosterone levels (277 ng/dl vs. 405 ng/dl) as well as reduced testicular size (8.5 ml vs 12.4 ml).	('USP26', 'Gene', (14, 19))	('testicular size', 'CPA', (131, 146))	('reduced testicular size', 'Phenotype', 'HP:0008734', (123, 146))	('testosterone', 'Chemical', 'MESH:D013739', (66, 78))	('Patients', 'Species', '9606', (0, 8))	('lower testosterone', 'Phenotype', 'HP:0040171', (60, 78))	('testosterone levels', 'MPA', (66, 85))	('mutations', 'Var', (20, 29))	('reduced', 'NegReg', (123, 130))	('lower', 'NegReg', (60, 65))
26955	24922532	This is noteworthy since particular USP26 mutations were associated with impairment in testosterone possibly due to impaired USPS26-androgen receptor interaction in Leydig cells.	('men', 'Species', '9606', (79, 82))	('androgen receptor', 'Gene', (132, 149))	('impairment', 'NegReg', (73, 83))	('impaired', 'NegReg', (116, 124))	('testosterone', 'MPA', (87, 99))	('USP26', 'Gene', (36, 41))	('testosterone', 'Chemical', 'MESH:D013739', (87, 99))	('androgen receptor', 'Gene', '367', (132, 149))	('interaction', 'Interaction', (150, 161))	('mutations', 'Var', (42, 51))	('associated', 'Reg', (57, 67))
26958	24922532	Confirmation of colocalization of USP26 with AR by immunofluorescence in normal testicular tissue provides the first evidence of this interaction in humans.	('colocalization', 'Var', (16, 30))	('AR', 'Gene', '367', (45, 47))	('humans', 'Species', '9606', (149, 155))	('USP26', 'Gene', (34, 39))
26964	24922532	Small-interfering RNA mediated knockdown of AR coactivators has resulted in marked decreases in androgen-induced bladder cancer cell proliferation.	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('decreases', 'NegReg', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('AR', 'Gene', '367', (44, 46))	('bladder cancer', 'Disease', (113, 127))	('knockdown', 'Var', (31, 40))
26965	24922532	Transfection of GFP-USP26 into HEK293 cells revealed nuclear localization with an accumulation and colocalization with AR in subnuclear foci which is similar to the effect of a specific AR mutation of the DNA-binding domain which confers androgen insensitivity syndrome (AIS) in patients via impaired ligand-dependent nuclear translocation, subnuclear foci formation, and intranuclear mobility of the receptor.	('AR', 'Gene', '367', (186, 188))	('accumulation', 'PosReg', (82, 94))	('AIS', 'Disease', 'OMIM:181800', (271, 274))	('AIS', 'Disease', (271, 274))	('confers', 'Reg', (230, 237))	('ligand-dependent nuclear translocation', 'MPA', (301, 339))	('androgen insensitivity syndrome', 'Disease', (238, 269))	('mutation', 'Var', (189, 197))	('HEK293', 'CellLine', 'CVCL:0045', (31, 37))	('AR', 'Gene', '367', (119, 121))	('patients', 'Species', '9606', (279, 287))	('nuclear localization', 'MPA', (53, 73))	('AIS', 'Phenotype', 'HP:0008226', (271, 274))	('androgen insensitivity syndrome', 'Phenotype', 'HP:0008226', (238, 269))	('impaired', 'NegReg', (292, 300))	('subnuclear foci formation', 'CPA', (341, 366))
26978	24922532	There is a significantly increased testicular germ cell tumor risk among men with shortened AR CAG repeat length which leads to increased AR transactivation that may be involved in seminoma development or progression of CIS/ITGCN to seminoma.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('AR', 'Gene', '367', (92, 94))	('seminoma', 'Disease', (181, 189))	('increased testicular', 'Phenotype', 'HP:0000053', (25, 45))	('involved', 'Reg', (169, 177))	('CAG', 'Protein', (95, 98))	('testicular', 'Disease', (35, 45))	('seminoma', 'Disease', 'MESH:D018239', (181, 189))	('men', 'Species', '9606', (73, 76))	('AR', 'Gene', '367', (138, 140))	('tumor', 'Disease', (56, 61))	('men', 'Species', '9606', (197, 200))	('seminoma', 'Disease', (233, 241))	('germ cell tumor', 'Phenotype', 'HP:0100728', (46, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('seminoma', 'Disease', 'MESH:D018239', (233, 241))	('increased', 'PosReg', (25, 34))	('increased', 'PosReg', (128, 137))	('shortened', 'Var', (82, 91))
26984	24922532	Several nuclear receptor interaction motifs (L2, L3, F2) were identified in USP26 to result in severely diminished binding to AR when mutated.	('AR', 'Gene', '367', (126, 128))	('mutated', 'Var', (134, 141))	('binding', 'Interaction', (115, 122))	('diminished', 'NegReg', (104, 114))
26989	24922532	Colocalization of USP26 with AR has been identified in benign and malignant breast and thyroid tissue as well.	('identified', 'Reg', (41, 51))	('AR', 'Gene', '367', (29, 31))	('benign', 'Disease', (55, 61))	('thyroid', 'Disease', (87, 94))	('USP26', 'Gene', (18, 23))	('Colocalization', 'Var', (0, 14))
27043	19549888	Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility.	('modify', 'Reg', (47, 53))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('adrenal tumor', 'Disease', (207, 220))	('Inactivating', 'NegReg', (117, 129))	('implicated', 'Reg', (193, 203))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('adrenal tumor', 'Phenotype', 'HP:0100631', (207, 220))	('PDE11A', 'Gene', (175, 181))	('germ cell tumors', 'Phenotype', 'HP:0100728', (100, 116))	('adrenal tumor', 'Disease', 'MESH:D000310', (207, 220))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('germ cell tumor', 'Phenotype', 'HP:0100728', (100, 115))	('phosphodiesterase 11A', 'Gene', '50940', (11, 32))	('phosphodiesterase 11A', 'Gene', '50940', (152, 173))	('phosphodiesterase 11A', 'Gene', (11, 32))	('phosphodiesterase 11A', 'Gene', (152, 173))
27046	19549888	We identified 8 non-synonymous substitutions in 20 patients from 15 families: four (R52T; F258Y; G291R; V820M) were newly-recognized, three (R804H; R867G; M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('R804H', 'Mutation', 'rs75127279', (141, 146))	('G291R', 'Mutation', 'rs767064669', (97, 102))	('adrenal tumor', 'Disease', 'MESH:D000310', (212, 225))	('F258Y', 'Mutation', 'rs1438588949', (90, 95))	('R52T; F258Y; G291R; V820M', 'Var', (84, 109))	('Y727C', 'Mutation', 'rs17400325', (251, 256))	('adrenal tumor', 'Phenotype', 'HP:0100631', (212, 225))	('R804H; R867G; M878V', 'Var', (141, 160))	('R867G', 'Mutation', 'rs61306957', (148, 153))	('M878V', 'Mutation', 'rs74357545', (155, 160))	('R52T', 'Mutation', 'rs77972073', (84, 88))	('patients', 'Species', '9606', (51, 59))	('V820M', 'Var', (104, 109))	('V820M', 'Mutation', 'rs140269105', (104, 109))	('adrenal tumor', 'Disease', (212, 225))
27047	19549888	We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously-reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls.	('R867G', 'Var', (205, 210))	('R804H', 'Var', (195, 200))	('endocrine diseases', 'Disease', 'MESH:D004700', (132, 150))	('R804H', 'Mutation', 'rs75127279', (195, 200))	('patients', 'Species', '9606', (51, 59))	('endocrine diseases', 'Disease', (132, 150))	('R867G', 'Mutation', 'rs61306957', (205, 210))
27048	19549888	The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P=0.0002), present in 19% of the families of our cohort.	('PDE11A-gene', 'Gene', (21, 32))	('patients', 'Species', '9606', (84, 92))	('higher', 'Reg', (71, 77))	('variants', 'Var', (33, 41))	('TGCT', 'Disease', (98, 102))
27049	19549888	Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers.	('mutations', 'Var', (100, 109))	('decreased', 'NegReg', (171, 180))	('reduced', 'NegReg', (110, 117))	('TGCT', 'Disease', (196, 200))	('PDE', 'Gene', '501', (141, 144))	('protein', 'Protein', (148, 155))	('PDE', 'Gene', '501', (118, 121))	('PDE', 'Gene', (141, 144))	('expression', 'Species', '29278', (156, 166))	('PDE', 'Gene', (118, 121))	('expression', 'MPA', (156, 166))	('activity', 'MPA', (122, 130))
27055	19549888	Several lines of evidence suggested that PDE11A might be a candidate gene for TGCT: 1) we have observed high expression of the PDE11A4 isoform in human testes; testicular tissue was also the only tissue to express all four known isoforms of PDE11A; 2) non-germ cell testicular tumors have been linked to genetic aberrations of the cAMP signaling pathway, including somatic activating mutations of the G-stimulatory subunit of the G-protein (GNAS1) in Leydig cell hyperplasia and tumors and in McCune-Albright syndrome, and germline inactivating PRKAR1A mutations are responsible for large cell calcifying Sertoli cell tumors (LCCSCT) in the context of Carney complex; and 3) male-limited infertility has been reported in the Pde11a-/- mouse, and is a known risk factor for TGCTs in humans.	('tumors', 'Phenotype', 'HP:0002664', (618, 624))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (605, 624))	('Leydig cell hyperplasia', 'Phenotype', 'HP:0010791', (451, 474))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('GNAS1', 'Gene', '2778', (441, 446))	('tumor', 'Phenotype', 'HP:0002664', (618, 623))	('expression', 'Species', '29278', (109, 119))	('infertility', 'Disease', (688, 699))	('cell tumors', 'Disease', (613, 624))	('GNAS1', 'Gene', (441, 446))	('Leydig cell hyperplasia and tumors', 'Disease', 'MESH:D007984', (451, 485))	('cell tumors', 'Disease', 'MESH:D005935', (613, 624))	('testicular tumors', 'Disease', (266, 283))	('responsible', 'Reg', (567, 578))	('PRKAR1A', 'Gene', (545, 552))	('mutations', 'Var', (553, 562))	('infertility', 'Disease', 'MESH:D007247', (688, 699))	('mouse', 'Species', '10090', (735, 740))	('tumor', 'Phenotype', 'HP:0002664', (479, 484))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (493, 517))	('humans', 'Species', '9606', (782, 788))	('cAMP', 'Chemical', 'MESH:D000242', (331, 335))	('human', 'Species', '9606', (782, 787))	('tumors', 'Phenotype', 'HP:0002664', (479, 485))	('testicular tumors', 'Phenotype', 'HP:0010788', (266, 283))	('infertility', 'Phenotype', 'HP:0000789', (688, 699))	('testicular tumors', 'Disease', 'MESH:D013736', (266, 283))	('McCune-Albright syndrome', 'Disease', (493, 517))	('human', 'Species', '9606', (146, 151))	('PRKAR1A', 'Gene', '5573', (545, 552))	('male-limited infertility', 'Phenotype', 'HP:0003251', (675, 699))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
27058	19549888	Our data suggest that germline PDE11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cell tumors', 'Disease', (110, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('PDE11A', 'Gene', (31, 37))	('cell tumors', 'Disease', 'MESH:D005935', (110, 121))	('modify', 'Reg', (52, 58))	('germ cell tumors', 'Phenotype', 'HP:0100728', (105, 121))	('mutations', 'Var', (38, 47))	('germ cell tumor', 'Phenotype', 'HP:0100728', (105, 120))
27062	19549888	The identified variants were compared with those found in three different control groups: 192 individuals specifically examined at Hopital Cochin, Paris, France, who were selected because they had no clinical or imaging evidence for any endocrine tumors (designated the "endo-negative" group) plus a negative family history of endocrine disorders; 95 unselected individuals negative for the most common adult diseases from the Coriell Institute database (the "Coriell" group); and, finally, 745 unselected healthy individuals enrolled in the New York Cancer Project (NYCP), who were already genotyped for the 5 PDE11A variants that we published previously (c.171Tdel/fs41X, R307X, c.1655_1657TCTdelCCins/fs15X, R804H and R867G).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('endocrine disorders', 'Disease', 'MESH:D004700', (327, 346))	('endocrine disorders', 'Phenotype', 'HP:0000818', (327, 346))	('c.1655_1657TCTdelCCins/fs15X', 'Var', (681, 709))	('Cancer', 'Phenotype', 'HP:0002664', (551, 557))	('c.171Tdel', 'Mutation', 'c.del171', (657, 666))	('R804H', 'Mutation', 'rs75127279', (711, 716))	('endocrine disorders', 'Disease', (327, 346))	('R307X', 'Var', (674, 679))	('endocrine tumors', 'Disease', 'MESH:D004701', (237, 253))	('R804H', 'Var', (711, 716))	('endocrine tumors', 'Disease', (237, 253))	('Cancer', 'Disease', (551, 557))	('c.171Tdel/fs41X', 'Var', (657, 672))	('R867G', 'Mutation', 'rs61306957', (721, 726))	('R867G', 'Var', (721, 726))	('R307X', 'Mutation', 'rs76308115', (674, 679))	('Cancer', 'Disease', 'MESH:D009369', (551, 557))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))
27063	19549888	For transfection experiments, the PDE11A ORF was cloned into pCR3.1, and the missense mutations (R52T, F258Y, G291R, A349T, D609N, Y727C, V820M and M878V were introduced by overlapping PCR, as previously described.	('M878V', 'Var', (148, 153))	('D609N', 'Var', (124, 129))	('G291R', 'Var', (110, 115))	('F258Y', 'Mutation', 'rs1438588949', (103, 108))	('G291R', 'Mutation', 'rs767064669', (110, 115))	('D609N', 'Mutation', 'rs77934668', (124, 129))	('R52T', 'Mutation', 'rs77972073', (97, 101))	('R52T', 'Var', (97, 101))	('Y727C', 'Mutation', 'rs17400325', (131, 136))	('M878V', 'Mutation', 'rs74357545', (148, 153))	('F258Y', 'Var', (103, 108))	('V820M', 'Var', (138, 143))	('men', 'Species', '9606', (23, 26))	('Y727C', 'Var', (131, 136))	('A349T', 'Mutation', 'rs77477862', (117, 122))	('V820M', 'Mutation', 'rs140269105', (138, 143))	('A349T', 'Var', (117, 122))
27066	19549888	Cells were transfected with 6 microg of plasmid DNA expressing either the wild type (WT) or the mutated form of PDE11A, harvested 48 hr after the transfection, and subjected to cAMP level and PDE activity assays.	('mutated', 'Var', (96, 103))	('PDE', 'Gene', (112, 115))	('PDE', 'Gene', (192, 195))	('cAMP', 'Chemical', 'MESH:D000242', (177, 181))	('PDE', 'Gene', '501', (112, 115))	('PDE', 'Gene', '501', (192, 195))
27072	19549888	Missense changes F258Y and G291R were encountered only among TGCT patients; they were not detected in the 1,032 individuals from any of the three control groups.	('TGCT', 'Disease', (61, 65))	('F258Y', 'Var', (17, 22))	('G291R', 'Var', (27, 32))	('G291R', 'Mutation', 'rs767064669', (27, 32))	('patients', 'Species', '9606', (66, 74))	('F258Y', 'Mutation', 'rs1438588949', (17, 22))
27073	19549888	The two previously-identified terminating mutations (c.171Tdel/FS41X and c.1655_1657del/insFS15X) were found in the newly-studied Coriell control panel, and all three known PDE11A nonsense mutations were present in the NYCP controls, as previously published.	('c.1655_1657del/insFS15X', 'Var', (73, 96))	('c.1655_1657del', 'Mutation', 'c.1655_1657del', (73, 87))	('c.171Tdel/FS41X', 'Var', (53, 68))	('c.171Tdel', 'Mutation', 'c.del171', (53, 62))	('PDE11A', 'Gene', (173, 179))
27074	19549888	We first compared the combined frequency of PDE11A sequence variants in the TGCT patients with the three control groups.	('variants', 'Var', (60, 68))	('TGCT', 'Disease', (76, 80))	('PDE11A', 'Gene', (44, 50))	('patients', 'Species', '9606', (81, 89))
27075	19549888	A higher prevalence of missense and nonsense mutations was observed in the TGCT patients compared with both the endo-negative and Coriell controls, but the difference reached statistical significance only for the first group (P=0.0002).	('patients', 'Species', '9606', (80, 88))	('TGCT', 'Disease', (75, 79))	('nonsense mutations', 'Var', (36, 54))	('missense', 'Var', (23, 31))
27076	19549888	When compared with the NYCP controls, all identified variants were seen with similar prevalence and were only slightly more frequent among the TGCT patients (see Table 1).	('TGCT', 'Disease', (143, 147))	('patients', 'Species', '9606', (148, 156))	('variants', 'Var', (53, 61))
27077	19549888	Analyzed individually, only two mutations - the novel substitutions F258Y and G291R - showed significant differences between the TGCT patients and each of the three control groups, Notably, both F258Y and G291R reside in the longest coding exon of PDE11A (exon 3), expressed only in the PDE11A4 isoform that is most common in steroidogenic tissues.	('F258Y', 'Var', (68, 73))	('F258Y', 'Var', (195, 200))	('G291R', 'Var', (205, 210))	('patients', 'Species', '9606', (134, 142))	('G291R', 'Var', (78, 83))	('G291R', 'Mutation', 'rs767064669', (205, 210))	('G291R', 'Mutation', 'rs767064669', (78, 83))	('F258Y', 'Mutation', 'rs1438588949', (195, 200))	('PDE11A', 'Gene', (248, 254))	('F258Y', 'Mutation', 'rs1438588949', (68, 73))
27078	19549888	A third novel substitution (R52T) was detected in the same exon; the combined frequency of these three PDE11A4-specific mutations was substantially greater among the TGCT cases compared with each of the control groups, as well as all controls combined (P=0.0005, OR12.96; 95%CI, 2.87-58.54).	('R52T', 'Mutation', 'rs77972073', (28, 32))	('PDE11A4-specific', 'Gene', (103, 119))	('greater', 'PosReg', (148, 155))	('TGCT', 'Disease', (166, 170))	('mutations', 'Var', (120, 129))
27079	19549888	Splice variants and synonymous substitutions showed similar frequency in all studied groups, with two exceptions: the known polymorphism C230C and the splice variant c.1072-3c/t were found more often in patients with TGCT than in the endo-negative controls.	('c.1072-3c/t', 'Mutation', 'rs13012088', (166, 177))	('TGCT', 'Disease', (217, 221))	('C230C', 'Var', (137, 142))	('patients', 'Species', '9606', (203, 211))	('c.1072-3c/t', 'Var', (166, 177))
27080	19549888	Transfection experiments in HEK293 and MLTC-1 cells with expression vectors harboring the substitutions R52T, F258Y, G291R, A349T, D609N, Y727C (the latter tested only in MLTC-1 cells), V820M and M878V were conducted along with the R804H and R867G for which we previously demonstrated impaired PDE11A function.	('MLTC-1', 'CellLine', 'CVCL:3544', (171, 177))	('men', 'Species', '9606', (19, 22))	('V820M', 'Var', (186, 191))	('V820M', 'Mutation', 'rs140269105', (186, 191))	('M878V', 'Mutation', 'rs74357545', (196, 201))	('D609N', 'Mutation', 'rs77934668', (131, 136))	('R52T', 'Mutation', 'rs77972073', (104, 108))	('R52T', 'Var', (104, 108))	('expression vectors', 'Species', '29278', (57, 75))	('R804H', 'Mutation', 'rs75127279', (232, 237))	('F258Y', 'Mutation', 'rs1438588949', (110, 115))	('HEK293', 'CellLine', 'CVCL:0045', (28, 34))	('G291R', 'Var', (117, 122))	('F258Y', 'Var', (110, 115))	('M878V', 'Var', (196, 201))	('G291R', 'Mutation', 'rs767064669', (117, 122))	('MLTC-1', 'CellLine', 'CVCL:3544', (39, 45))	('A349T', 'Var', (124, 129))	('Y727C', 'Var', (138, 143))	('Y727C', 'Mutation', 'rs17400325', (138, 143))	('A349T', 'Mutation', 'rs77477862', (124, 129))	('R867G', 'Mutation', 'rs61306957', (242, 247))	('D609N', 'Var', (131, 136))
27081	19549888	Higher (relative to the WT) cAMP levels were measured in both tumore cell lines for all PDE11A missense mutations, indicating an a reduced ability of the variant PDE11A proteins to degrade cAMP (Figure 1A and C).	('ability', 'MPA', (139, 146))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('missense mutations', 'Var', (95, 113))	('tumor', 'Disease', (62, 67))	('reduced', 'NegReg', (131, 138))	('variant', 'Var', (154, 161))	('degrade cAMP', 'MPA', (181, 193))	('cAMP', 'Chemical', 'MESH:D000242', (189, 193))	('cAMP', 'Chemical', 'MESH:D000242', (28, 32))	('PDE11A', 'Gene', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
27084	19549888	In general, the presence of TGCT and the family mutation were concordant: 17 of 21 (81%) of TGCT patients were heterozygous for a missense mutation.	('TGCT', 'Gene', (92, 96))	('missense mutation', 'Var', (130, 147))	('patients', 'Species', '9606', (97, 105))
27085	19549888	In one family (Family 1), R804H was independently transmitted from two unrelated family branches and was present in three of the four available for analysis male individuals (individuals #05, #11 and #14): two of these patients had TCGT, and the one who did not have the disease (#14) was 18 years old at the time of his investigation.	('TCGT', 'Disease', (232, 236))	('R804H', 'Var', (26, 31))	('R804H', 'Mutation', 'rs75127279', (26, 31))	('patients', 'Species', '9606', (219, 227))
27087	19549888	IHC in tumor tissue from 4 patients with TGCT who carried a PDE11A mutation showed very low or no PDE11A protein expression in tumor cells compared with surrounding normal testicular tissue (Figure 3, panels A-D: representative stained sections from an M878V-related tumor).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('expression', 'MPA', (113, 123))	('mutation', 'Var', (67, 75))	('M878V', 'Mutation', 'rs74357545', (253, 258))	('tumor', 'Disease', (7, 12))	('PDE11A', 'Gene', (60, 66))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('PDE11A', 'Gene', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('expression', 'Species', '29278', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
27090	19549888	There was strong but not perfect concordance between the presence of a tumor and the presence of a mutation.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutation', 'Var', (99, 107))
27091	19549888	Transfection experiments demonstrated that each of the missense mutations resulted in lower levels of PDE and higher levels of cAMP.	('PDE', 'Gene', (102, 105))	('PDE', 'Gene', '501', (102, 105))	('lower', 'NegReg', (86, 91))	('cAMP', 'Chemical', 'MESH:D000242', (127, 131))	('missense mutations', 'Var', (55, 73))	('men', 'Species', '9606', (19, 22))	('higher', 'PosReg', (110, 116))	('cAMP', 'MPA', (127, 131))
27092	19549888	The mutations had a greater impact in a murine testicular Leydig cell tumor (MLTC-1) cell line known to be cAMP-responsive.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('MLTC-1', 'CellLine', 'CVCL:3544', (77, 83))	('Leydig cell tumor', 'Disease', (58, 75))	('murine', 'Species', '10090', (40, 46))	('Leydig cell tumor', 'Disease', 'MESH:D007984', (58, 75))	('Leydig cell tumor', 'Phenotype', 'HP:0100618', (58, 75))	('mutations', 'Var', (4, 13))	('cAMP', 'Chemical', 'MESH:D000242', (107, 111))
27094	19549888	Finally, there was a suggestion that cancer-free family members who carried these mutations manifested non-malignant GU abnormalities that have been associated with increased risk of TGCT, as well as diverse non-testicular cancers.	('cancers', 'Disease', (223, 230))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('testicular cancers', 'Phenotype', 'HP:0010788', (212, 230))	('GU abnormalities', 'Phenotype', 'HP:0000119', (117, 133))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('malignant GU abnormalities', 'Phenotype', 'HP:0006758', (107, 133))	('cancer', 'Disease', (37, 43))	('TGCT', 'Disease', (183, 187))	('associated', 'Reg', (149, 159))	('mutations', 'Var', (82, 91))	('testicular cancer', 'Phenotype', 'HP:0010788', (212, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (223, 229))	('cancers', 'Disease', 'MESH:D009369', (223, 230))
27097	19549888	Since this and previous studies clearly demonstrated that the mutant variants alter PDE function, their presence may produce compensatory changes in other members of the PDE family and/or additional factors that regulate cAMP levels and PKA activity, thereby offering a possible explanation for their reduced penetrance.	('cAMP', 'Chemical', 'MESH:D000242', (221, 225))	('alter', 'Reg', (78, 83))	('PDE', 'Gene', (170, 173))	('PDE', 'Gene', '501', (84, 87))	('variants', 'Var', (69, 77))	('PDE', 'Gene', (84, 87))	('cAMP levels', 'MPA', (221, 232))	('PDE', 'Gene', '501', (170, 173))	('changes', 'Reg', (138, 145))	('function', 'MPA', (88, 96))	('mutant variants', 'Var', (62, 77))
27098	19549888	The comparison between PDE11A variants associated with testicular and adrenocortical tumors showed a similar frequency distribution (Supplementary Table 2).	('variants', 'Var', (30, 38))	('adrenocortical tumors', 'Disease', (70, 91))	('testicular', 'Disease', (55, 65))	('PDE11A', 'Gene', (23, 29))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (70, 91))	('men', 'Species', '9606', (139, 142))	('associated', 'Reg', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
27099	19549888	It is tempting to speculate that other cAMP-sensitive tissues would also be possible targets of a PDE defect.	('defect', 'Var', (102, 108))	('PDE', 'Gene', (98, 101))	('PDE', 'Gene', '501', (98, 101))	('cAMP', 'Chemical', 'MESH:D000242', (39, 43))
27100	19549888	It is noteworthy, that different classes of PDE11A gene variants have variable distributions between the multiple "control" groups in this study: nonsense mutations were absent among the 192 individuals in whom endocrine neoplasms were aggressively sought and excluded, while they were detected in our other two control groups from the general population (see Supplemental Table 1).	('neoplasms', 'Phenotype', 'HP:0002664', (221, 230))	('endocrine neoplasms', 'Disease', (211, 230))	('PDE11A', 'Gene', (44, 50))	('endocrine neoplasms', 'Disease', 'MESH:D004701', (211, 230))	('variants', 'Var', (56, 64))	('absent', 'NegReg', (170, 176))	('endocrine neoplasms', 'Phenotype', 'HP:0100568', (211, 230))	('men', 'Species', '9606', (366, 369))
27139	19718320	Mutation in the SLC34A2 gene (Chr 4p15) is found to be seen in patients with pulmonary alveolar microliths.	('SLC34A2', 'Gene', '10568', (16, 23))	('Mutation', 'Var', (0, 8))	('pulmonary alveolar microliths', 'Disease', 'MESH:D011649', (77, 106))	('SLC34A2', 'Gene', (16, 23))	('pulmonary alveolar microliths', 'Disease', (77, 106))	('patients', 'Species', '9606', (63, 71))
27140	19718320	Male patients with this mutation are found to have testicular microliths as well.	('testicular microliths', 'Phenotype', 'HP:0012215', (51, 72))	('testicular microliths', 'Disease', (51, 72))	('patients', 'Species', '9606', (5, 13))	('mutation', 'Var', (24, 32))
27179	19718320	Limited cases of testicular biopsy in patients with infertility and TM revealed microliths in 30-40% of the seminiferous tubules with obstruction of the tubular lumen, increased cytoplasmic swelling, vacuolization and atrophy of seminiferous epithelium.	('increased', 'PosReg', (168, 177))	('infertility', 'Disease', 'MESH:D007247', (52, 63))	('men', 'Species', '9606', (163, 166))	('atrophy', 'Disease', 'MESH:D001284', (218, 225))	('vacuolization', 'CPA', (200, 213))	('infertility', 'Phenotype', 'HP:0000789', (52, 63))	('infertility', 'Disease', (52, 63))	('atrophy', 'Disease', (218, 225))	('cytoplasmic swelling', 'CPA', (178, 198))	('patients', 'Species', '9606', (38, 46))	('microliths', 'Var', (80, 90))
27249	33139720	Preclinical studies using in vivo mouse model with implanted EnzR1-C4-2 cells also demonstrated that Cis plus Enz therapy resulted in better suppression of EnzR CRPC progression than Enz treatment alone.	('Cis', 'Var', (101, 104))	('Enz', 'Chemical', 'MESH:C540278', (61, 64))	('suppression', 'NegReg', (141, 152))	('mouse', 'Species', '10090', (34, 39))	('Enz', 'Chemical', 'MESH:C540278', (110, 113))	('Enz', 'Chemical', 'MESH:C540278', (183, 186))	('Enz', 'Chemical', 'MESH:C540278', (156, 159))	('men', 'Species', '9606', (192, 195))	('EnzR CRPC', 'Disease', (156, 165))
27256	33139720	Clinical studies indicated the failure of ADT with Enz (ADT-Enz) treatment might be linked to the AR splicing variant ARv7, a process that involves the splicing of full-length AR pre-mRNA and altering the RNA splicing pattern.	('Enz', 'Chemical', 'MESH:C540278', (60, 63))	('AR splicing variant', 'Var', (98, 117))	('altering', 'Reg', (192, 200))	('ADT', 'Chemical', '-', (56, 59))	('ADT', 'Chemical', '-', (42, 45))	('men', 'Species', '9606', (70, 73))	('RNA splicing pattern', 'MPA', (205, 225))	('Enz', 'Chemical', 'MESH:C540278', (51, 54))	('ARv7', 'Gene', (118, 122))	('ADT-Enz', 'Chemical', '-', (56, 63))
27257	33139720	While other mechanistic studies also indicated that the development of Enz-resistance could also be due to Glucocorticoid receptor (GR) activation, AR gain, ligand binding domain mutations, or alternative AR variants, the emergence of the ARv7 splice variant remains the most interesting explanation, supported by clear and strong evidence from human clinical sample surveys.	('gain', 'PosReg', (151, 155))	('Enz', 'Chemical', 'MESH:C540278', (71, 74))	('men', 'Species', '9606', (63, 66))	('Glucocorticoid receptor', 'Gene', '2908', (107, 130))	('human', 'Species', '9606', (345, 350))	('GR', 'Gene', '2908', (132, 134))	('activation', 'PosReg', (136, 146))	('variants', 'Var', (208, 216))	('Glucocorticoid receptor', 'Gene', (107, 130))
27288	33139720	We then added different doses of Cis to this EnzR1_C4-2 cell line and found Cis could degrade ARv7 (and full-length AR, fAR) at the protein level (Fig.	('degrade', 'NegReg', (86, 93))	('Cis', 'Var', (76, 79))	('Enz', 'Chemical', 'MESH:C540278', (45, 48))
27293	33139720	1a-g suggest that Cis and Carboplatin may degrade ARv7 and AR mutants of AR-F876L at low doses that have minimal effects on the induction of apoptosis in multiple EnzR CRPC cells.	('AR-F876L', 'Gene', (73, 81))	('F876L', 'Mutation', 'p.F876L', (76, 81))	('mutants', 'Var', (62, 69))	('degrade', 'NegReg', (42, 49))	('Carboplatin', 'Chemical', 'MESH:D016190', (26, 37))	('Enz', 'Chemical', 'MESH:C540278', (163, 166))	('ARv7', 'Gene', (50, 54))
27304	33139720	In addition to restoring the Enz sensitivity to further suppress the EnzR cell proliferation, we were interested to see if Cis-degraded ARv7 can also delay the development of Enz-resistance in the CRPC cells treated with Enz.	('ARv7', 'Gene', (136, 140))	('delay', 'NegReg', (150, 155))	('Enz', 'Chemical', 'MESH:C540278', (175, 178))	('Enz', 'Chemical', 'MESH:C540278', (69, 72))	('Enz', 'Chemical', 'MESH:C540278', (221, 224))	('Cis-degraded', 'Var', (123, 135))	('development of Enz-resistance', 'MPA', (160, 189))	('men', 'Species', '9606', (167, 170))	('Enz', 'Chemical', 'MESH:C540278', (29, 32))
27336	33139720	6b), the tumor growth rate showed the EnzR3_CW22Rv1 xenograft tumor growth could be significantly suppressed by Cis + Enz as compared with control, Enz, and Cis single treatment group (Fig.	('suppressed', 'NegReg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('CW22Rv1', 'CellLine', 'CVCL:1045', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Cis + Enz', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (62, 67))	('EnzR3_CW22Rv1', 'Var', (38, 51))	('men', 'Species', '9606', (173, 176))	('Enz', 'Chemical', 'MESH:C540278', (38, 41))	('tumor', 'Disease', (9, 14))	('Enz', 'Chemical', 'MESH:C540278', (148, 151))	('Enz', 'Chemical', 'MESH:C540278', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
27339	33139720	S6-S7), and ARv7 IHC stainings are lower in Cis and Cis+Enz groups (Fig.	('ARv7', 'Gene', (12, 16))	('lower', 'NegReg', (35, 40))	('Cis+Enz', 'Var', (52, 59))	('Enz', 'Chemical', 'MESH:C540278', (56, 59))
27344	33139720	Early clinical data revealed that 3 of 29 CRPC patients receiving ARN509 treatment had the AR-F876L mutant.	('F876L', 'Mutation', 'p.F876L', (94, 99))	('patients', 'Species', '9606', (47, 55))	('ARN509', 'Chemical', 'MESH:C572045', (66, 72))	('men', 'Species', '9606', (78, 81))	('CRPC', 'Disease', (42, 46))	('AR-F876L', 'Var', (91, 99))
27345	33139720	further confirmed these findings by showing that AR-F876L could convert Enz into an AR agonist and reverse the growth inhibition of Enz treatment.	('men', 'Species', '9606', (141, 144))	('AR-F876L', 'Var', (49, 57))	('Enz', 'Chemical', 'MESH:C540278', (72, 75))	('Enz', 'Chemical', 'MESH:C540278', (132, 135))	('growth inhibition', 'MPA', (111, 128))	('F876L', 'Mutation', 'p.F876L', (52, 57))
27346	33139720	Enz might also increase the glucocorticoid receptor (GR) signals in a subset of PCa cells due to relief of AR-mediated feedback repression of GR expression.	('relief', 'NegReg', (97, 103))	('glucocorticoid receptor', 'Gene', (28, 51))	('Enz', 'Chemical', 'MESH:C540278', (0, 3))	('GR', 'Gene', '2908', (142, 144))	('increase', 'PosReg', (15, 23))	('GR', 'Gene', '2908', (53, 55))	('Enz', 'Var', (0, 3))	('glucocorticoid receptor', 'Gene', '2908', (28, 51))
27349	33139720	However, the emergence of the AR splicing variant ARv7 may represent the key factor for the development of Enz-resistance as recent clinical studies from CRPC patients demonstrated that 39% of metastatic CRPC patients treated with Enz had detectable ARv7 in their circulating tumor cells, and these ARv7 positive patients had lower PSA response rates than ARv7 negative patients with shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months), suggesting CRPC patients with ARv7 might have poor response to Enz treatment, and Enz treatment might enhance ARv7 expression.	('men', 'Species', '9606', (550, 553))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('expression', 'MPA', (574, 584))	('Enz', 'Chemical', 'MESH:C540278', (107, 110))	('patients', 'Species', '9606', (475, 483))	('Enz', 'Chemical', 'MESH:C540278', (541, 544))	('men', 'Species', '9606', (531, 534))	('patients', 'Species', '9606', (370, 378))	('enhance', 'PosReg', (561, 568))	('patients', 'Species', '9606', (313, 321))	('Enz', 'Chemical', 'MESH:C540278', (231, 234))	('lower', 'NegReg', (326, 331))	('Enz', 'Chemical', 'MESH:C540278', (522, 525))	('tumor', 'Disease', (276, 281))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('ARv7', 'Gene', (569, 573))	('ARv7', 'Var', (489, 493))	('men', 'Species', '9606', (99, 102))
27352	33139720	Importantly, ASC-J9 , but not the anti-androgens Enz or Casodex, could degrade both full-length AR and the AR variant ARv7 or AR mutants including AR-F876L.	('degrade', 'NegReg', (71, 78))	('Casodex', 'Chemical', 'MESH:C053541', (56, 63))	('AR-F876L', 'Var', (147, 155))	('Enz', 'Chemical', 'MESH:C540278', (49, 52))	('F876L', 'Mutation', 'p.F876L', (150, 155))	('ARv7', 'Gene', (118, 122))
27355	33139720	The microRNA (miR), miR-124, has recently been identified as a tumor suppressor to suppress the PCa progression, and miR-124 could also suppress ARv7 along with EZH2 and Src signals.	('tumor', 'Disease', (63, 68))	('EZH2', 'Gene', '2146', (161, 165))	('EZH2', 'Gene', (161, 165))	('Src', 'Gene', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR-124', 'Var', (117, 124))	('ARv7', 'Gene', (145, 149))	('Src', 'Gene', '6714', (170, 173))	('suppress', 'NegReg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PCa progression', 'CPA', (96, 111))	('suppress', 'NegReg', (83, 91))
27362	33139720	The potential adverse effects of Cis treatment include myelosuppression, asthenia and gastrointestinal disorders, as well as long-term cardiac, renal and neurological consequences, which may result in its discontinuation and limit its therapeutic efficacy.	('asthenia', 'Phenotype', 'HP:0025406', (73, 81))	('men', 'Species', '9606', (42, 45))	('gastrointestinal disorders', 'Phenotype', 'HP:0011024', (86, 112))	('discontinuation', 'NegReg', (205, 220))	('Cis', 'Var', (33, 36))	('asthenia', 'Disease', 'MESH:D001247', (73, 81))	('limit', 'NegReg', (225, 230))	('myelosuppression', 'Disease', 'MESH:D001855', (55, 71))	('gastrointestinal disorders', 'Disease', 'MESH:D005767', (86, 112))	('gastrointestinal disorders', 'Disease', (86, 112))	('myelosuppression', 'Disease', (55, 71))	('asthenia', 'Disease', (73, 81))
27391	29499525	Unsilenced supernumerical X-chromosomes have been reported in TGCT patients and men with TGCT have been observed to confer a four-fold increased risk of TGCT to their sons as opposed to an eight-fold increased risk to their brothers.	('patients', 'Species', '9606', (67, 75))	('TGCT', 'Disease', (62, 66))	('Unsilenced supernumerical X-chromosomes', 'Var', (0, 39))	('men', 'Species', '9606', (80, 83))	('TGCT', 'Disease', (153, 157))
27410	24603304	We have established DNMT3B or POU5F1 (hereafter referred to as OCT4) knockdown in teratocarcinoma stem cells N2102Ep and TERA1 and in the pluripotent NTERA2 by a doxycycline-inducible system, and tested the cytotoxicity induced by Aza-dC.	('OCT4', 'Gene', (63, 67))	('teratocarcinoma', 'Disease', (82, 97))	('doxycycline', 'Chemical', 'MESH:D004318', (162, 173))	('cytotoxicity', 'Disease', 'MESH:D064420', (207, 219))	('POU5F1', 'Gene', '5460', (30, 36))	('NTERA2', 'CellLine', 'CVCL:0034', (150, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('teratocarcinoma', 'Disease', 'MESH:D018243', (82, 97))	('tested', 'Reg', (196, 202))	('Aza-dC', 'Chemical', '-', (231, 237))	('DNMT3B', 'Gene', (20, 26))	('POU5F1', 'Gene', (30, 36))	('cytotoxicity', 'Disease', (207, 219))	('knockdown', 'Var', (69, 78))	('OCT4', 'Gene', '5460', (63, 67))
27411	24603304	Silencing of DNMT3B led to apoptosis of human teratocarcinoma stem cells N2102Ep and TERA1.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('teratocarcinoma', 'Disease', 'MESH:D018243', (46, 61))	('apoptosis', 'CPA', (27, 36))	('teratocarcinoma', 'Disease', (46, 61))	('DNMT3B', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('human', 'Species', '9606', (40, 45))
27412	24603304	Further, we found that induction of apoptosis or differentiation in NTERA2 and human embryonic stem cells by Aza-dC requires DNMT3B.	('human', 'Species', '9606', (79, 84))	('differentiation', 'CPA', (49, 64))	('apoptosis', 'CPA', (36, 45))	('NTERA2', 'CellLine', 'CVCL:0034', (68, 74))	('Aza-dC', 'Chemical', '-', (109, 115))	('Aza-dC', 'Var', (109, 115))
27414	24603304	Treatment with Aza-dC reduced cell number of differentiated cells to a lesser extent than their undifferentiated parental stem cells.	('Aza-dC', 'Chemical', '-', (15, 21))	('cell number of differentiated cells', 'CPA', (30, 65))	('reduced', 'NegReg', (22, 29))	('men', 'Species', '9606', (5, 8))	('Aza-dC', 'Var', (15, 21))
27416	24603304	Our finding suggests that DNMT3B acts as an antiapoptotic gene in teratocarcinoma stem cells, and mediates apoptosis and differentiation of human pluripotent stem cells induced by Aza-dC, and that Aza-dC specifically induces apoptosis of teratocarcinoma stem cells.	('Aza-dC', 'Chemical', '-', (180, 186))	('apoptosis', 'CPA', (225, 234))	('differentiation', 'CPA', (121, 136))	('teratocarcinoma', 'Disease', 'MESH:D018243', (66, 81))	('human', 'Species', '9606', (140, 145))	('teratocarcinoma', 'Disease', 'MESH:D018243', (238, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('induces', 'Reg', (217, 224))	('teratocarcinoma', 'Disease', (66, 81))	('DNMT3B', 'Gene', (26, 32))	('Aza-dC', 'Chemical', '-', (197, 203))	('teratocarcinoma', 'Disease', (238, 253))	('apoptosis', 'CPA', (107, 116))	('Aza-dC', 'Var', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))
27419	24603304	However, in some cases, these tumours may be composed entirely of EC cells, without any differentiated cell components, whereas many cell lines such as N2102Ep and TERA1 derived from testicular GCTs also appear to be composed of EC cells that have lost the ability to differentiate.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('EC', 'Phenotype', 'HP:0002898', (229, 231))	('tumours', 'Disease', (30, 37))	('GCT', 'Phenotype', 'HP:0100728', (194, 197))	('EC', 'Phenotype', 'HP:0002898', (66, 68))	('N2102Ep', 'Var', (152, 159))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
27422	24603304	Nevertheless, nullipotent EC cells can be induced to differentiate following genetic manipulation to knockdown expression of OCT4.	('OCT4', 'Gene', (125, 129))	('EC', 'Phenotype', 'HP:0002898', (26, 28))	('OCT4', 'Gene', '5460', (125, 129))	('knockdown', 'Var', (101, 110))
27436	24603304	However, DNMT3B knockdown did not induce apoptosis in pluripotent NTERA2 and ES cells, but did attenuate apoptosis or differentiation induced by Aza-dC in NTERA2 and ES cells, suggesting that DNMT3B is required for apoptosis or differentiation induced by Aza-dC.	('attenuate', 'NegReg', (95, 104))	('Aza-dC', 'Chemical', '-', (145, 151))	('apoptosis', 'CPA', (105, 114))	('differentiation', 'CPA', (118, 133))	('knockdown', 'Var', (16, 25))	('NTERA2', 'CellLine', 'CVCL:0034', (66, 72))	('DNMT3B', 'Var', (9, 15))	('Aza-dC', 'Chemical', '-', (255, 261))	('NTERA2', 'CellLine', 'CVCL:0034', (155, 161))
27437	24603304	However, when N2102Ep and TERA1 were caused to differentiate by a knockdown of POU5F1 (hereafter referred to as OCT4) Aza-dC-induced apoptosis was antagonised.	('Aza-dC', 'Chemical', '-', (118, 124))	('N2102Ep', 'Var', (14, 21))	('OCT4', 'Gene', '5460', (112, 116))	('OCT4', 'Gene', (112, 116))	('POU5F1', 'Gene', '5460', (79, 85))	('knockdown', 'Var', (66, 75))	('POU5F1', 'Gene', (79, 85))
27438	24603304	Our studies suggest differential roles of DNMT3B in nullipotent and pluripotent stem cells, and highlight an evidence of cancer stem cells, but not their differentiated derivatives, which undergo apoptosis induced by the epigenetic drug.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('DNMT3B', 'Gene', (42, 48))	('cancer', 'Disease', (121, 127))	('epigenetic drug', 'Var', (221, 236))
27468	24603304	Next, we performed cloning-efficiency assay to determine whether DNMT3B might facilitate clonal propagation of teratocarcinoma stem cells.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('teratocarcinoma', 'Disease', 'MESH:D018243', (111, 126))	('DNMT3B', 'Var', (65, 71))	('teratocarcinoma', 'Disease', (111, 126))	('facilitate', 'PosReg', (78, 88))
27469	24603304	The clonal ability test reveals that silencing of DNMT3B led to a reduction of cloning efficiency of EC cells N2102Ep and TERA1 (Figure 1B), suggesting a role of DNMT3B in clonal propagation of the cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('EC', 'Phenotype', 'HP:0002898', (101, 103))	('cancer', 'Disease', (198, 204))	('DNMT3B', 'Gene', (50, 56))	('silencing', 'Var', (37, 46))	('cloning efficiency', 'CPA', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('reduction', 'NegReg', (66, 75))
27470	24603304	Similarly, DNMT3B knockdown also reduced clonal ability of human pluripotent stem cells NTERA2 and H7 (Figure 1B).	('clonal ability', 'CPA', (41, 55))	('knockdown', 'Var', (18, 27))	('human', 'Species', '9606', (59, 64))	('NTERA2', 'CellLine', 'CVCL:0034', (88, 94))	('reduced', 'NegReg', (33, 40))	('DNMT3B', 'Gene', (11, 17))
27471	24603304	DNMT has been proposed to mediate DNA mutagenicity and hence cellular cytotoxicity induced by Aza-dC through a covalent trapping mechanism between Aza-dC-incorporated DNA adduct and the methyltransferase.	('Aza-dC', 'Chemical', '-', (94, 100))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('DNA', 'MPA', (34, 37))	('covalent trapping', 'MPA', (111, 128))	('Aza-dC', 'Var', (94, 100))	('rat', 'Species', '10116', (161, 164))	('DNMT', 'Gene', '1786', (0, 4))	('cytotoxicity', 'Disease', (70, 82))	('DNMT', 'Gene', (0, 4))	('Aza-dC', 'Chemical', '-', (147, 153))
27472	24603304	To define whether Aza-dC treatment might diminish colony survival, and whether DNMT3B might mediate the cytotoxic effect in human nullipotent EC cells, N2102Ep and TERA1, and human pluripotent stem cells NTERA2 and H7, DNMT3B expression was silenced for 3 days, and the cells were subsequently treated with Aza-dC.	('human', 'Species', '9606', (175, 180))	('DNMT3B', 'Gene', (79, 85))	('silenced', 'NegReg', (241, 249))	('NTERA2', 'CellLine', 'CVCL:0034', (204, 210))	('colony survival', 'CPA', (50, 65))	('Aza-dC', 'Chemical', '-', (18, 24))	('Aza-dC', 'Chemical', '-', (307, 313))	('EC', 'Phenotype', 'HP:0002898', (142, 144))	('human', 'Species', '9606', (124, 129))	('Aza-dC', 'Var', (18, 24))	('DNMT3B', 'Gene', (219, 225))	('men', 'Species', '9606', (30, 33))	('diminish', 'NegReg', (41, 49))
27473	24603304	The result shows that Aza-dC treatment reduced cloning efficiency of the stem cells to a greater extent than the DNMT3B knockdown (Figure 1B).	('Aza-dC', 'Chemical', '-', (22, 28))	('reduced', 'NegReg', (39, 46))	('cloning efficiency of the stem cells', 'CPA', (47, 83))	('Aza-dC', 'Var', (22, 28))	('men', 'Species', '9606', (34, 37))
27475	24603304	Next, apoptosis assay using a double staining of Annexin V together with the stem cell marker SSEA3 was employed to elucidate whether silencing of DNMT3B induces apoptosis of human nullipotent stem cells N2102Ep and TERA1 and pluripotent stem cells NTERA2 and H7.	('human', 'Species', '9606', (175, 180))	('induces', 'Reg', (154, 161))	('NTERA2', 'CellLine', 'CVCL:0034', (249, 255))	('silencing', 'Var', (134, 143))	('DNMT3B', 'Gene', (147, 153))	('apoptosis', 'CPA', (162, 171))
27476	24603304	Upon DNMT3B silencing, population numbers of SSEA3+/Annexin V+, of which represents 'apoptotic stem cells', in Dox-treated N2102Ep and TERA1 were two-fold increased approximately in comparison with the controls (Figure 2A and B).	('increased', 'PosReg', (155, 164))	('DNMT3B', 'Gene', (5, 11))	('SSEA3+/Annexin V+', 'Protein', (45, 62))	('Dox', 'Chemical', 'MESH:D004318', (111, 114))	('silencing', 'Var', (12, 21))
27478	24603304	These results suggest that DNMT3B might prevent apoptosis in the human nullipotent EC cells N2102Ep and TERA1, but not in pluripotent NTERA2 and human ES cells.	('human', 'Species', '9606', (65, 70))	('EC', 'Phenotype', 'HP:0002898', (83, 85))	('human', 'Species', '9606', (145, 150))	('NTERA2', 'CellLine', 'CVCL:0034', (134, 140))	('DNMT3B', 'Var', (27, 33))	('apoptosis', 'CPA', (48, 57))	('prevent', 'NegReg', (40, 47))
27479	24603304	We found that Aza-dC treatment led to an increase in the numbers of SSEA3+/Annexin V+ population in N2102Ep, TERA1, NTERA2 and H7 (Figure 2), suggesting that the apoptotic effect of Aza-dC on the stem cells is a general feature as in mouse ES cells.	('Aza-dC', 'Chemical', '-', (14, 20))	('mouse', 'Species', '10090', (234, 239))	('NTERA2', 'CellLine', 'CVCL:0034', (116, 122))	('Aza-dC', 'Var', (14, 20))	('apoptotic', 'CPA', (162, 171))	('men', 'Species', '9606', (26, 29))	('SSEA3+/Annexin V+ population', 'MPA', (68, 96))	('N2102Ep', 'Var', (100, 107))	('Aza-dC', 'Chemical', '-', (182, 188))	('increase', 'PosReg', (41, 49))
27480	24603304	We also observed that in pluripotent NTERA2 cells treated with Aza-dC, a further depletion of DNMT3B by shRNAi resulted in a reduction in the SSEA3+/Annexin V+ population compared with cells treated with Aza-dC alone (Figure 3A).	('reduction', 'NegReg', (125, 134))	('NTERA2', 'CellLine', 'CVCL:0034', (37, 43))	('Aza-dC', 'Chemical', '-', (63, 69))	('DNMT3B', 'Gene', (94, 100))	('Aza-dC', 'Chemical', '-', (204, 210))	('Aza-dC', 'Var', (63, 69))	('SSEA3+/Annexin V+ population', 'MPA', (142, 170))	('shRNAi', 'Gene', (104, 110))	('depletion', 'MPA', (81, 90))
27482	24603304	These results suggest that DNMT3B mediates an induction of apoptosis induced by Aza-dC in the pluripotent stem cells NTERA2 but not in N2102Ep, TERA1 and human ES cells.	('human', 'Species', '9606', (154, 159))	('Aza-dC', 'Chemical', '-', (80, 86))	('DNMT3B', 'Var', (27, 33))	('apoptosis', 'CPA', (59, 68))	('NTERA2', 'CellLine', 'CVCL:0034', (117, 123))	('Aza-dC', 'Var', (80, 86))
27483	24603304	As Aza-dC has been originally reported to induce cellular differentiation, we next asked whether Aza-dC might induce differentiation of human teratocarcinoma stem cells N2102Ep and TERA1 and pluripotent stem cells NTERA2 and H7.	('human', 'Species', '9606', (136, 141))	('differentiation', 'CPA', (117, 132))	('teratocarcinoma', 'Disease', 'MESH:D018243', (142, 157))	('Aza-dC', 'Chemical', '-', (97, 103))	('teratocarcinoma', 'Disease', (142, 157))	('induce', 'PosReg', (110, 116))	('Aza-dC', 'Var', (97, 103))	('Aza-dC', 'Chemical', '-', (3, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('NTERA2', 'CellLine', 'CVCL:0034', (214, 220))
27484	24603304	Treatment with Aza-dC resulted in an increase in numbers of SSEA3-/Annexin V- cells, of which represents 'non-apoptotic differentiated cells', in pluripotent NTERA2 and H7 (Figure 3).	('SSEA3-/Annexin V- cells', 'Protein', (60, 83))	('NTERA2', 'CellLine', 'CVCL:0034', (158, 164))	('Aza-dC', 'Chemical', '-', (15, 21))	('pluripotent NTERA2', 'MPA', (146, 164))	('increase', 'PosReg', (37, 45))	('men', 'Species', '9606', (5, 8))	('Aza-dC', 'Var', (15, 21))
27485	24603304	On the other hand, the numbers of SSEA3-/Annexin V- cells in N2102Ep and TERA1 were not increased by Aza-dC treatment (Figure 2A and B).	('N2102Ep', 'Var', (61, 68))	('Aza-dC', 'Chemical', '-', (101, 107))	('men', 'Species', '9606', (113, 116))	('Aza-dC', 'Var', (101, 107))	('SSEA3-/Annexin V-', 'Protein', (34, 51))
27486	24603304	This result indicates that Aza-dC induces differentiation of pluripotent NTERA2 and H7 cells.	('differentiation', 'CPA', (42, 57))	('NTERA2', 'CellLine', 'CVCL:0034', (73, 79))	('Aza-dC', 'Var', (27, 33))	('pluripotent', 'MPA', (61, 72))	('Aza-dC', 'Chemical', '-', (27, 33))
27487	24603304	To establish whether DNMT3B mediates differentiation of pluripotent NTERA2 and H7 induced by Aza-dC, we treated the cells with Aza-dC in the absence or presence of DNMT3B silencing.	('Aza-dC', 'Chemical', '-', (93, 99))	('NTERA2', 'CellLine', 'CVCL:0034', (68, 74))	('pluripotent', 'MPA', (56, 67))	('silencing', 'Var', (171, 180))	('Aza-dC', 'Chemical', '-', (127, 133))
27490	24603304	This result suggests that DNMT3B mediates an induction of differentiation induced by Aza-dC in human ES cells but not in pluripotent stem cells NTERA2.	('Aza-dC', 'Var', (85, 91))	('DNMT3B', 'Var', (26, 32))	('differentiation', 'CPA', (58, 73))	('human', 'Species', '9606', (95, 100))	('NTERA2', 'CellLine', 'CVCL:0034', (144, 150))	('Aza-dC', 'Chemical', '-', (85, 91))
27491	24603304	Consistent with flow cytometry analysis, we found that Aza-dC treatment led to a reduction of the expression level of stem cell-associated genes OCT4, NANOG and SOX2 in pluripotent NTERA2 and H7 ES cells (Figure 4).	('Aza-dC', 'Chemical', '-', (55, 61))	('H7 ES', 'CellLine', 'CVCL:0I14', (192, 197))	('OCT4', 'Gene', '5460', (145, 149))	('OCT4', 'Gene', (145, 149))	('NANOG', 'Gene', '79923', (151, 156))	('men', 'Species', '9606', (67, 70))	('NTERA2', 'CellLine', 'CVCL:0034', (181, 187))	('NANOG', 'Gene', (151, 156))	('Aza-dC', 'Var', (55, 61))	('reduction', 'NegReg', (81, 90))	('expression level', 'MPA', (98, 114))	('SOX2', 'Gene', (161, 165))	('SOX2', 'Gene', '6657', (161, 165))
27493	24603304	Further, silencing of DNMT3B in Aza-dC-treated NTERA2 and H7 resulted in a higher expression of OCT4, NANOG and SOX2 compared with cells treated with Aza-dC alone.	('OCT4', 'Gene', (96, 100))	('NTERA2', 'Gene', (47, 53))	('NANOG', 'Gene', '79923', (102, 107))	('NTERA2', 'CellLine', 'CVCL:0034', (47, 53))	('expression', 'MPA', (82, 92))	('silencing', 'Var', (9, 18))	('higher', 'PosReg', (75, 81))	('DNMT3B', 'Gene', (22, 28))	('NANOG', 'Gene', (102, 107))	('Aza-dC', 'Chemical', '-', (32, 38))	('Aza-dC', 'Chemical', '-', (150, 156))	('SOX2', 'Gene', '6657', (112, 116))	('SOX2', 'Gene', (112, 116))	('OCT4', 'Gene', '5460', (96, 100))
27494	24603304	This result indicates that DNMT3B might also mediate downregulation of OCT4, NANOG and SOX2 in pluripotent NTERA2 and H7 ES cells induced by Aza-dC.	('SOX2', 'Gene', '6657', (87, 91))	('Aza-dC', 'Chemical', '-', (141, 147))	('NANOG', 'Gene', '79923', (77, 82))	('NANOG', 'Gene', (77, 82))	('SOX2', 'Gene', (87, 91))	('downregulation', 'NegReg', (53, 67))	('H7 ES', 'CellLine', 'CVCL:0I14', (118, 123))	('Aza-dC', 'Var', (141, 147))	('DNMT3B', 'Var', (27, 33))	('OCT4', 'Gene', '5460', (71, 75))	('OCT4', 'Gene', (71, 75))	('NTERA2', 'CellLine', 'CVCL:0034', (107, 113))	('pluripotent', 'MPA', (95, 106))
27495	24603304	Although many human EC cell lines fail to differentiate after manipulation of culture conditions, we have previously shown that N2102Ep and TERA1 do differentiate following knockdown of OCT4 using siRNA.	('OCT4', 'Gene', '5460', (186, 190))	('differentiate', 'Reg', (149, 162))	('human', 'Species', '9606', (14, 19))	('knockdown', 'Var', (173, 182))	('OCT4', 'Gene', (186, 190))	('EC', 'Phenotype', 'HP:0002898', (20, 22))
27497	24603304	Consistent with the previous works, the inducible OCT4 knockdown N2102Ep and TERA1 by shRNAi showed an upregulation of genes representing trophoblastic and endodermal lineages, indicating their differentiation (Figure 5B).	('genes', 'MPA', (119, 124))	('upregulation', 'PosReg', (103, 115))	('OCT4', 'Gene', '5460', (50, 54))	('trophoblastic', 'CPA', (138, 151))	('OCT4', 'Gene', (50, 54))	('N2102Ep', 'Var', (65, 72))
27500	24603304	This result indicates that the cancer stem cells are more sensitive to Aza-dC than their differentiated derivatives.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Aza-dC', 'Chemical', '-', (71, 77))	('sensitive', 'MPA', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('Aza-dC', 'Var', (71, 77))	('cancer', 'Disease', (31, 37))
27501	24603304	Flow cytometric analysis reveals that silencing of OCT4 gave rise to more Annexin V+ cells (Figure 2C and D), suggesting that OCT4 might inhibit apoptosis of nullipotent EC cells.	('apoptosis', 'CPA', (145, 154))	('Annexin V+', 'Protein', (74, 84))	('EC', 'Phenotype', 'HP:0002898', (170, 172))	('OCT4', 'Gene', (126, 130))	('inhibit', 'NegReg', (137, 144))	('OCT4', 'Gene', '5460', (126, 130))	('more', 'PosReg', (69, 73))	('OCT4', 'Gene', '5460', (51, 55))	('silencing', 'Var', (38, 47))	('OCT4', 'Gene', (51, 55))
27502	24603304	We found that expression of DNMT3B was diminished by silencing of OCT4 (Figure 5A) supporting the role of DNMT3B in preventing apoptosis in N2102Ep and TERA1 (Figure 2A and B).	('OCT4', 'Gene', (66, 70))	('diminished', 'NegReg', (39, 49))	('N2102Ep', 'Var', (140, 147))	('apoptosis', 'CPA', (127, 136))	('preventing', 'NegReg', (116, 126))	('expression', 'MPA', (14, 24))	('silencing', 'Var', (53, 62))	('DNMT3B', 'Gene', (28, 34))	('OCT4', 'Gene', '5460', (66, 70))
27503	24603304	Next, upon Aza-dC treatment we compared the level of Annexin V+ cells of the stem cells and their OCT4 knockdown differentiated cells to ascertain whether Aza-dC is able to induce apoptosis of the differentiated cancer cells.	('Aza-dC', 'Chemical', '-', (155, 161))	('cancer', 'Disease', (212, 218))	('Aza-dC', 'Var', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('OCT4', 'Gene', '5460', (98, 102))	('men', 'Species', '9606', (23, 26))	('OCT4', 'Gene', (98, 102))	('apoptosis', 'CPA', (180, 189))	('Aza-dC', 'Chemical', '-', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
27505	24603304	This result suggests that the apoptotic response induced by Aza-dC is specific to undifferentiated stem cells.	('Aza-dC', 'Var', (60, 66))	('apoptotic response', 'CPA', (30, 48))	('Aza-dC', 'Chemical', '-', (60, 66))
27509	24603304	DNMT3B is also necessary to prevent apoptosis in EC cells N2102Ep and TERA1, but not in pluripotent NTERA2 and ES cells (Figure 2A and B and Figure 3A and B).	('EC', 'Phenotype', 'HP:0002898', (49, 51))	('apoptosis', 'CPA', (36, 45))	('N2102Ep', 'Var', (58, 65))	('DNMT3B', 'Var', (0, 6))	('NTERA2', 'CellLine', 'CVCL:0034', (100, 106))
27511	24603304	Similar to our finding, knockdown of DNMT3L, which is another DNA methyltransferase without the catalytic activity, induces two-fold increase of numbers of apoptotic cells in human EC cells.	('human', 'Species', '9606', (175, 180))	('increase of numbers of apoptotic cells', 'Phenotype', 'HP:0030887', (133, 171))	('increase', 'PosReg', (133, 141))	('EC', 'Phenotype', 'HP:0002898', (181, 183))	('DNMT3L', 'Gene', (37, 43))	('knockdown', 'Var', (24, 33))	('DNMT3L', 'Gene', '29947', (37, 43))
27513	24603304	We find that Aza-dC induces apoptosis of nullipotent EC cells (N2102Ep and TERA1) as well as pluripotent EC and ES cells (NTERA2 and H7).	('Aza-dC', 'Var', (13, 19))	('EC', 'Phenotype', 'HP:0002898', (53, 55))	('NTERA2', 'CellLine', 'CVCL:0034', (122, 128))	('EC', 'Phenotype', 'HP:0002898', (105, 107))	('apoptosis', 'CPA', (28, 37))	('Aza-dC', 'Chemical', '-', (13, 19))
27514	24603304	Our result supports a recent study, which shows that Aza-dC treatment at the concentration of 10 nM is enough to attenuate clonal ability and to induce apoptosis of NTERA2.	('men', 'Species', '9606', (65, 68))	('NTERA2', 'Gene', (165, 171))	('rat', 'Species', '10116', (84, 87))	('Aza-dC', 'Chemical', '-', (53, 59))	('induce', 'PosReg', (145, 151))	('NTERA2', 'CellLine', 'CVCL:0034', (165, 171))	('clonal ability', 'CPA', (123, 137))	('apoptosis', 'CPA', (152, 161))	('Aza-dC', 'Var', (53, 59))	('attenuate', 'NegReg', (113, 122))
27516	24603304	We show that Aza-dC induces not only apoptosis, but also differentiation of pluripotent NTERA2 and H7 (Figure 3A and B).	('NTERA2', 'CellLine', 'CVCL:0034', (88, 94))	('apoptosis', 'CPA', (37, 46))	('Aza-dC', 'Var', (13, 19))	('induces', 'Reg', (20, 27))	('differentiation', 'CPA', (57, 72))	('Aza-dC', 'Chemical', '-', (13, 19))
27517	24603304	Our results suggest that the epigenetic drug Aza-dC alters fates of pluripotent stem cells by driving these cells toward differentiation and apoptosis.	('differentiation', 'CPA', (121, 136))	('fates of pluripotent stem cells', 'MPA', (59, 90))	('Aza-dC', 'Var', (45, 51))	('alters', 'Reg', (52, 58))	('driving', 'PosReg', (94, 101))	('apoptosis', 'CPA', (141, 150))	('Aza-dC', 'Chemical', '-', (45, 51))
27518	24603304	We show in this study that DNMT3B mediates apoptosis induced by Aza-dC in pluripotent NTERA2 (Figure 3A), whereas it mediates downregulation of SSEA3 expression induced by Aza-dC in pluripotent H7 ES cells (Figure 3B).	('expression', 'MPA', (150, 160))	('Aza-dC', 'Var', (64, 70))	('downregulation', 'NegReg', (126, 140))	('apoptosis', 'CPA', (43, 52))	('H7 ES', 'CellLine', 'CVCL:0I14', (194, 199))	('NTERA2', 'CellLine', 'CVCL:0034', (86, 92))	('DNMT3B', 'Var', (27, 33))	('Aza-dC', 'Chemical', '-', (64, 70))	('pluripotent NTERA2', 'MPA', (74, 92))	('Aza-dC', 'Chemical', '-', (172, 178))	('SSEA3', 'Gene', (144, 149))
27519	24603304	Nonetheless, DNMT3B has a role in Aza-dC-induced downregulation of OCT4, NANOG and SOX2 expression in both NTERA2 and H7 (Figure 4).	('SOX2', 'Gene', (83, 87))	('SOX2', 'Gene', '6657', (83, 87))	('DNMT3B', 'Var', (13, 19))	('expression', 'MPA', (88, 98))	('OCT4', 'Gene', '5460', (67, 71))	('OCT4', 'Gene', (67, 71))	('Aza-dC', 'Chemical', '-', (34, 40))	('downregulation', 'NegReg', (49, 63))	('NTERA2', 'CellLine', 'CVCL:0034', (107, 113))	('NANOG', 'Gene', '79923', (73, 78))	('NANOG', 'Gene', (73, 78))
27520	24603304	Our results support previous findings that DNMT3B mediates the effects of Aza-dC to induce apoptosis in mouse ES cells and human pluripotent stem cells NTERA2.	('DNMT3B', 'Var', (43, 49))	('NTERA2', 'CellLine', 'CVCL:0034', (152, 158))	('apoptosis', 'CPA', (91, 100))	('human', 'Species', '9606', (123, 128))	('mouse', 'Species', '10090', (104, 109))	('Aza-dC', 'Chemical', '-', (74, 80))	('induce', 'PosReg', (84, 90))
27521	24603304	In contrast to the pluripotent stem cells, as DNMT3B is important to prevent apoptosis of N2102Ep and TERA1 (Figure 2A and B), knockdown of DNMT3B in the nullipotent N2102Ep and TERA1 might not allow the nullipotent EC cells to encounter the apoptotic effect of Aza-dC.	('EC', 'Phenotype', 'HP:0002898', (216, 218))	('knockdown', 'Var', (127, 136))	('Aza-dC', 'Chemical', '-', (262, 268))	('DNMT3B', 'Var', (140, 146))
27523	24603304	A mechanism underlying cytotoxicity induced by Aza-dC has been proposed to occur through a covalent trapping of DNA methyltransferases, which then induces DNA mutagenicity.	('cytotoxicity', 'Disease', (23, 35))	('Aza-dC', 'Var', (47, 53))	('induces', 'Reg', (147, 154))	('DNA mutagenicity', 'MPA', (155, 171))	('cytotoxicity', 'Disease', 'MESH:D064420', (23, 35))	('Aza-dC', 'Chemical', '-', (47, 53))
27527	24603304	We show that silencing of OCT4 led to apoptosis of N2102Ep and TERA1 (Figure 2C and D).	('apoptosis', 'CPA', (38, 47))	('OCT4', 'Gene', '5460', (26, 30))	('N2102Ep', 'Var', (51, 58))	('OCT4', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
27528	24603304	Because somatic cells respond poorly to Aza-dC compared with teratocarcinoma stem cells, we induced differentiation of N2102Ep and TERA1 using shRNAi-inducible OCT4 knockdown, and found that differentiated OCT4 knockdown cells respond poorly to the epigenetic drug Aza-dC (Figure 2C and D).	('N2102Ep', 'Var', (119, 126))	('OCT4', 'Gene', '5460', (160, 164))	('OCT4', 'Gene', (160, 164))	('teratocarcinoma', 'Disease', 'MESH:D018243', (61, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Aza-dC', 'Chemical', '-', (40, 46))	('teratocarcinoma', 'Disease', (61, 76))	('OCT4', 'Gene', '5460', (206, 210))	('OCT4', 'Gene', (206, 210))	('Aza-dC', 'Chemical', '-', (265, 271))
27566	31354629	GSTM3 is a critical GSTs variant and previous evidences showed that GSTM3 polymorphism is associated with an increased risk to develope a cancer.	('cancer', 'Disease', (138, 144))	('GSTs', 'Gene', '373156', (20, 24))	('GSTs', 'Gene', (20, 24))	('GSTM3', 'Gene', (0, 5))	('associated', 'Reg', (90, 100))	('GSTM3', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('GSTM3', 'Gene', '2947', (0, 5))	('GSTM3', 'Gene', '2947', (68, 73))	('polymorphism', 'Var', (74, 86))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
27567	31354629	A lot of studies previously investigated the association of GSTM3 gene polymorphism with the risk to develop a lung cancer.	('association', 'Interaction', (45, 56))	('GSTM3', 'Gene', (60, 65))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('GSTM3', 'Gene', '2947', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('polymorphism', 'Var', (71, 83))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
27570	31354629	The GSTM3 gene is polymorphic and GSTM3 polymorphisms control the enzyme activity by the modulation of substrate binding.	('control', 'Reg', (54, 61))	('polymorphisms', 'Var', (40, 53))	('activity', 'MPA', (73, 81))	('substrate binding', 'Interaction', (103, 120))	('modulation', 'Reg', (89, 99))	('GSTM3', 'Gene', (4, 9))	('enzyme', 'Enzyme', (66, 72))	('GSTM3', 'Gene', (34, 39))	('GSTM3', 'Gene', '2947', (34, 39))	('GSTM3', 'Gene', '2947', (4, 9))
27571	31354629	In particular, the study published in 2009, performed on a large population of patients who survived TGCT, reported that GSTP1 genotype influences the risk of developing a TGCT.	('influences', 'Reg', (136, 146))	('TGCT', 'Disease', (172, 176))	('genotype', 'Var', (127, 135))	('GSTP1', 'Gene', (121, 126))	('patients', 'Species', '9606', (79, 87))	('GSTP1', 'Gene', '2950', (121, 126))
27572	31354629	M3 and P1 polymorphisms of GSTM3 represent promising markers for predicting the risk of TGTC formation.	('TGTC formation', 'Disease', (88, 102))	('GSTM3', 'Gene', '2947', (27, 32))	('polymorphisms', 'Var', (10, 23))	('TGTC', 'Chemical', '-', (88, 92))	('GSTM3', 'Gene', (27, 32))
27586	31354629	The modulation of CDK10 expression in colorectal cancer indicates that CDK10 is involved in cell growth and it is associated with a reduction in chemosensitivity.	('CDK10', 'Gene', '8558', (71, 76))	('modulation', 'Var', (4, 14))	('CDK10', 'Gene', (71, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('reduction', 'NegReg', (132, 141))	('colorectal cancer', 'Disease', (38, 55))	('chemosensitivity', 'CPA', (145, 161))	('CDK10', 'Gene', '8558', (18, 23))	('CDK10', 'Gene', (18, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('involved', 'Reg', (80, 88))
27590	31354629	Some of these proteins are testis specific: Y177 encoded-like protein 4, cytokeratins, glutamine synthetase, and StAR-related lipid transfer protein 7 (StarD7).	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('StarD7', 'Gene', (152, 158))	('glutamine synthetase', 'Gene', (87, 107))	('StarD7', 'Gene', '56910', (152, 158))	('glutamine synthetase', 'Gene', '2752', (87, 107))	('Y177', 'Var', (44, 48))
27597	31354629	The loss of StarD7 might induce cancer development.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('induce', 'Reg', (25, 31))	('cancer', 'Disease', (32, 38))	('StarD7', 'Gene', (12, 18))	('men', 'Species', '9606', (46, 49))	('StarD7', 'Gene', '56910', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('loss', 'Var', (4, 8))
27619	31354629	It was previously related with colorectal cancer for the variant rs11169552.	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('colorectal cancer', 'Disease', (31, 48))	('rs11169552', 'Var', (65, 75))	('related', 'Reg', (18, 25))	('rs11169552', 'Mutation', 'rs11169552', (65, 75))
27620	31354629	The Tubulin Polymerization-Promoting Protein Family Member 2 (TPPP2) and its variant rs1952524 was linked to liver cancer.	('liver cancer', 'Disease', (109, 121))	('rs1952524', 'Var', (85, 94))	('rs1952524', 'Mutation', 'rs1952524', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TPPP2', 'Gene', '122664', (62, 67))	('liver cancer', 'Phenotype', 'HP:0002896', (109, 121))	('linked', 'Reg', (99, 105))	('Tubulin Polymerization-Promoting Protein Family Member 2', 'Gene', '122664', (4, 60))	('liver cancer', 'Disease', 'MESH:D006528', (109, 121))	('TPPP2', 'Gene', (62, 67))
27621	31354629	Another protein is the Protease Serine 55 (PRSS55) along with the variant rs4404875, which has been mainly identified in Leydig and Sertoli cells and it is is associated with prostate and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Protease Serine 55', 'Gene', '203074', (23, 41))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('PRSS55', 'Gene', (43, 49))	('associated', 'Reg', (159, 169))	('rs4404875', 'Mutation', 'rs4404875', (74, 83))	('rs4404875', 'Var', (74, 83))	('Protease Serine 55', 'Gene', (23, 41))	('prostate and ovarian cancer', 'Disease', 'MESH:D010051', (175, 202))	('PRSS55', 'Gene', '203074', (43, 49))	('Sertoli cells', 'Phenotype', 'HP:0100619', (132, 145))
27693	25289098	Frohman et al described how autoreactive T cells can cause inflammatory demyelination of the central nervous system.	('cause', 'Reg', (53, 58))	('inflammatory demyelination', 'Phenotype', 'HP:0011096', (59, 85))	('inflammatory demyelination of the central nervous system', 'Disease', 'MESH:D003711', (59, 115))	('demyelination of the central nervous', 'Phenotype', 'HP:0007305', (72, 108))	('autoreactive', 'Var', (28, 40))
27738	24369137	Another example is illustrated by the influence of smoking and alcohol intake on the impact of polymorphisms in the genes encoding apoE and alcohol dehydrogenase, respectively, on coronary heart disease (reviewed by Talmud).	('alcohol dehydrogenase', 'Gene', (140, 161))	('polymorphisms', 'Var', (95, 108))	('coronary heart disease', 'Disease', 'MESH:D003324', (180, 202))	('apoE', 'Gene', '348', (131, 135))	('alcohol', 'Chemical', 'MESH:D000438', (140, 147))	('alcohol dehydrogenase', 'Gene', '10327', (140, 161))	('rat', 'Species', '10116', (25, 28))	('alcohol', 'Chemical', 'MESH:D000438', (63, 70))	('coronary heart disease', 'Disease', (180, 202))	('apoE', 'Gene', (131, 135))	('coronary heart disease', 'Phenotype', 'HP:0001677', (180, 202))
27754	24369137	AHR knockout mice are characterized by liver fibrosis as well as hampered embryonic development of a wide range of organs, reduced xenobiotic metabolism, immune system defects and regulation of hematopoiesis.	('embryonic development of a wide range', 'CPA', (74, 111))	('mice', 'Species', '10090', (13, 17))	('hematopoiesis', 'Disease', 'MESH:C536227', (194, 207))	('immune system defects', 'CPA', (154, 175))	('liver fibrosis', 'Disease', 'MESH:D008103', (39, 53))	('hampered', 'NegReg', (65, 73))	('men', 'Species', '9606', (91, 94))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (131, 152))	('knockout', 'Var', (4, 12))	('liver fibrosis', 'Phenotype', 'HP:0001395', (39, 53))	('hematopoiesis', 'Disease', (194, 207))	('AHR', 'Gene', (0, 3))	('xenobiotic metabolism', 'Disease', (131, 152))	('reduced', 'NegReg', (123, 130))	('liver fibrosis', 'Disease', (39, 53))
27756	24369137	Knocking out the AHR gene in a prostate cancer mouse model (TRAMP) inhibited prostatic carcinogenesis, while treating TRAMP mice with an AHR modulator inhibited metastasis.	('prostatic carcinogenesis', 'Disease', 'MESH:D063646', (77, 101))	('TRAMP', 'Gene', (118, 123))	('TRAMP', 'Gene', '85030', (118, 123))	('inhibited', 'NegReg', (67, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (31, 46))	('prostate cancer', 'Phenotype', 'HP:0012125', (31, 46))	('TRAMP', 'Gene', (60, 65))	('TRAMP', 'Gene', '85030', (60, 65))	('mouse', 'Species', '10090', (47, 52))	('prostatic carcinogenesis', 'Disease', (77, 101))	('mice', 'Species', '10090', (124, 128))	('inhibited', 'NegReg', (151, 160))	('AHR', 'Gene', (17, 20))	('prostate cancer', 'Disease', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Knocking out', 'Var', (0, 12))	('metastasis', 'CPA', (161, 171))
27766	24369137	Boys that were exposed to TCDD in Seveso during infancy or puberty exhibited permanently reduced estradiol and increased follicle-stimulating hormone (FSH) levels, whereas boys born to Yucheng mothers showed decreased serum testosterone and increased serum estradiol and FSH at the age of puberty.	('increased serum estradiol', 'Phenotype', 'HP:0025134', (241, 266))	('decreased serum testosterone', 'Phenotype', 'HP:0040171', (208, 236))	('increased follicle', 'Phenotype', 'HP:0100874', (111, 129))	('age of puberty', 'Phenotype', 'HP:0000826', (282, 296))	('reduced', 'NegReg', (89, 96))	('decreased', 'NegReg', (208, 217))	('testosterone', 'Chemical', 'MESH:D013739', (224, 236))	('TCDD', 'Chemical', 'MESH:D000072317', (26, 30))	('increased follicle-stimulating hormone', 'Phenotype', 'HP:0008232', (111, 149))	('increased', 'PosReg', (241, 250))	('estradiol', 'Chemical', 'MESH:D004958', (257, 266))	('estradiol', 'Chemical', 'MESH:D004958', (97, 106))	('serum testosterone', 'MPA', (218, 236))	('TCDD', 'Var', (26, 30))	('estradiol', 'MPA', (97, 106))	('Boys', 'Species', '9606', (0, 4))	('serum estradiol', 'MPA', (251, 266))	('boys', 'Species', '9606', (172, 176))	('increased', 'PosReg', (111, 120))	('decreased serum testosterone and increased serum estradiol', 'Phenotype', 'HP:0008214', (208, 266))	('reduced estradiol', 'Phenotype', 'HP:0008214', (89, 106))
27774	24369137	A recent study on 135 men from Seveso, who were exposed to TCDD during infancy, showed reduced sperm concentration and motility, whereas it had the opposite effect in men exposed during puberty and no effect in an older group with a mean age at exposure of 21.5 years.	('rat', 'Species', '10116', (108, 111))	('TCDD', 'Var', (59, 63))	('reduced', 'NegReg', (87, 94))	('reduced sperm concentration and motility', 'Phenotype', 'HP:0012207', (87, 127))	('men', 'Species', '9606', (22, 25))	('TCDD', 'Chemical', 'MESH:D000072317', (59, 63))	('sperm concentration', 'CPA', (95, 114))	('motility', 'CPA', (119, 127))	('men', 'Species', '9606', (167, 170))
27798	24369137	Recently, Bjork and Giwercman reported that the suppressive effect of TCDD on AR activity depends on the polymorphic glutamine repeat in the transactivating domain of AR, lending further support that crosstalk between AR and AHR signaling is mediated at the level of cofactor binding.	('glutamine', 'Chemical', 'MESH:D005973', (117, 126))	('TCDD', 'Chemical', 'MESH:D000072317', (70, 74))	('polymorphic glutamine repeat', 'Var', (105, 133))	('TCDD', 'Gene', (70, 74))	('AR', 'Gene', '367', (218, 220))	('AR', 'Gene', '367', (167, 169))	('AR', 'Gene', '367', (78, 80))	('suppressive', 'NegReg', (48, 59))
27804	24369137	Polymorphisms in the AHR gene, enzymes that are transcriptionally regulated by AHR, or other genes involved in the AHR signaling pathway, may not only cause variations in the individual susceptibility to dioxin-like compounds, but may also affect the cross talk between AHR signaling and other signaling pathways as described above.	('affect', 'Reg', (240, 246))	('Polymorphisms', 'Var', (0, 13))	('other signaling pathways', 'Pathway', (288, 312))	('susceptibility to dioxin-like compounds', 'MPA', (186, 225))	('dioxin', 'Chemical', 'MESH:D004147', (204, 210))	('cross talk', 'MPA', (251, 261))	('AHR signaling', 'Pathway', (270, 283))	('AHR', 'Gene', (21, 24))	('cause variations', 'Reg', (151, 167))	('AHR', 'Gene', (79, 82))
27805	24369137	As such, these polymorphisms may determine to what extent dioxins and dioxin-like compounds disrupt for example androgen signaling.	('dioxins', 'Chemical', 'MESH:D004147', (58, 65))	('androgen signaling', 'MPA', (112, 130))	('dioxin', 'Chemical', 'MESH:D004147', (58, 64))	('dioxin', 'Chemical', 'MESH:D004147', (70, 76))	('disrupt', 'Reg', (92, 99))	('polymorphisms', 'Var', (15, 28))
27806	24369137	For example, a single nucleotide change at codon 375 in the ligand binding domain of the murine AHR reduces the binding affinity for TCDD approximately 10-fold in the resistant DBA/2 strain as compared to the sensitive C57BL/6J strain.	('binding', 'Interaction', (112, 119))	('reduces', 'NegReg', (100, 107))	('single nucleotide change', 'Var', (15, 39))	('TCDD', 'Chemical', 'MESH:D000072317', (133, 137))	('murine', 'Species', '10090', (89, 95))	('TCDD', 'Protein', (133, 137))	('DBA/2', 'Gene', (177, 182))	('DBA/2', 'Gene', '114086', (177, 182))	('AHR', 'Gene', (96, 99))
27808	24369137	Due to a deletion in the transactivation domain of the rat AHR, the Han/Wistar rat strain is a 1000-fold more resistant to TCDD than the sensitive Long-Evans rat strain.	('more', 'PosReg', (105, 109))	('resistant', 'MPA', (110, 119))	('deletion in', 'Var', (9, 20))	('TCDD', 'Chemical', 'MESH:D000072317', (123, 127))	('rat', 'Species', '10116', (158, 161))	('rat', 'Species', '10116', (79, 82))	('rat', 'Species', '10116', (55, 58))	('AHR', 'Gene', (59, 62))
27811	24369137	Besides important implications for testing of pollutants in animal models, these inter- and intraspecies differences indicate that genetic polymorphisms in the AHR structure can have profound effects on the individual sensitivity to polycyclic and halogenated aromatic hydrocarbons.	('aromatic hydrocarbons', 'Chemical', 'MESH:D006841', (260, 281))	('effects', 'Reg', (192, 199))	('polymorphisms', 'Var', (139, 152))	('AHR structure', 'Gene', (160, 173))
27813	24369137	The first identified and most widely studied single-nucleotide polymorphism (SNP) in the human AHR gene is a G > A substitution in exon 10, which causes an arginine to lysine change at codon 554 (Arg554Lys) in the transactivating domain of the receptor.	('human', 'Species', '9606', (89, 94))	('arginine to lysine change at codon 554', 'Mutation', 'rs2066853', (156, 194))	('AHR', 'Gene', (95, 98))	('Arg554Lys', 'Var', (196, 205))	('arginine to lysine', 'MPA', (156, 174))	('transactivating', 'MPA', (214, 229))	('Arg554Lys', 'SUBSTITUTION', 'None', (196, 205))	('causes', 'Reg', (146, 152))
27814	24369137	Its functional significance is currently unclear as both upregulation as well as loss of transactivational activity have been reported for the lysine variant.	('transactivational activity', 'MPA', (89, 115))	('lysine', 'Var', (143, 149))	('upregulation', 'PosReg', (57, 69))	('loss', 'NegReg', (81, 85))	('lysine', 'Chemical', 'MESH:D008239', (143, 149))
27817	24369137	The Arg554Lys SNP is in linkage disequilibrium with two other non-synonymous SNPs in exon 10 (Pro517Ser and Val570Ile), which are very rare except in African ancestry.	('Arg554Lys', 'Var', (4, 13))	('Pro517Ser', 'Chemical', '-', (94, 103))	('Val570Ile', 'Mutation', 'rs4986826', (108, 117))	('Pro517Ser', 'Var', (94, 103))	('Val570Ile', 'Var', (108, 117))	('Arg554Lys', 'SUBSTITUTION', 'None', (4, 13))
27818	24369137	Combinations of Lys554/Ile570 or Lys554/Ile570/Ser517 variant alleles are unable to drive the CYP1A1 gene expression in vitro.	('Ser517', 'Chemical', '-', (47, 53))	('Ile570', 'Chemical', '-', (40, 46))	('Lys554/Ile570/Ser517', 'Var', (33, 53))	('expression', 'MPA', (106, 116))	('Lys554', 'Chemical', '-', (33, 39))	('Lys554', 'Chemical', '-', (16, 22))	('Ile570', 'Chemical', '-', (23, 29))	('Lys554/Ile570', 'Var', (16, 29))	('CYP1A1 gene', 'Gene', (94, 105))	('drive', 'Reg', (84, 89))	('unable', 'NegReg', (74, 80))
27820	24369137	A recent study confirmed that lower AHR, ARNT and CYP1B1 mRNA expression was associated with the homozygous variant Lys554 genotype of the AHR, but it remains to be seen whether humans who carry the variant codons at 570 and 517 will have a lower cancer risk as well.	('lower', 'NegReg', (30, 35))	('ARNT', 'MPA', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Lys554', 'Var', (116, 122))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('Lys554', 'Chemical', '-', (116, 122))	('AHR', 'MPA', (36, 39))	('humans', 'Species', '9606', (178, 184))	('CYP1B1', 'Gene', '1545', (50, 56))	('variant Lys554', 'Var', (108, 122))	('CYP1B1', 'Gene', (50, 56))
27821	24369137	Four additional human AHR variants (Lys17Thr, Lys401Arg, Asn487Asp and Ile514Thr) have been described.	('Asn487Asp', 'Var', (57, 66))	('Lys401Arg', 'SUBSTITUTION', 'None', (46, 55))	('Ile514Thr', 'Var', (71, 80))	('Lys17Thr', 'Var', (36, 44))	('AHR', 'Gene', (22, 25))	('Asn487Asp', 'SUBSTITUTION', 'None', (57, 66))	('Lys401Arg', 'Var', (46, 55))	('Lys17Thr', 'SUBSTITUTION', 'None', (36, 44))	('human', 'Species', '9606', (16, 21))	('Ile514Thr', 'Chemical', '-', (71, 80))
27822	24369137	Reduced transcriptional activity was reported in the Lys401Arg and Asn487Asp variants, but so far the phenotypic consequences of these variants remain unknown.	('Lys401Arg', 'SUBSTITUTION', 'None', (53, 62))	('Asn487Asp', 'SUBSTITUTION', 'None', (67, 76))	('Reduced', 'NegReg', (0, 7))	('Lys401Arg', 'Var', (53, 62))	('transcriptional activity', 'MPA', (8, 32))	('Asn487Asp', 'Var', (67, 76))
27823	24369137	The AHRR gene harbors a missense mutation leading to a Pro185Ala amino acid change in exon 6.	('Pro185Ala', 'SUBSTITUTION', 'None', (55, 64))	('Pro185Ala', 'Var', (55, 64))	('AHRR', 'Gene', '57491', (4, 8))	('AHRR', 'Gene', (4, 8))
27824	24369137	Although the functional properties of this variant are unclear, it has been linked with endometriosis in women and infertility in men, possibly through a reduced negative feedback on dioxin-induced AHR signaling.	('negative feedback', 'MPA', (162, 179))	('dioxin-induced AHR signaling', 'MPA', (183, 211))	('endometriosis', 'Phenotype', 'HP:0030127', (88, 101))	('linked', 'Reg', (76, 82))	('men', 'Species', '9606', (107, 110))	('women', 'Species', '9606', (105, 110))	('infertility', 'Phenotype', 'HP:0000789', (115, 126))	('infertility', 'Disease', 'MESH:D007247', (115, 126))	('variant', 'Var', (43, 50))	('infertility', 'Disease', (115, 126))	('dioxin', 'Chemical', 'MESH:D004147', (183, 189))	('reduced', 'NegReg', (154, 161))	('endometriosis', 'Disease', 'MESH:D004715', (88, 101))	('men', 'Species', '9606', (130, 133))	('endometriosis', 'Disease', (88, 101))
27826	24369137	Recently, in a candidate association study on testicular cancer in a combined Swedish and Danish cohort, it was shown that the risk of disseminated TGCC was associated with four different SNPs that tag two haplotypes in the AHRR, whereas no association was found with SNPs in the AHR.	('testicular cancer', 'Phenotype', 'HP:0010788', (46, 63))	('testicular cancer', 'Disease', 'MESH:D013736', (46, 63))	('associated', 'Reg', (157, 167))	('SNPs', 'Var', (188, 192))	('testicular cancer', 'Disease', (46, 63))	('AHRR', 'Gene', '57491', (224, 228))	('disseminated TGCC', 'Disease', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('AHRR', 'Gene', (224, 228))
27828	24369137	Two other variants, Asp511Asn and Asp517Glu, have also been identified in the ARNT gene, but since both are located in exon 16, which does not contain a known functional domain, the significance of these SNPs has not been determined to date.	('Asp517Glu', 'Var', (34, 43))	('Asp511Asn', 'SUBSTITUTION', 'None', (20, 29))	('Asp511Asn', 'Var', (20, 29))	('Asp517Glu', 'SUBSTITUTION', 'None', (34, 43))	('ARNT', 'Gene', (78, 82))
27830	24369137	In ARNT2 on the other hand, which is a close structural homologue of ARNT and expressed in parallel with ARNT in many tissues, a significant association was observed between two SNPs (rs2278705 and rs5000770) and having either cryptorchidism, hypospadias or both in Japanese boys, whereas, rs5000770 was linked to at least one genital malformation in Italian men.	('cryptorchidism', 'Disease', (227, 241))	('cryptorchidism', 'Disease', 'MESH:D003456', (227, 241))	('ARNT2', 'Gene', '9915', (3, 8))	('hypospadias', 'Phenotype', 'HP:0000047', (243, 254))	('men', 'Species', '9606', (359, 362))	('rs5000770', 'Var', (198, 207))	('cryptorchidism', 'Phenotype', 'HP:0000028', (227, 241))	('rs5000770', 'Mutation', 'rs5000770', (198, 207))	('ARNT2', 'Gene', (3, 8))	('hypospadias', 'Disease', 'MESH:D007021', (243, 254))	('genital malformation', 'Phenotype', 'HP:0000078', (327, 347))	('rs2278705', 'Mutation', 'rs2278705', (184, 193))	('boys', 'Species', '9606', (275, 279))	('rs5000770', 'Mutation', 'rs5000770', (290, 299))	('hypospadias', 'Disease', (243, 254))	('rs2278705', 'Var', (184, 193))
27831	24369137	Studies in populations that have been exposed to significant dioxin levels may be needed to further confirm the possible role of ARNT or ANRT2 variants in male genital development.	('dioxin', 'Chemical', 'MESH:D004147', (61, 67))	('male genital development', 'CPA', (155, 179))	('ANRT2', 'Gene', (137, 142))	('men', 'Species', '9606', (175, 178))	('ARNT', 'Gene', (129, 133))	('variants', 'Var', (143, 151))
27832	24369137	One could argue that the human AHR is not likely to be polymorphic with respect to susceptibility for two reasons: (i) the human AHR already harbors the mutation that in the DBA/2-mouse reduces its affinity or CYP1A1 inducibility, which may not be overcome by additional mutations and (ii) the critical importance of the AHR during development may not allow additional deleterious mutations in this gene.	('CYP1A1 inducibility', 'MPA', (210, 229))	('affinity', 'MPA', (198, 206))	('DBA/2', 'Gene', (174, 179))	('DBA/2', 'Gene', '114086', (174, 179))	('human', 'Species', '9606', (123, 128))	('human', 'Species', '9606', (25, 30))	('mouse', 'Species', '10090', (180, 185))	('AHR', 'Gene', (129, 132))	('reduces', 'NegReg', (186, 193))	('men', 'Species', '9606', (339, 342))	('mutation', 'Var', (153, 161))
27833	24369137	However, a recent genetic association study in a Chinese cohort of 580 idiopathic infertile men and 580 fertile controls observed that men homozygous for the AHR rs2158041 AA genotype had lower sperm counts than carriers of the GG genotype.	('sperm counts', 'CPA', (194, 206))	('lower', 'NegReg', (188, 193))	('rs2158041', 'Mutation', 'rs2158041', (162, 171))	('lower sperm counts', 'Phenotype', 'HP:0000798', (188, 206))	('men', 'Species', '9606', (135, 138))	('rs2158041 AA', 'Var', (162, 174))	('AHR', 'Gene', (158, 161))	('men', 'Species', '9606', (92, 95))
27834	24369137	Interestingly, the same polymorphism also associated with risk of lung cancer in a similarly-sized Chinese study.	('polymorphism', 'Var', (24, 36))	('associated with', 'Reg', (42, 57))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
27837	24369137	Animal studies have shown that daily sperm production is affected less by TCDD exposure in utero as well as during adulthood in resistant Han/Wistar rats who carry a mutated transactivation domain of the AHR as compared to Long-Evans rats carrying the wildtype allele.	('Wistar rats', 'Species', '10116', (142, 153))	('sperm production', 'CPA', (37, 53))	('rats', 'Species', '10116', (234, 238))	('mutated', 'Var', (166, 173))	('AHR', 'Gene', (204, 207))	('TCDD', 'Chemical', 'MESH:D000072317', (74, 78))	('rats', 'Species', '10116', (149, 153))	('less', 'NegReg', (66, 70))	('transactivation', 'MPA', (174, 189))
27839	24369137	For example, a polymorphism in CYP1A1 and hydroxysteroid 17b-dehydrogenase 4 modifies the association between exposure levels to different PCB congeners and the risk of testicular cancer.	('PCB', 'Gene', (139, 142))	('testicular cancer', 'Disease', 'MESH:D013736', (169, 186))	('testicular cancer', 'Phenotype', 'HP:0010788', (169, 186))	('PCB', 'Gene', '5091', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('association', 'Interaction', (90, 101))	('modifies', 'Reg', (77, 85))	('testicular cancer', 'Disease', (169, 186))	('polymorphism', 'Var', (15, 27))	('CYP1A1', 'Gene', (31, 37))
27841	24369137	Another study reported increased sperm DNA fragmentation in men with a variant of the detoxifying enzyme glutathione-S-transferase M1 when exposed to polycyclic aromatic hydrocarbon metabolites found in air pollution.	('variant', 'Var', (71, 78))	('glutathione-S-transferase M1', 'Gene', (105, 133))	('polycyclic aromatic hydrocarbon', 'Chemical', 'MESH:D011084', (150, 181))	('sperm DNA fragmentation', 'CPA', (33, 56))	('increased', 'PosReg', (23, 32))	('men', 'Species', '9606', (60, 63))	('men', 'Species', '9606', (47, 50))	('glutathione-S-transferase M1', 'Gene', '2944', (105, 133))
27843	24369137	On the other hand, polymorphisms in genes involved in AHR signaling pathway have been identified in humans, and in a limited number of studies these have been associated with male reproductive functions.	('polymorphisms', 'Var', (19, 32))	('associated', 'Reg', (159, 169))	('male reproductive', 'CPA', (175, 192))	('AHR signaling pathway', 'Pathway', (54, 75))	('humans', 'Species', '9606', (100, 106))
27845	24369137	Although animals show large differences in sensitivity to dioxins due to these polymorphisms, the functional effects are less obvious in humans.	('polymorphisms', 'Var', (79, 92))	('humans', 'Species', '9606', (137, 143))	('sensitivity', 'MPA', (43, 54))	('dioxins', 'Chemical', 'MESH:D004147', (58, 65))
27848	24369137	Many environmental pollutants exert there biological effects through activation of the AHR signaling cascade and polymorphisms in the genes involved in this pathway may affect an individual's response to these pollutants.	('polymorphisms', 'Var', (113, 126))	('affect', 'Reg', (169, 175))	('men', 'Species', '9606', (12, 15))	('response to these pollutants', 'MPA', (192, 220))	('AHR signaling cascade', 'Pathway', (87, 108))	('activation', 'PosReg', (69, 79))
27849	24369137	It may not be likely that polymorphisms in the human AHR gene affect receptor function, but there is evidence to suggest that polymorphisms in AHRR may indeed affect an individual's susceptibility to dioxin-related reproductive health effects.	('affect', 'Reg', (62, 68))	('susceptibility', 'MPA', (182, 196))	('affect', 'Reg', (159, 165))	('polymorphisms', 'Var', (126, 139))	('AHRR', 'Gene', '57491', (143, 147))	('dioxin', 'Chemical', 'MESH:D004147', (200, 206))	('AHRR', 'Gene', (143, 147))	('human', 'Species', '9606', (47, 52))
27856	24369137	However, given the fact that AHR receptor signaling is crucially important during development, the human AHR which already harbors a polymorphism that in the mouse reduces its activity may not allow further compromising genetic modifications.	('reduces', 'NegReg', (164, 171))	('mouse', 'Species', '10090', (158, 163))	('activity', 'MPA', (176, 184))	('AHR', 'Gene', (105, 108))	('men', 'Species', '9606', (89, 92))	('polymorphism', 'Var', (133, 145))	('human', 'Species', '9606', (99, 104))
27926	22310892	In at least one case, a Dmrt1 gene has taken over sex determination: in the teleost fish medaka (Oryzias latipes; XX/XY sex determination), a gene duplication of the autosomal Dmrt1a generated a new Y chromosome on which the new Dmrt1 gene, called DM domain on Y (Dmy; also known as Dmrt1y), acts as a male-linked dominant 'master regulator' of sex determination and is both necessary and sufficient to trigger male development, much like SRY in mammals.	('Dmy', 'Gene', '100049231', (264, 267))	('teleost fish', 'Species', '70862', (76, 88))	('Dmrt1a', 'Gene', (176, 182))	('gene duplication', 'Var', (142, 158))	('Dmrt1a', 'Gene', '101161472', (176, 182))	('Dmrt1y', 'Gene', (283, 289))	('Dmrt1', 'Gene', (229, 234))	('Dmrt1y', 'Gene', '100049231', (283, 289))	('DM', 'Disease', 'MESH:D009223', (248, 250))	('male development', 'CPA', (411, 427))	('Oryzias latipes', 'Species', '8090', (97, 112))	('medaka', 'Species', '8090', (89, 95))	('Dmy', 'Gene', (264, 267))
27927	22310892	The discovery of Dmy beautifully illustrates how a conserved downstream sex regulator can acquire control of the sex determination hierarchy through a straightforward mutational event.	('Dmy', 'Gene', '100049231', (17, 20))	('Dmy', 'Gene', (17, 20))	('mutational', 'Var', (167, 177))
27933	22310892	Ito and colleagues recently found that a duplicated variant of Dmrt1 resides on the W chromosome of the frog Xenopus laevis (which also has ZZ/ZW genetic sex determination) and serves as an ovarian determinant.	('variant', 'Var', (52, 59))	('Xenopus laevis', 'Species', '8355', (109, 123))	('Dmrt1', 'Gene', (63, 68))
27939	22310892	From the widespread involvement of Dmrt1 in vertebrates with diverse sex-determining mechanisms, it seems likely that further examples in which mutations that affect Dmrt1 are associated with SDM transition await discovery.	('mutations', 'Var', (144, 153))	('DM', 'Disease', 'MESH:D009223', (193, 195))	('Dmrt1', 'Gene', (166, 171))	('associated', 'Reg', (176, 186))
27944	22310892	In the fetal ovary, Dmrt1 mutant germ cells have severely reduced Stra8 expression and undergo abnormal meiotic prophase.	('meiotic prophase', 'CPA', (104, 120))	('Stra8', 'Gene', (66, 71))	('expression', 'MPA', (72, 82))	('undergo', 'Reg', (87, 94))	('mutant', 'Var', (26, 32))	('Stra8', 'Gene', '20899', (66, 71))	('reduced', 'NegReg', (58, 65))	('Dmrt1', 'Gene', (20, 25))
27946	22310892	Dmrt1 mutant males have no obvious phenotype until after birth, except on the 129Sv inbred genetic background, where Dmrt1 mutants develop testicular teratomas at a very high frequency during fetal development.	('Dmrt1', 'Gene', (117, 122))	('teratomas', 'Phenotype', 'HP:0009792', (150, 159))	('mutant', 'Var', (6, 12))	('testicular teratomas', 'Disease', (139, 159))	('testicular teratomas', 'Phenotype', 'HP:0100616', (139, 159))	('develop', 'PosReg', (131, 138))	('129Sv', 'Species', '10090', (78, 83))	('testicular teratomas', 'Disease', 'MESH:C562472', (139, 159))	('mutants', 'Var', (123, 130))
27949	22310892	First, it is required for germ cells to resume development just after birth: Dmrt1 mutant cells do not reinitiate mitosis, nor do they migrate to the basal lamina or undergo spermatogonial differentiation.	('mitosis', 'Disease', (114, 121))	('mutant', 'Var', (83, 89))	('mitosis', 'Disease', 'None', (114, 121))	('spermatogonial differentiation', 'CPA', (174, 204))	('Dmrt1', 'Gene', (77, 82))	('undergo', 'Reg', (166, 173))
27951	22310892	Deletion of Dmrt1 in undifferentiated spermatogonia causes them to abandon normal development and differentiation and instead express high levels of Stra8 and precociously and constitutively enter meiosis.	('Stra8', 'Gene', '20899', (149, 154))	('express', 'Reg', (126, 133))	('normal development', 'CPA', (75, 93))	('enter', 'Reg', (191, 196))	('abandon', 'NegReg', (67, 74))	('Dmrt1', 'Gene', (12, 17))	('causes', 'Reg', (52, 58))	('abandon normal development', 'Phenotype', 'HP:0002376', (67, 93))	('Stra8', 'Gene', (149, 154))	('Deletion', 'Var', (0, 8))
27956	22310892	Dmrt1-null mutant mice are born male and have apparently normal Sertoli cells.	('Sertoli cells', 'Phenotype', 'HP:0100619', (64, 77))	('mutant', 'Var', (11, 17))	('mice', 'Species', '10090', (18, 22))	('Dmrt1-null', 'Gene', (0, 10))	('Sertoli cells', 'CPA', (64, 77))
27958	22310892	Androgen activity is reduced and oestradiol levels are elevated in mutants, suggesting a male-to-female tilt in hormone signalling, which is probably due in part to elevated expression of the oestrogenic enzyme cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1; also known as aromatase).	('reduced', 'NegReg', (21, 28))	('cytochrome P450 family 19 subfamily A polypeptide 1', 'Gene', '13075', (211, 262))	('oestradiol', 'Chemical', 'MESH:D004958', (33, 43))	('expression', 'MPA', (174, 184))	('CYP19A1', 'Gene', (264, 271))	('hormone signalling', 'MPA', (112, 130))	('mutants', 'Var', (67, 74))	('oestradiol levels', 'MPA', (33, 50))	('Androgen activity', 'MPA', (0, 17))	('elevated', 'PosReg', (165, 173))	('elevated', 'PosReg', (55, 63))	('bab', 'Chemical', '-', (144, 147))	('CYP19A1', 'Gene', '13075', (264, 271))
27961	22310892	However, the two networks are clearly not identical: loss of Sox9 only causes sex reversal if it occurs before testicular differentiation, and neither Dmrt1 nor Foxl2 is essential for primary sex determination.	('Sox9', 'Gene', (61, 65))	('Foxl2', 'Gene', '26927', (161, 166))	('sex reversal', 'Phenotype', 'HP:0012245', (78, 90))	('loss', 'Var', (53, 57))	('Foxl2', 'Gene', (161, 166))	('causes', 'Reg', (71, 77))	('sex reversal', 'CPA', (78, 90))
27962	22310892	Postnatal loss of Foxl2 causes a reciprocal reprogramming of granulosa cells to Sertoli-like cells, activating Sox9 and Dmrt1, inducing formation of cells resembling Leydig cells and remodelling the ovary to a more testis-like morphology.	('loss', 'Var', (10, 14))	('Foxl2', 'Gene', (18, 23))	('remodelling the ovary', 'Disease', (183, 204))	('activating', 'PosReg', (100, 110))	('Dmrt1', 'Gene', (120, 125))	('remodelling the ovary', 'Disease', 'MESH:D010051', (183, 204))	('inducing', 'PosReg', (127, 135))	('Foxl2', 'Gene', '26927', (18, 23))
27966	22310892	Recent work in medaka suggests this may be the case: XY fish that are mutant for Dmrt1 develop gonads that initially appear to be male (presumably owing to Dmy) but go on to become fertile XY females.	('Dmy', 'Gene', (156, 159))	('mutant', 'Var', (70, 76))	('Dmy', 'Gene', '100049231', (156, 159))	('medaka', 'Species', '8090', (15, 21))	('Dmrt1', 'Gene', (81, 86))
27968	22310892	Plasticity of gonadal sex also exists in C. elegans, although it may not involve DM domain genes: ectopic expression of egl-5 in XX hermaphrodites can induce male gene expression in the somatic gonad long after gonadal sex determination.	('hermaphrodites', 'Disease', (132, 146))	('DM', 'Disease', 'MESH:D009223', (81, 83))	('egl-5', 'Gene', (120, 125))	('C. elegans', 'Species', '6239', (41, 51))	('induce', 'PosReg', (151, 157))	('ectopic expression', 'Var', (98, 116))	('hermaphrodites', 'Disease', 'MESH:D012734', (132, 146))	('male gene expression', 'MPA', (158, 178))
27971	22310892	Given that both Dmrt1 and Foxl2 are implicated in modulating retinoic acid signalling, it will be important to find out whether elevated retinoic acid signalling plays a part in male-to-female reprogramming in Dmrt1 mutants.	('retinoic acid signalling', 'MPA', (61, 85))	('mutants', 'Var', (216, 223))	('Dmrt1', 'Gene', (210, 215))	('retinoic acid', 'Chemical', 'MESH:D014212', (61, 74))	('retinoic acid', 'Chemical', 'MESH:D014212', (137, 150))	('Foxl2', 'Gene', '26927', (26, 31))	('Foxl2', 'Gene', (26, 31))	('modulating', 'Reg', (50, 60))
27973	22310892	LRH1 is normally expressed in the ovary and not in the testis, but it is highly expressed in Dmrt1 mutant Sertoli cells; this raises the possibility that the reprogramming may involve a pluripotent intermediate state.	('Dmrt1', 'Gene', (93, 98))	('Sertoli cells', 'Phenotype', 'HP:0100619', (106, 119))	('LRH1', 'Gene', '26424', (0, 4))	('LRH1', 'Gene', (0, 4))	('mutant', 'Var', (99, 105))
27974	22310892	Sox9 and Sox8 are candidates for helping to maintain male fates, as loss of both genes after sex determination causes testicular defects that are similar to those seen in Dmrt1 mutants.	('Sox8', 'Gene', '20681', (9, 13))	('Sox8', 'Gene', (9, 13))	('mutants', 'Var', (177, 184))	('causes', 'Reg', (111, 117))	('loss', 'NegReg', (68, 72))	('Dmrt1', 'Gene', (171, 176))	('testicular defects', 'Disease', 'MESH:D013733', (118, 136))	('testicular defects', 'Disease', (118, 136))
27999	22310892	In mice, mutants for four of the seven DM domain genes (Dmrt1, Dmrt2, Dmrt4 and Dmrt7) have been described.	('Dmrt1', 'Gene', (56, 61))	('Dmrt7', 'Gene', '71241', (80, 85))	('Dmrt2', 'Gene', (63, 68))	('Dmrt7', 'Gene', (80, 85))	('mice', 'Species', '10090', (3, 7))	('Dmrt2', 'Gene', '226049', (63, 68))	('Dmrt4', 'Gene', (70, 75))	('mutants', 'Var', (9, 16))	('DM', 'Disease', 'MESH:D009223', (39, 41))	('Dmrt4', 'Gene', '242523', (70, 75))
28005	22310892	Comparative studies in the Drosophila genus have helped to show how sexually dimorphic gene expression can evolve and have also revealed two discrete mechanisms by which evolutionary changes in doublesex (DSX)-dependent transcriptional output can mediate the diversification of sexually dimorphic features over short evolutionary timescales (see the figure).	('DSX', 'Gene', '40940', (205, 208))	('doublesex', 'Gene', (194, 203))	('doublesex', 'Gene', '40940', (194, 203))	('mediate', 'Reg', (247, 254))	('DSX', 'Gene', (205, 208))	('Drosophila', 'Species', '7227', (27, 37))	('changes', 'Var', (183, 190))
28010	22310892	Similarly, in the second example (b), involving the evolution of abdominal pigmentation, changes in the number, arrangement and spacing of abdominal B (ABDB; indicated by the black oval) and DSX binding sites altered the size the female-specific bric a brac (bab) expression domain in the abdominal cuticle, and hence the extent of male-specific pigmentation, which is inhibited by bab.	('DSX', 'Gene', '40940', (191, 194))	('bab', 'Chemical', '-', (382, 385))	('size', 'MPA', (221, 225))	('bab', 'Chemical', '-', (259, 262))	('changes', 'Var', (89, 96))	('bab', 'Gene', (259, 262))	('ABDB', 'Gene', '47763', (152, 156))	('abdominal pigmentation', 'Disease', 'MESH:D010859', (65, 87))	('DSX', 'Gene', (191, 194))	('abdominal pigmentation', 'Disease', (65, 87))	('altered', 'Reg', (209, 216))	('ABDB', 'Gene', (152, 156))
28014	22310892	However, the recently discovered sex maintenance function of Dmrt1 in mice suggests a third possibility: DMRT1 may not affect the initial specification of testicular cell fates but may, in some cases, lead to later reprogramming of pre-Sertoli or Sertoli cells into granulosa-like cells.	('Sertoli cells', 'Phenotype', 'HP:0100619', (247, 260))	('mice', 'Species', '10090', (70, 74))	('reprogramming', 'CPA', (215, 228))	('DMRT1', 'Var', (105, 110))	('lead to', 'Reg', (201, 208))
28021	22310892	Amplification of DMRT1 is associated with spermatocytic seminomas, which are tumours that are believed to initiate in later germ cells, possibly in premeiotic or meiotic spermatocytes.	('DMRT1', 'Gene', (17, 22))	('spermatocytic seminomas', 'Disease', (42, 65))	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('Amplification', 'Var', (0, 13))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (77, 84))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (42, 65))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('associated', 'Reg', (26, 36))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (42, 65))
28024	22310892	DMRT1 has not been linked to human ovarian disorders, but point mutations in FOXL2 : which probably activate its function : are found in most ovarian granulosa cell tumours.	('ovarian disorders', 'Disease', (35, 52))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian disorders', 'Disease', 'MESH:D010049', (35, 52))	('ovarian granulosa cell tumours', 'Disease', 'MESH:D006106', (142, 172))	('point mutations', 'Var', (58, 73))	('FOXL2', 'Gene', (77, 82))	('ovarian disorders', 'Phenotype', 'HP:0000137', (35, 52))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('human', 'Species', '9606', (29, 34))	('ovarian granulosa cell tumours', 'Disease', (142, 172))	('bab', 'Chemical', '-', (94, 97))
28025	22310892	We speculate that loss of DMRT1 combined with these FOXL2 point mutations might be associated with the rarer granulosa cell tumours of the testis.	('loss', 'NegReg', (18, 22))	('FOXL2', 'Gene', (52, 57))	('granulosa cell tumours of the testis', 'Disease', 'MESH:D006106', (109, 145))	('granulosa cell tumours of the testis', 'Disease', (109, 145))	('point mutations', 'Var', (58, 73))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('associated', 'Reg', (83, 93))	('DMRT1', 'Gene', (26, 31))
28037	22310892	In the postnatal mouse gonad, sex-specific expression of Dmrt1 relies, at least in part, on Foxl2, as loss of FOXL2 causes ectopic expression of Dmrt1 in somatic cells of the ovary.	('causes', 'Reg', (116, 122))	('mouse', 'Species', '10090', (17, 22))	('ectopic expression', 'MPA', (123, 141))	('Dmrt1', 'Gene', (145, 150))	('FOXL2', 'Gene', (110, 115))	('Foxl2', 'Gene', (92, 97))	('Foxl2', 'Gene', '26927', (92, 97))	('loss', 'Var', (102, 106))
28066	19440400	In human cells in vitro, theobromine induced sister chromatid exchange and chromosomal breaks.	('theobromine', 'Var', (25, 36))	('chromosomal breaks', 'Phenotype', 'HP:0040012', (75, 93))	('human', 'Species', '9606', (3, 8))	('induced', 'Reg', (37, 44))	('sister chromatid exchange', 'CPA', (45, 70))	('theobromine', 'Chemical', 'MESH:D013805', (25, 36))	('chromosomal breaks', 'CPA', (75, 93))
28109	19440400	In vivo, theobromine induced sister chromatid exchange and micronuclei in the bone marrow of Chinese hamsters.	('theobromine', 'Chemical', 'MESH:D013805', (9, 20))	('micronuclei', 'CPA', (59, 70))	('induced', 'Reg', (21, 28))	('theobromine', 'Var', (9, 20))	('Chinese hamsters', 'Species', '10029', (93, 109))	('sister chromatid exchange', 'CPA', (29, 54))
28111	19440400	In particular, theobromine was found to produce a higher and more linear rate of sister chromatid exchange damage than caffeine.	('theobromine', 'Chemical', 'MESH:D013805', (15, 26))	('caffeine', 'Chemical', 'MESH:D002110', (119, 127))	('sister chromatid exchange damage', 'CPA', (81, 113))	('theobromine', 'Var', (15, 26))
28161	33135391	11 ,  12 ,  13  Methylation of RASSF1A, HIC1, MGMT, and CALCA has been shown to correlate with cisplatin resistance.	('CALCA', 'Gene', (56, 61))	('MGMT', 'Gene', (46, 50))	('RASSF1A', 'Gene', (31, 38))	('MGMT', 'Gene', '4255', (46, 50))	('correlate with', 'Reg', (80, 94))	('CALCA', 'Gene', '796', (56, 61))	('RASSF1A', 'Gene', '11186', (31, 38))	('Methylation', 'Var', (16, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('HIC1', 'Gene', (40, 44))	('cisplatin resistance', 'MPA', (95, 115))	('HIC1', 'Gene', '3090', (40, 44))
28162	33135391	14 ,  15 ,  16   For some solid tumor types, there is a correlation between increased DNA methylation and resistance to chemotherapy that can be reversed by hypomethylating agents (HMAs).	('DNA', 'Protein', (86, 89))	('increased', 'PosReg', (76, 85))	('HMAs', 'Chemical', '-', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('resistance to chemotherapy', 'CPA', (106, 132))	('hypomethylating agents', 'Chemical', '-', (157, 179))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('methylation', 'Var', (90, 101))	('tumor', 'Disease', (32, 37))
28238	33135391	TGCTs appear to have distinct epigenetic profiles, including hypomethylated DNA that has been suggested to correlate with sensitivity to cisplatin.	('GCTs', 'Phenotype', 'HP:0100728', (1, 5))	('hypomethylated', 'Var', (61, 75))	('DNA', 'Gene', (76, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('correlate', 'Reg', (107, 116))	('TGCTs', 'Gene', (0, 5))
28251	33135391	21  However, the 6-month PFS was significantly higher in the guadecitabine plus carboplatin group (37% vs. 11%, p = 0.003), validating the potential utility of HMAs as re-sensitization agents.	('guadecitabine', 'Chemical', 'MESH:C580831', (61, 74))	('PFS', 'MPA', (25, 28))	('higher', 'PosReg', (47, 53))	('carboplatin', 'Chemical', 'MESH:D016190', (80, 91))	('guadecitabine', 'Var', (61, 74))	('HMAs', 'Chemical', '-', (160, 164))
28314	12402143	RBC transfusions may be associated with adverse effects such as viral infections, e.g.	('viral infections', 'Disease', (64, 80))	('viral infections', 'Disease', 'MESH:D001102', (64, 80))	('RBC transfusion', 'Phenotype', 'HP:0011888', (0, 15))	('transfusions', 'Var', (4, 16))
28393	12402143	Interactions may be possible on several levels such as, e.g., increased bloodflow and drug delivery to the tumour in less anaemic patients or higher effectiveness of radical generating agents in the presence of better oxygen supply as postulated for radiotherapy (Haensgen et al, 2001).	('increased', 'PosReg', (62, 71))	('bloodflow', 'MPA', (72, 81))	('effectiveness', 'MPA', (149, 162))	('drug delivery', 'MPA', (86, 99))	('Interactions', 'Var', (0, 12))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (130, 138))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('oxygen', 'Chemical', 'MESH:D010100', (218, 224))	('tumour', 'Disease', (107, 113))
28401	32117067	The origin of TGCT, probably starting at early stages of embryogenesis, seems to be a part of the Testicular Dysgenesis Syndrome (TDS) where some early PGC/gonocytes are blocked in their differentiation, are tightly regulated by epigenetic modification in terms of microRNA expression and DNA methylation, retaining their early marker profile (Baroni et al.).	('TDS', 'Disease', 'MESH:D013733', (130, 133))	('Testicular Dysgenesis', 'Phenotype', 'HP:0008715', (98, 119))	('TDS', 'Disease', (130, 133))	('Testicular Dysgenesis Syndrome', 'Disease', 'MESH:D013733', (98, 128))	('epigenetic', 'Var', (229, 239))	('Testicular Dysgenesis Syndrome', 'Disease', (98, 128))
28411	32117067	Testicular microlithiasis (TM) represents itself a risk factor for TGCT, because in infertile men the presence of TM is associated to an ~18-fold higher prevalence of testicular cancer as reported in a full meta-analysis of eight carefully selected studies (Barbonetti et al.).	('higher', 'PosReg', (146, 152))	('infertile', 'Disease', (84, 93))	('TM', 'Phenotype', 'HP:0012215', (114, 116))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('men', 'Species', '9606', (94, 97))	('testicular cancer', 'Phenotype', 'HP:0010788', (167, 184))	('Testicular microlithiasis', 'Disease', (0, 25))	('TM', 'Disease', 'MESH:C566478', (27, 29))	('Testicular microlithiasis', 'Disease', 'MESH:C566478', (0, 25))	('testicular cancer', 'Disease', 'MESH:D013736', (167, 184))	('presence', 'Var', (102, 110))	('TM', 'Disease', 'MESH:C566478', (114, 116))	('infertile', 'Disease', 'MESH:D007246', (84, 93))	('TM', 'Phenotype', 'HP:0012215', (27, 29))	('Testicular microlithiasis', 'Phenotype', 'HP:0012215', (0, 25))	('testicular cancer', 'Disease', (167, 184))
28424	32117067	The alterations in the expression of proteins related with the Warburg effect and hyper-glycolytic and acid-resistant phenotype are associated with aggressive clinicopathological parameters (Bonatelli et al.).	('alterations', 'Var', (4, 15))	('proteins', 'Protein', (37, 45))	('hyper-glycolytic', 'Disease', 'MESH:D053306', (82, 98))	('associated', 'Reg', (132, 142))	('hyper-glycolytic', 'Disease', (82, 98))	('expression of', 'MPA', (23, 36))
28441	31181810	This was dominated by a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination, and expression of BMI1.	('decrease', 'NegReg', (184, 192))	('BMI1', 'Gene', '648', (255, 259))	('men', 'Species', '9606', (49, 52))	('methylation', 'Var', (91, 102))	('PRC2', 'Gene', (142, 146))	('expression', 'MPA', (241, 251))	('H2AK119', 'Protein', (213, 220))	('BMI1', 'Gene', (255, 259))	('global', 'MPA', (196, 202))	('H3K27', 'Protein', (85, 90))
28442	31181810	Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells.	('EZH2', 'Gene', (54, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('demethylase', 'Gene', '8932', (187, 198))	('methylation', 'MPA', (151, 162))	('methylation', 'Var', (33, 44))	('H3K27', 'Protein', (145, 150))	('repression', 'NegReg', (13, 23))	('cisplatin resistance', 'MPA', (87, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('increased', 'PosReg', (228, 237))	('conferred', 'Reg', (77, 86))	('EZH2', 'Gene', '2146', (54, 58))	('demethylase', 'Gene', (187, 198))	('cisplatin sensitivity', 'MPA', (238, 259))	('H3K27', 'Protein', (27, 32))
28444	31181810	Our data indicates that repression of H3K27 methylation is a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function is a viable approach to overcome treatment failure.	('methylation', 'Var', (44, 55))	('overcome treatment failure', 'Disease', (183, 209))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('cisplatin acquired resistance', 'MPA', (74, 103))	('repression', 'NegReg', (24, 34))	('mechanism', 'Reg', (61, 70))	('H3K27', 'Protein', (38, 43))	('TGCTs', 'Disease', (107, 112))	('overcome treatment failure', 'Disease', 'MESH:D016609', (183, 209))
28458	31181810	In comparison to other tumors, TGCTs possess unique epigenetic states due to the origins from primordial germ cells, including distinct patterns of DNA methylation and repressive and active histone modifications associated with pluripotent states.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('DNA methylation', 'Var', (148, 163))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
28459	31181810	Aberrant epigenetics are likely a major driving force in TGCT etiology and progression, since these tumors have a relative paucity of genetic alterations in cancer drivers.	('TGCT', 'Disease', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Aberrant epigenetics', 'Var', (0, 20))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (157, 163))
28460	31181810	In the current study, we employed unique cisplatin resistant cell models and de novo transcriptional profiling approaches that unexpectedly uncovered an important role for polycomb in TGCT sensitivity and resistance to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('TGCT', 'MPA', (184, 188))	('polycomb', 'Var', (172, 180))	('resistance', 'MPA', (205, 215))
28462	31181810	Importantly, repression of H3K27 methylation conferred cisplatin resistance to parental cells, while induction of H3K27 methylation resulted in increased cisplatin sensitivity.	('methylation', 'Var', (33, 44))	('conferred', 'Reg', (45, 54))	('cisplatin sensitivity', 'MPA', (154, 175))	('H3K27', 'Protein', (27, 32))	('cisplatin resistance', 'MPA', (55, 75))	('methylation', 'Var', (120, 131))	('repression', 'NegReg', (13, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('H3K27 methylation', 'Var', (114, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('increased', 'PosReg', (144, 153))
28464	31181810	Furthermore, we provide evidence that repression of H3K27 methylation is a mechanism of cisplatin acquired resistance in TGCTs and suggest that drugs targeting PRC2 function are a viable approach to overcome treatment failure in TGCT patients and to potentially sensitize other solid tumors to chemotherapy.	('TGCTs', 'Disease', (121, 126))	('solid tumors', 'Disease', 'MESH:D009369', (278, 290))	('PRC2', 'Gene', (160, 164))	('overcome treatment failure', 'Disease', 'MESH:D016609', (199, 225))	('methylation', 'Var', (58, 69))	('solid tumors', 'Disease', (278, 290))	('overcome treatment failure', 'Disease', (199, 225))	('repression', 'NegReg', (38, 48))	('mechanism', 'Reg', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('patients', 'Species', '9606', (234, 242))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('TGCT', 'Disease', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('cisplatin acquired resistance', 'MPA', (88, 117))	('H3K27', 'Protein', (52, 57))
28477	31181810	The gene set enrichment analysis (GSEA) revealed that the cisplatin resistant cells, as compared with their respective parental cells, exhibited dramatic upregulation in genes associated with H3K27 methylation and polycomb repressive complex 2 (PRC2) pathways (Figure 2B,C and Supplementary Table S2).	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('H3K27 methylation', 'Protein', (192, 209))	('men', 'Species', '9606', (283, 286))	('men', 'Species', '9606', (19, 22))	('cisplatin', 'Var', (58, 67))	('upregulation', 'PosReg', (154, 166))	('GSEA', 'Chemical', '-', (34, 38))	('genes', 'Gene', (170, 175))
28484	31181810	Consistent with the premise that cisplatin resistant cells repress PRC2 signaling, GSEA also revealed that resistant cells decreased expression of genes that were downregulated when PRC2 component SUZ12 was deleted in mouse ES cells (Supplementary Figure S3).	('GSEA', 'Chemical', '-', (83, 87))	('men', 'Species', '9606', (240, 243))	('decreased', 'NegReg', (123, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('deleted', 'Var', (207, 214))	('downregulated', 'NegReg', (163, 176))	('mouse', 'Species', '10090', (218, 223))	('expression of genes', 'MPA', (133, 152))
28491	31181810	Consistent with the upregulation in expression of genes normally repressed by PRC1/PRC2, the PRC2-mediated repressive mark H3K27me3 was consistently downregulated in the resistant cells as was the PRC1 repressive mark H2A-K119Ub (Figure 3B).	('H2A-K', 'Gene', (218, 223))	('PRC1', 'Gene', '9055', (78, 82))	('H3K27me3', 'Var', (123, 131))	('downregulated', 'NegReg', (149, 162))	('PRC1', 'Gene', (197, 201))	('PRC1', 'Gene', (78, 82))	('upregulation', 'PosReg', (20, 32))	('H2A-K', 'Gene', '8333', (218, 223))	('PRC1', 'Gene', '9055', (197, 201))
28498	31181810	The GSK126 treatment resulted in decreased H3K27me3 levels and conferred cisplatin resistance to NT2/D1, 2010EP, and 833K cells (Figure 4B,C).	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('GSK126', 'Chemical', 'MESH:C577920', (4, 10))	('H3K27me3 levels', 'MPA', (43, 58))	('men', 'Species', '9606', (16, 19))	('GSK126', 'Var', (4, 10))	('cisplatin resistance', 'MPA', (73, 93))	('decreased', 'NegReg', (33, 42))	('conferred', 'Reg', (63, 72))
28499	31181810	In a reciprocal experiment, pretreatment of randomly chosen cisplatin resistant cells NT2/D1-A4, NT2/D1-H1, 2010EP-B3, and 833K-B4 with the specific JMJD3 H3K27 demethylase inhibitor, GSKJ4, (0.5 microM) resulted in increased H3K27me3 and sensitized the cells to cisplatin (Figure 4B-D).	('JMJD3', 'Gene', (149, 154))	('JMJD3', 'Gene', '23135', (149, 154))	('demethylase', 'Gene', (161, 172))	('H3K27me3', 'Protein', (226, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('men', 'Species', '9606', (22, 25))	('men', 'Species', '9606', (36, 39))	('demethylase', 'Gene', '8932', (161, 172))	('increased', 'PosReg', (216, 225))	('sensitized', 'Reg', (239, 249))	('0.5', 'Var', (192, 195))
28500	31181810	These results indicate that modulating H3K27 methylation alters cisplatin sensitivity in TGCT cells.	('cisplatin sensitivity', 'MPA', (64, 85))	('H3K27', 'Protein', (39, 44))	('alters', 'Reg', (57, 63))	('methylation', 'Var', (45, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('modulating', 'Var', (28, 38))
28509	31181810	When patients were divided by the median of the sum Z-score, Kaplan-Meier analysis indicated that those with a higher expression of the H3K27me3 gene signature had a lower rate of disease-free survival (p = 0.034, hazard ratio = 2.1) (Figure 5E).	('patients', 'Species', '9606', (5, 13))	('H3K27me3', 'Var', (136, 144))	('lower', 'NegReg', (166, 171))	('disease-free survival', 'CPA', (180, 201))	('higher', 'PosReg', (111, 117))	('expression', 'MPA', (118, 128))
28514	31181810	Importantly, repression of H3K27 methylation conferred cisplatin resistance to parental cells while induction of H3K27 methylation resulted in an increased cisplatin sensitivity.	('methylation', 'Var', (33, 44))	('conferred', 'Reg', (45, 54))	('increased', 'PosReg', (146, 155))	('methylation', 'Var', (119, 130))	('cisplatin resistance', 'MPA', (55, 75))	('repression', 'NegReg', (13, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('H3K27 methylation', 'Var', (113, 130))	('cisplatin sensitivity', 'MPA', (156, 177))	('H3K27', 'Protein', (27, 32))
28526	31181810	The EZH2 catalyzes H3K27 trimethylation which is a docking site for the PRC1 complex that catalyzes monoubiquitination of H2A on K119.	('EZH2', 'Gene', '2146', (4, 8))	('H3K27', 'Protein', (19, 24))	('EZH2', 'Gene', (4, 8))	('PRC1', 'Gene', (72, 76))	('PRC1', 'Gene', '9055', (72, 76))	('H2A', 'Protein', (122, 125))	('K119', 'Var', (129, 133))	('monoubiquitination', 'MPA', (100, 118))
28527	31181810	In solid tumors, PRC2 has mainly been associated with oncogenesis and a poor outcome, as a large number of epithelial malignancies have gain-of-function mutations or overexpression of polycomb components which has spurred the clinical development of EZH2 inhibitors.	('EZH2', 'Gene', (250, 254))	('mutations', 'Var', (153, 162))	('epithelial malignancies', 'Disease', 'MESH:D002277', (107, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('gain-of-function', 'PosReg', (136, 152))	('solid tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('men', 'Species', '9606', (242, 245))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (107, 130))	('epithelial malignancies', 'Disease', (107, 130))	('EZH2', 'Gene', '2146', (250, 254))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))	('overexpression', 'PosReg', (166, 180))
28528	31181810	However, a loss-of-function of PRC2 mutations has also been shown to occur in a subset of tumor types including malignant peripheral nerve sheath tumor (MPNST), pediatric gliomas, myelodysplastic syndrome/AML, and T cell acute lymphoblastic leukemia.	('T cell acute lymphoblastic leukemia', 'Disease', (214, 249))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (180, 204))	('tumor', 'Disease', (146, 151))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (221, 249))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (180, 204))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (214, 249))	('peripheral nerve sheath tumor', 'Disease', 'MESH:D010524', (122, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('PRC2', 'Gene', (31, 35))	('tumor', 'Disease', (90, 95))	('loss-of-function', 'NegReg', (11, 27))	('malignant peripheral nerve sheath tumor', 'Phenotype', 'HP:0100697', (112, 151))	('T cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (214, 249))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (227, 249))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('AML', 'Disease', 'MESH:D015470', (205, 208))	('pediatric gliomas', 'Disease', 'MESH:D005910', (161, 178))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('AML', 'Disease', (205, 208))	('myelodysplastic syndrome', 'Disease', (180, 204))	('gliomas', 'Phenotype', 'HP:0009733', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutations', 'Var', (36, 45))	('leukemia', 'Phenotype', 'HP:0001909', (241, 249))	('pediatric gliomas', 'Disease', (161, 178))	('peripheral nerve sheath tumor', 'Disease', (122, 151))
28531	31181810	The finding that repression of PRC1/2 signaling induces cisplatin resistance in TGCTs was unexpected.	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('induces', 'PosReg', (48, 55))	('cisplatin resistance', 'MPA', (56, 76))	('PRC1/2', 'Gene', (31, 37))	('repression', 'Var', (17, 27))	('PRC1/2', 'Gene', '9055', (31, 37))
28535	31181810	Higher expression of EZH2 or H3K27m3e was associated with cisplatin resistance in ovarian cancer, non-small cell lung cancer, osteosarcoma, and glioblastoma.	('osteosarcoma', 'Disease', (126, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cisplatin resistance', 'MPA', (58, 78))	('osteosarcoma', 'Disease', 'MESH:D012516', (126, 138))	('non-small cell lung cancer', 'Disease', (98, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('osteosarcoma', 'Phenotype', 'HP:0002669', (126, 138))	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('expression', 'MPA', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('ovarian cancer', 'Disease', (82, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('associated', 'Reg', (42, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('glioblastoma', 'Disease', (144, 156))	('H3K27m3e', 'Var', (29, 37))	('Higher', 'PosReg', (0, 6))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))
28536	31181810	Hypermethylation of H3K27 in these studies was linked to the suppression of tumor suppressor genes such as RASSF1A, MLH1, and CYT19, as well as apoptosis.	('CYT19', 'Gene', (126, 131))	('MLH1', 'Gene', (116, 120))	('Hypermethylation', 'Var', (0, 16))	('MLH1', 'Gene', '4292', (116, 120))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('apoptosis', 'CPA', (144, 153))	('RASSF1A', 'Gene', (107, 114))	('suppression', 'NegReg', (61, 72))	('H3K27', 'Protein', (20, 25))	('RASSF1A', 'Gene', '11186', (107, 114))	('CYT19', 'Gene', '57412', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
28540	31181810	NT2/D1, 833K, and 2102EP are human testicular cancer derived EC cell lines purchased from ATCC and authenticated by ATCC with karyotyping and short tandem repeat profiling.	('2102EP', 'Var', (18, 24))	('testicular cancer', 'Disease', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (29, 34))	('testicular cancer', 'Phenotype', 'HP:0010788', (35, 52))	('testicular cancer', 'Disease', 'MESH:D013736', (35, 52))
28564	31181810	Antibodies to actin (1:1000; MA1-744, Thermo Fisher Scientific, Waltham, MA, USA), histone H2A (1:1000; 8240, Cell Signaling Technology, Danvers, MA, USA), histone H3 (1:1000; ab1791, Abcam, Cambridge, MA, USA), Ubiquitin H2A-K119 (1:1000; 3240, Cell Signaling Technology), BMI1 (1:1000; 6964, Cell Signaling Technology), EZH2 (1:1000; 5246, Cell Signaling Technology) and H3K27me3 (1:1000; 9733, Cell Signaling Technology) were used.	('EZH2', 'Gene', (322, 326))	('H2A-K', 'Gene', (222, 227))	('BMI1', 'Gene', (274, 278))	('H3K27me3', 'Var', (373, 381))	('H2A-K', 'Gene', '8333', (222, 227))	('BMI1', 'Gene', '648', (274, 278))	('EZH2', 'Gene', '2146', (322, 326))
28571	31181810	(3) Inhibition of H3K27 methylation mediates cisplatin resistance and inhibition of H3K27 demethylation sensitizes testicular cancer cells to cisplatin.	('inhibition', 'NegReg', (70, 80))	('testicular cancer', 'Disease', 'MESH:D013736', (115, 132))	('sensitizes', 'Reg', (104, 114))	('testicular cancer', 'Phenotype', 'HP:0010788', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('methylation', 'MPA', (24, 35))	('H3K27', 'Protein', (84, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('Inhibition', 'NegReg', (4, 14))	('mediates', 'Reg', (36, 44))	('cisplatin resistance', 'MPA', (45, 65))	('testicular cancer', 'Disease', (115, 132))	('H3K27', 'Protein', (18, 23))	('demethylation', 'Var', (90, 103))
28574	31181810	We employed unique cisplatin resistant cell models and de novo transcriptional profiling that unexpectedly uncovered an important role for polycomb in TGCT sensitivity and resistance to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (186, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('sensitivity', 'MPA', (156, 167))	('polycomb', 'Var', (139, 147))	('resistance to cisplatin', 'MPA', (172, 195))
28575	31181810	Furthermore, we provide evidence that repression of H3K27 methylation is a mechanism of cisplatin-acquired resistance in TGCTs and suggest that drugs targeting PRC2 function may be a viable approach to overcome treatment failure in testicular cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('testicular cancer', 'Phenotype', 'HP:0010788', (232, 249))	('testicular cancer', 'Disease', 'MESH:D013736', (232, 249))	('patients', 'Species', '9606', (250, 258))	('PRC2', 'Gene', (160, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('methylation', 'Var', (58, 69))	('repression', 'NegReg', (38, 48))	('mechanism', 'Reg', (75, 84))	('testicular cancer', 'Disease', (232, 249))	('overcome treatment failure', 'Disease', 'MESH:D016609', (202, 228))	('overcome treatment failure', 'Disease', (202, 228))	('cisplatin-acquired resistance', 'MPA', (88, 117))	('H3K27', 'Protein', (52, 57))
28585	21199783	Finally, we will discuss how crosstalk among desmosome-like junctions, tight junctions, ectoplasmic specializations, and gap junctions facilitates the movement of preleptotene/leptotene spermatocytes across the BTB from stages VIII to XI of the seminiferous epithelial cycle.	('preleptotene', 'Chemical', '-', (163, 175))	('crosstalk', 'Var', (29, 38))	('leptotene', 'Chemical', '-', (176, 185))	('leptotene', 'Chemical', '-', (166, 175))	('VIII', 'Gene', '1351', (227, 231))	('VIII', 'Gene', (227, 231))	('facilitates', 'PosReg', (135, 146))	('movement', 'CPA', (151, 159))
28633	21199783	For example, in keratinocytes isolated from plakoglobin knockout mice, the incorporation of desmosomal proteins such as desmogleins-1 and -2 into the plasma membrane was impaired.	('rat', 'Species', '10116', (18, 21))	('impaired', 'NegReg', (170, 178))	('mice', 'Species', '10090', (65, 69))	('rat', 'Species', '10116', (82, 85))	('incorporation of desmosomal proteins', 'MPA', (75, 111))	('desmogleins-1 and -2', 'Gene', '13511', (120, 140))	('knockout', 'Var', (56, 64))
28634	21199783	In another related study published by a separate group of investigators, keratinocytes from plakoglobin knockout mice were still capable of clustering desmosomal cadherins on the cell surface and forming desmosome-like junctions, except that in this case beta-catenin appeared to compensate for the loss in plakoglobin.	('cadherin', 'Gene', (162, 170))	('mice', 'Species', '10090', (113, 117))	('rat', 'Species', '10116', (75, 78))	('rat', 'Species', '10116', (44, 47))	('knockout', 'Var', (104, 112))	('plakoglobin', 'Gene', (92, 103))	('clustering', 'MPA', (140, 150))	('cadherin', 'Gene', '999;414745;1000;12558;1003', (162, 170))
28639	21199783	For instance, the adhesive strength of desmosomes was shown to be downregulated by phosphorylation of plakoglobin following activation of the epidermal growth factor receptor (EGFR).	('activation', 'PosReg', (124, 134))	('EGFR', 'Gene', '1956', (176, 180))	('adhesive strength of desmosomes', 'CPA', (18, 49))	('downregulated', 'NegReg', (66, 79))	('epidermal growth factor receptor', 'Gene', (142, 174))	('EGFR', 'Gene', (176, 180))	('epidermal growth factor receptor', 'Gene', '1956', (142, 174))	('phosphorylation', 'Var', (83, 98))
28645	21199783	For instance, mutations in plakophilin-1 result in ectodermal dysplasia/skin fragility syndrome, whereas mutations in plakophilin-2 associate with arrhythmogenic right ventricular cardiomyopathy.	('ectodermal dysplasia/skin fragility syndrome', 'Disease', (51, 95))	('ectodermal dysplasia/skin fragility syndrome', 'Disease', 'MESH:C536183', (51, 95))	('plakophilin-1', 'Gene', (27, 40))	('arrhythmogenic right ventricular cardiomyopathy', 'Disease', 'MESH:D019571', (147, 194))	('plakophilin-2', 'Gene', (118, 131))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (180, 194))	('skin fragility', 'Phenotype', 'HP:0001030', (72, 86))	('plakophilin-1', 'Gene', '5317', (27, 40))	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (51, 71))	('associate with', 'Reg', (132, 146))	('mutations', 'Var', (105, 114))	('arrhythmogenic right ventricular cardiomyopathy', 'Disease', (147, 194))	('plakophilin-2', 'Gene', '5318', (118, 131))	('result in', 'Reg', (41, 50))	('right ventricular cardiomyopathy', 'Phenotype', 'HP:0011663', (162, 194))	('mutations', 'Var', (14, 23))
28718	21199783	The disruption of this multiprotein complex by plakophilin-2 silencing rendered desmoplakin less phosphorylated which then associated with the intermediate filament network.	('less', 'NegReg', (92, 96))	('associated', 'Interaction', (123, 133))	('plakophilin-2', 'Gene', (47, 60))	('silencing', 'Var', (61, 70))	('plakophilin-2', 'Gene', '5318', (47, 60))
28732	21199783	Cleavage of these proteins produces two or more intracellular and extracellular fragments, which are then further processed into smaller fragments and internalized from the cell surface, resulting in the disintegration of desmosomal structure.	('disintegration', 'MPA', (204, 218))	('Cleavage', 'Var', (0, 8))	('rat', 'Species', '10116', (212, 215))
28751	21199783	Disruption of this complex by plakophilin-2 knockdown not only blocked desmoplakin recruitment but also resulted in the release of PKC-alpha and in the increase in phosphorylation of PKC-alpha substrates, indicating a role for plakophilin-2 in the sequestration of PKC-alpha.	('plakophilin-2', 'Gene', (227, 240))	('desmoplakin recruitment', 'MPA', (71, 94))	('increase', 'PosReg', (152, 160))	('phosphorylation', 'MPA', (164, 179))	('plakophilin-2', 'Gene', '5318', (227, 240))	('PKC-alpha', 'Gene', (265, 274))	('PKC-alpha', 'Gene', (131, 140))	('release', 'MPA', (120, 127))	('rat', 'Species', '10116', (198, 201))	('PKC-alpha', 'Gene', '5578', (265, 274))	('PKC-alpha', 'Gene', (183, 192))	('plakophilin-2', 'Gene', (30, 43))	('knockdown', 'Var', (44, 53))	('rat', 'Species', '10116', (255, 258))	('PKC-alpha', 'Gene', '5578', (131, 140))	('blocked', 'NegReg', (63, 70))	('PKC-alpha', 'Gene', '5578', (183, 192))	('plakophilin-2', 'Gene', '5318', (30, 43))
28755	21199783	For instance, an increase in cell motility was noted in keratinocytes isolated from the skin of plakoglobin knockout mice.	('mice', 'Species', '10090', (117, 121))	('rat', 'Species', '10116', (58, 61))	('increase', 'PosReg', (17, 25))	('knockout', 'Var', (108, 116))	('cell motility', 'CPA', (29, 42))
28758	21199783	Interestingly, simultaneous knockdown of desmoglein-2 and desmocollin-2 by RNA interference (RNAi) led to the relocation of Src from the Sertoli cell surface to the cytoplasm, suggesting that desmoglein-2 is a docking site for Src (; Fig.	('desmoglein-2', 'Gene', (41, 53))	('relocation', 'MPA', (110, 120))	('desmoglein-2', 'Gene', '1829', (192, 204))	('desmocollin-2', 'Gene', (58, 71))	('Sertoli cell', 'Phenotype', 'HP:0100619', (137, 149))	('desmocollin-2', 'Gene', '1824', (58, 71))	('desmoglein-2', 'Gene', '1829', (41, 53))	('Src', 'Gene', (227, 230))	('Src', 'Gene', (124, 127))	('Src', 'Gene', '6714', (227, 230))	('desmoglein-2', 'Gene', (192, 204))	('knockdown', 'Var', (28, 37))	('Src', 'Gene', '6714', (124, 127))
28759	21199783	Concurrent with the mislocalization of Src, a decrease in the integrity of the tight junction barrier was noted, possibly resulting from the disruptive effects of Src on occludin-zonula occludens-1 (ZO-1) and connexin-43-ZO-1 interactions, which are critical for barrier dynamics.	('Src', 'Gene', (39, 42))	('disruptive effects', 'NegReg', (141, 159))	('connexin-43', 'Gene', (209, 220))	('Src', 'Gene', '6714', (39, 42))	('Src', 'Gene', '6714', (163, 166))	('interactions', 'Interaction', (226, 238))	('ZO-1', 'Gene', '7082', (221, 225))	('integrity', 'MPA', (62, 71))	('ZO-1', 'Gene', (199, 203))	('connexin-43', 'Gene', '2697', (209, 220))	('ZO-1', 'Gene', (221, 225))	('occludin-zonula occludens-1', 'Gene', (170, 197))	('Src', 'Gene', (163, 166))	('occludin-zonula occludens-1', 'Gene', '7082', (170, 197))	('decrease', 'NegReg', (46, 54))	('mislocalization', 'Var', (20, 35))	('ZO-1', 'Gene', '7082', (199, 203))
28769	21199783	However, phosphorylation of Tyr-549 by Fer kinase increased plakoglobin's association with adherens junctions.	('Tyr', 'Chemical', 'MESH:D014443', (28, 31))	('increased', 'PosReg', (50, 59))	('Tyr-549', 'Var', (28, 35))	('Fer kinase', 'Enzyme', (39, 49))	('association', 'Interaction', (74, 85))	('phosphorylation', 'MPA', (9, 24))
28784	21199783	The necessity of these proteolytic products for the propagation of apoptotic signals was also reflected by the knockdown of desmoglein-1 and desmoglein-2, two caspase 3 targets which protected epithelial cells from apoptosis.	('knockdown', 'Var', (111, 120))	('desmoglein-1', 'Gene', '1828', (124, 136))	('apoptosis', 'CPA', (215, 224))	('caspase 3', 'Gene', (159, 168))	('desmoglein-2', 'Gene', (141, 153))	('caspase 3', 'Gene', '836', (159, 168))	('desmoglein-1', 'Gene', (124, 136))	('desmoglein-2', 'Gene', '1829', (141, 153))
28801	21199783	Interestingly, knockdown of FAK, a nonreceptor tyrosine kinase, by RNAi was shown to desensitize Sertoli cells from the adverse effects of cadmium on the permeability barrier, demonstrating that FAK is an important regulator of BTB restructuring in vivo.	('rat', 'Species', '10116', (183, 186))	('knockdown', 'Var', (15, 24))	('FAK', 'Gene', '5747', (28, 31))	('FAK', 'Gene', (195, 198))	('FAK', 'Gene', '5747', (195, 198))	('Sertoli cells', 'MPA', (97, 110))	('Sertoli cells', 'Phenotype', 'HP:0100619', (97, 110))	('cadmium', 'Chemical', 'MESH:D002104', (139, 146))	('FAK', 'Gene', (28, 31))	('Sertoli cell', 'Phenotype', 'HP:0100619', (97, 109))	('desensitize', 'NegReg', (85, 96))
28817	21199783	There are numerous studies reporting cadherin function to be regulated by cytokines, androgens, estrogens, protein kinases, and phosphatases, and small GTPases, as well as by phosphorylation, changes in protein-protein interactions and endocytosis.	('cadherin', 'Gene', '999;414745;1000;12558;1003', (37, 45))	('endocytosis', 'MPA', (236, 247))	('changes', 'Reg', (192, 199))	('cadherin', 'Gene', (37, 45))	('protein-protein', 'Protein', (203, 218))	('phosphorylation', 'Var', (175, 190))
28823	21199783	In terms of biological activity, the NTF of N-cadherin has been shown to associate with the extracellular matrix, suggesting a role in cell movement.	('N-cadherin', 'Gene', '1000', (44, 54))	('associate', 'Interaction', (73, 82))	('cell movement', 'CPA', (135, 148))	('NTF', 'Var', (37, 40))	('role', 'Reg', (127, 131))	('N-cadherin', 'Gene', (44, 54))
28824	21199783	Indeed, the NTF of cadherin 11 (generated via ADAMs 9 and 13) was demonstrated to promote cell migration in the X. laevis neural crest.	('promote', 'PosReg', (82, 89))	('rat', 'Species', '10116', (36, 39))	('X. laevis', 'Species', '8355', (112, 121))	('NTF', 'Var', (12, 15))	('cadherin 11', 'Gene', (19, 30))	('cadherin 11', 'Gene', '108714048', (19, 30))	('rat', 'Species', '10116', (98, 101))	('ADAMs 9 and 13', 'Gene', '373605;386623', (46, 60))	('cell migration in the X. laevis neural crest', 'CPA', (90, 134))	('rat', 'Species', '10116', (73, 76))
28838	21199783	This is in agreement with our recent findings which demonstrated a compromise in tight junction permeability barrier function following the knockdown of desmosomal proteins.	('compromise', 'NegReg', (67, 77))	('knockdown', 'Var', (140, 149))	('tight junction permeability barrier function', 'MPA', (81, 125))	('rat', 'Species', '10116', (59, 62))
28839	21199783	Simultaneous knockdown of desmoglein-2 and desmocollin-2 by RNAi in cultured Sertoli cells having an assembled barrier:one which mimicked the BTB in vivo:resulted in a marked decrease in tight junction barrier function when assessed by transepithelial electrical resistance (TER) measurements.	('Sertoli cell', 'Phenotype', 'HP:0100619', (77, 89))	('Sertoli cells', 'Phenotype', 'HP:0100619', (77, 90))	('desmoglein-2', 'Gene', '1829', (26, 38))	('decrease', 'NegReg', (175, 183))	('desmocollin-2', 'Gene', (43, 56))	('desmoglein-2', 'Gene', (26, 38))	('tight junction barrier function', 'MPA', (187, 218))	('knockdown', 'Var', (13, 22))	('desmocollin-2', 'Gene', '1824', (43, 56))
28905	20978513	In addition, meta-analytic synthesis of all available pre- and perinatal data has implicated low-birth order, maternal bleeding during pregnancy, larger sibship size, low-birth weight, twinning, gestational age, and inguinal hernia in the etiopathogenesis of testicular cancer.	('low-birth weight', 'Var', (167, 183))	('inguinal hernia', 'Phenotype', 'HP:0000023', (216, 231))	('testicular cancer', 'Phenotype', 'HP:0010788', (259, 276))	('testicular cancer', 'Disease', 'MESH:D013736', (259, 276))	('inguinal hernia', 'Disease', (216, 231))	('bleeding', 'Disease', 'MESH:D006470', (119, 127))	('inguinal hernia', 'Disease', 'MESH:D006552', (216, 231))	('bleeding', 'Disease', (119, 127))	('testicular cancer', 'Disease', (259, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('low-birth', 'Var', (93, 102))	('low-birth order', 'Phenotype', 'HP:0001518', (93, 108))	('low-birth weight', 'Phenotype', 'HP:0001518', (167, 183))	('hernia', 'Phenotype', 'HP:0100790', (225, 231))	('maternal bleeding during pregnancy', 'Phenotype', 'HP:0030244', (110, 144))
28907	20978513	There is some evidence that high fat or high dairy intake in childhood is associated with both adult body size and risk for testicular cancer.	('testicular cancer', 'Disease', (124, 141))	('high dairy', 'Var', (40, 50))	('adult body size', 'CPA', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('high fat', 'Var', (28, 36))	('testicular cancer', 'Phenotype', 'HP:0010788', (124, 141))	('testicular cancer', 'Disease', 'MESH:D013736', (124, 141))	('associated with', 'Reg', (74, 89))
28915	20978513	BMI (kg m-2) was also examined as an ordinal variable using groupings of normal (BMI <25), overweight (BMI 25-29.9), and obese (BMI >=30).	('obese', 'Disease', (121, 126))	('obese', 'Disease', 'MESH:D009765', (121, 126))	('overweight', 'Phenotype', 'HP:0025502', (91, 101))	('BMI', 'Var', (103, 106))
28922	20978513	When we compared the obese group with the referent group, BMI was not related to TGCT, with a summary risk estimate of 0.92 per unit BMI (95% CI: 0.75-1.15, P=0.496) with an I2 of 46% (95% UI: 0-100%).	('BMI', 'Var', (133, 136))	('TGCT', 'Disease', (81, 85))	('obese', 'Disease', 'MESH:D009765', (21, 26))	('TGCT', 'Phenotype', 'HP:0010788', (81, 85))	('obese', 'Disease', (21, 26))
28968	19480691	As previously discussed, TSE may improve high-risk men's sense of control over their own health.	('improve', 'PosReg', (33, 40))	('sense of control', 'MPA', (57, 73))	('TSE', 'Var', (25, 28))	('men', 'Species', '9606', (51, 54))
29063	15150569	KIT has been shown to be expressed in some TGCT (Strohmeyer et al, 1995; Bokemeyer et al, 1996) and somatic mutations in KIT have recently been identified in testicular (Tian et al, 1999) and mediastinal germ cell tumours (Przygodzki et al, 2002).	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('germ cell tumours', 'Disease', (204, 221))	('KIT', 'Gene', (121, 124))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('testicular', 'Disease', (158, 168))	('germ cell tumours', 'Disease', 'MESH:D009373', (204, 221))	('identified', 'Reg', (144, 154))
29064	15150569	Mutations have been reported in a high proportion of patients with bilateral disease, and in a much smaller proportion of unilateral cases (Looijenga et al, 2003).	('bilateral disease', 'Disease', 'MESH:D006312', (67, 84))	('reported', 'Reg', (20, 28))	('patients', 'Species', '9606', (53, 61))	('bilateral disease', 'Disease', (67, 84))	('Mutations', 'Var', (0, 9))
29066	15150569	As a consequence, primordial germ cells with KIT mutations are distributed to both testes and hence KIT mutations are associated with bilateral disease (Looijenga et al, 2003).	('KIT', 'Gene', (100, 103))	('KIT', 'Gene', (45, 48))	('mutations', 'Var', (104, 113))	('mutations', 'Var', (49, 58))	('bilateral disease', 'Disease', 'MESH:D006312', (134, 151))	('bilateral disease', 'Disease', (134, 151))	('associated', 'Reg', (118, 128))
29067	15150569	Previous studies have indicated that KIT mutations found in germ cell tumours are somatic.	('mutations', 'Var', (41, 50))	('germ cell tumours', 'Disease', (60, 77))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('KIT', 'Gene', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('germ cell tumours', 'Disease', 'MESH:D009373', (60, 77))
29075	15150569	Mutations of KIT are predominantly located in exons 10, 11 and 17 (Pignon et al, 1997; Tian et al, 1999; Rubin et al, 2001; Przygodzki et al, 2002; Looijenga et al, 2003); therefore, the tumour material was examined only at these exons.	('tumour', 'Disease', (187, 193))	('Mutations', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('KIT', 'Gene', (13, 16))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
29081	15150569	Two conservative nonsynonymous constitutional sequence variants were detected, M541L and V399I (Table 3  ).	('M541L', 'Var', (79, 84))	('V399I', 'Mutation', 'rs143707288', (89, 94))	('M541L', 'Mutation', 'rs3822214', (79, 84))	('V399I', 'Var', (89, 94))
29084	15150569	V399 is not conserved in other species (mouse, zebrafish and xenopus) and the amino-acid substitution is conservative, suggesting that this variant is a rare polymorphism rather than a disease-causing change.	('xenopus', 'Species', '8355', (61, 68))	('variant', 'Var', (140, 147))	('zebrafish', 'Species', '7955', (47, 56))	('mouse', 'Species', '10090', (40, 45))	('V399', 'Var', (0, 4))
29085	15150569	Overall, the results provide no evidence that germline KIT mutations are associated with an increased risk of testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (110, 127))	('testicular cancer', 'Disease', 'MESH:D013736', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('germline KIT mutations', 'Var', (46, 68))	('associated', 'Reg', (73, 83))	('testicular cancer', 'Disease', (110, 127))
29086	15150569	Three mutations involved codon 816, a known hotspot for KIT mutations in testicular (Tian et al, 1999; Przygodzki et al, 2002; Looijenga et al, 2003) and other cancers (Rubin et al, 2001).	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('testicular', 'Disease', (73, 83))	('cancers', 'Disease', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (60, 69))
29087	15150569	In-frame deletions of this region are common in gastrointestinal stromal tumours (GIST) (Rubin et al, 2001) but have not been documented in TGCT.	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (48, 80))	('deletions', 'Var', (9, 18))	('gastrointestinal stromal tumours', 'Disease', (48, 80))	('common', 'Reg', (38, 44))
29088	15150569	Unfortunately, samples of the other tumour/ITGCN from the two bilateral cases with KIT mutations were not available to evaluate the presence of the mutations.	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (87, 96))	('tumour', 'Disease', (36, 42))
29089	15150569	While the frequency of KIT mutations in unilateral TGCT is similar to that detected previously, the proportion of cases with bilateral disease is much lower despite the fact that we examined a larger proportion of the KIT gene than in the study by Looijenga et al (2003).	('mutations', 'Var', (27, 36))	('bilateral disease', 'Disease', (125, 142))	('bilateral disease', 'Disease', 'MESH:D006312', (125, 142))
29121	32252147	However, intrauterine torsion of the gonadal vessel and failure of the intrauterine testicular blood supply may also cause testicular agenesis or in utero infarction and atrophy of normal testis, resulting in vanishing testis or testicular regression.	('testicular agenesis', 'CPA', (123, 142))	('atrophy', 'Disease', 'MESH:D001284', (170, 177))	('testicular regression', 'Phenotype', 'HP:0012870', (229, 250))	('atrophy', 'Disease', (170, 177))	('vanishing testis', 'Phenotype', 'HP:0012870', (209, 225))	('vanishing', 'NegReg', (209, 218))	('intrauterine', 'Var', (9, 21))	('infarction', 'Disease', 'MESH:D007238', (155, 165))	('testicular agenesis', 'Phenotype', 'HP:0010469', (123, 142))	('infarction', 'Disease', (155, 165))	('cause', 'Reg', (117, 122))	('testicular regression', 'CPA', (229, 250))
29147	32252147	Abnormalities in gonocyte transformation can cause infertility.	('gonocyte transformation', 'CPA', (17, 40))	('infertility', 'Disease', 'MESH:D007247', (51, 62))	('Abnormalities', 'Var', (0, 13))	('infertility', 'Phenotype', 'HP:0000789', (51, 62))	('infertility', 'Disease', (51, 62))	('cause', 'Reg', (45, 50))
29156	32252147	In a meta-analysis, patients with undescended testis are at a threefold increased risk of testicular cancer later in life.	('testicular cancer', 'Phenotype', 'HP:0010788', (90, 107))	('testicular cancer', 'Disease', 'MESH:D013736', (90, 107))	('undescended', 'Var', (34, 45))	('testicular cancer', 'Disease', (90, 107))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('undescended testis', 'Phenotype', 'HP:0000028', (34, 52))
29157	32252147	In another study, the risk of testicular cancer is increased sevenfold in patients with undescended testes and 32-fold if orchiopexy is delayed after puberty.	('undescended', 'Var', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('testicular cancer', 'Phenotype', 'HP:0010788', (30, 47))	('patients', 'Species', '9606', (74, 82))	('testicular cancer', 'Disease', 'MESH:D013736', (30, 47))	('undescended testes', 'Phenotype', 'HP:0000028', (88, 106))	('testicular cancer', 'Disease', (30, 47))
29190	31774524	Furthermore, marijuana use is associated with histopathologic bronchial inflammatory changes comparable to changes observed with smoking tobacco.	('marijuana use', 'Var', (13, 26))	('bronchial inflammatory', 'Disease', (62, 84))	('marijuana', 'Species', '3483', (13, 22))	('tobacco', 'Species', '4097', (137, 144))
29195	31774524	In contrast, cannabinoids, including tetrahydrocannabinol, can inhibit proliferation of some cancer cell types, impede angiogenesis in vitro, and reduce cancer growth in some animal models.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (153, 159))	('tetrahydrocannabinol', 'Var', (37, 57))	('impede', 'NegReg', (112, 118))	('tetrahydrocannabinol', 'Chemical', 'MESH:D013759', (37, 57))	('angiogenesis', 'CPA', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('proliferation', 'CPA', (71, 84))	('inhibit', 'NegReg', (63, 70))	('reduce', 'NegReg', (146, 152))	('cannabinoids', 'Chemical', 'MESH:D002186', (13, 25))
29249	31774524	Finally, a prospective study found that marijuana use among HIV-infected white men was associated with risk for developing Kaposi sarcoma (hazard ratio, 1.52; 95% CI, 0.99-2.32) in the 5-year lagged analysis.	('men', 'Species', '9606', (79, 82))	('HIV-infected', 'Disease', 'MESH:D015658', (60, 72))	('marijuana', 'Var', (40, 49))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (123, 137))	('Kaposi sarcoma', 'Disease', (123, 137))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (123, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('marijuana', 'Species', '3483', (40, 49))	('HIV-infected', 'Disease', (60, 72))
29289	29910774	Histology sections were incubated with primary antibodies including anti-placental-like alkaline phosphatase (PLAP), anti-C-Kit, anti-D2-40, and anti-Oct3/4.	('placental-like alkaline phosphatase', 'Gene', (73, 108))	('placental-like alkaline phosphatase', 'Gene', '251', (73, 108))	('C-Kit', 'Gene', '3815', (122, 127))	('PLAP', 'Gene', '251', (110, 114))	('PLAP', 'Gene', (110, 114))	('C-Kit', 'Gene', (122, 127))	('anti-D2-40', 'Var', (129, 139))	('Oct3/4', 'Gene', '5460', (150, 156))	('Oct3/4', 'Gene', (150, 156))
29303	29910774	We recently published our findings of positive immunostaining of spermatogonia in biopsies from 404 cryptorchid boys with PLAP, C-Kit, D2-40, and Oct3/4, aged up to 15 years without histological features of concomitant cancer or ITGCN, except for two boys.	('boys', 'Species', '9606', (112, 116))	('cryptorchid boys', 'Phenotype', 'HP:0000028', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('C-Kit', 'Gene', '3815', (128, 133))	('PLAP', 'Gene', (122, 126))	('C-Kit', 'Gene', (128, 133))	('Oct3/4', 'Gene', '5460', (146, 152))	('D2-40', 'Var', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('PLAP', 'Gene', '251', (122, 126))	('Oct3/4', 'Gene', (146, 152))	('cancer', 'Disease', (219, 225))	('cryptorchid', 'Disease', (100, 111))	('boys', 'Species', '9606', (251, 255))
29304	29910774	One boy 13 months old was diagnosed with Prader-Willi syndrome and had been treated with growth hormone; the other was 44 months old with 45X/46XY, penoscrotal hypospadia, persistent vaginal, and uterine remnants, and both testes located intra-abdominally.	('penoscrotal hypospadia', 'Phenotype', 'HP:0000808', (148, 170))	('hypospadia', 'Phenotype', 'HP:0000047', (160, 170))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (41, 62))	('boy', 'Species', '9606', (4, 7))	('penoscrotal hypospadia', 'Disease', 'MESH:C566526', (148, 170))	('Prader-Willi syndrome', 'Disease', (41, 62))	('penoscrotal hypospadia', 'Disease', (148, 170))	('45X/46XY', 'Var', (138, 146))
29321	29910774	Histology sections were incubated with primary antibodies, including anti-PLAP (1:200, PL8-F6, Biogenex), anti-C-Kit receptor (1:50, C-Kit, Dako, Glostrup, Denmark), D2-40 (1:25, M3619, Dako, Glostrup, Denmark), and anti-Oct3/4 (RTU, MRG, Cellmarque, CA, USA).	('C-Kit', 'Gene', (111, 116))	('C-Kit', 'Gene', '3815', (111, 116))	('MRG', 'Gene', '116511', (234, 237))	('PLAP', 'Gene', (74, 78))	('PLAP', 'Gene', '251', (74, 78))	('C-Kit', 'Gene', '3815', (133, 138))	('MRG', 'Gene', (234, 237))	('C-Kit', 'Gene', (133, 138))	('Oct3/4', 'Gene', '5460', (221, 227))	('Oct3/4', 'Gene', (221, 227))	('1:25', 'Var', (173, 177))
29352	29910774	Indeed, D2-40 and Oct3/4 positive germ cells persist in cryptorchid testes into the second year of life and PLAP and C-Kit positive germ cells persist with almost the same frequency as in our material of normal testes (Table 3).	('Oct3/4', 'Gene', '5460', (18, 24))	('Oct3/4', 'Gene', (18, 24))	('PLAP', 'Gene', (108, 112))	('D2-40', 'Var', (8, 13))	('cryptorchid testes', 'Phenotype', 'HP:0000028', (56, 74))	('C-Kit', 'Gene', (117, 122))	('PLAP', 'Gene', '251', (108, 112))	('C-Kit', 'Gene', '3815', (117, 122))
29404	27798627	This showed that rs10908557 on Chr 1 is in high LD with non-synonymous SNPs in CRTC2 (rs11264680; r2=0.98) and CREB3L4 (rs11264743; r2=0.94) (see Causal genes, Supplementary Table 5).	('CRTC2', 'Gene', '200186', (79, 84))	('rs11264743;', 'Var', (120, 131))	('CREB3L4', 'Gene', '148327', (111, 118))	('rs11264743', 'Mutation', 'rs11264743', (120, 130))	('men', 'Species', '9606', (166, 169))	('rs10908557', 'Var', (17, 27))	('rs11264680;', 'Var', (86, 97))	('CRTC2', 'Gene', (79, 84))	('rs10908557', 'Mutation', 'rs10908557', (17, 27))	('CREB3L4', 'Gene', (111, 118))	('rs11264680', 'Mutation', 'rs11264680', (86, 96))
29405	27798627	Interestingly, rs11264743 is considered 'deleterious' and 'probably damaging' by SIFT and PolyPhen, respectively (Ensembl release 83).	('rs11264743', 'Mutation', 'rs11264743', (15, 25))	('rs11264743', 'Var', (15, 25))	('SIFT', 'Disease', 'None', (81, 85))	('SIFT', 'Disease', (81, 85))
29406	27798627	In addition, rs2777888 on Chr 3 is in high LD with two non-synonymous SNPs in MST1R (rs2230590; r2=0.95 and rs1062633; r2=0.95) (Table 1, Supplementary Table 5).	('rs2777888', 'Var', (13, 22))	('men', 'Species', '9606', (144, 147))	('rs2777888', 'Mutation', 'rs2777888', (13, 22))	('rs1062633', 'Var', (108, 117))	('MST1R', 'Gene', (78, 83))	('rs1062633', 'Mutation', 'rs1062633', (108, 117))	('rs2230590; r2=0.95', 'Var', (85, 103))	('rs2230590', 'Mutation', 'rs2230590', (85, 94))	('MST1R', 'Gene', '4486', (78, 83))
29408	27798627	The most promising SNP in the Chr 1 locus (rs6680140) is located in an H3K27ac mark, often found near active regulatory elements, and lies in a DNaseI hypersensitivity cluster where eight proteins are anticipated to bind.	('men', 'Species', '9606', (123, 126))	('hypersensitivity', 'Disease', (151, 167))	('rs6680140', 'Mutation', 'rs6680140', (43, 52))	('rs6680140', 'Var', (43, 52))	('hypersensitivity', 'Disease', 'MESH:D004342', (151, 167))
29410	27798627	In the Chr 3 locus, rs2526397 is located in a transcription factor-binding site and is an eQTL for HYAL3 in monocytes, while rs2247510 and rs1800688 are located in H3K27ac sites and DNaseI hypersensitivity clusters where a large number of transcription factors are expected to bind (see Causal genes, Supplementary Table 6).	('hypersensitivity', 'Disease', (189, 205))	('hypersensitivity', 'Disease', 'MESH:D004342', (189, 205))	('ran', 'Gene', (47, 50))	('men', 'Species', '9606', (307, 310))	('ran', 'Gene', '5901', (47, 50))	('rs1800688', 'Mutation', 'rs1800688', (139, 148))	('ran', 'Gene', (240, 243))	('ran', 'Gene', '5901', (240, 243))	('rs2526397', 'Var', (20, 29))	('rs2526397', 'Mutation', 'rs2526397', (20, 29))	('rs2247510', 'Var', (125, 134))	('HYAL3', 'Gene', '8372', (99, 104))	('rs2247510', 'Mutation', 'rs2247510', (125, 134))	('rs1800688', 'Var', (139, 148))	('HYAL3', 'Gene', (99, 104))
29411	27798627	An analysis using Haplotter showed that rs2247510 and rs7628058 in the Chr 3 locus are amongst the 5% of signals that show most evidence of positive selection in the population.	('rs7628058', 'Var', (54, 63))	('rs2247510', 'Var', (40, 49))	('rs2247510', 'Mutation', 'rs2247510', (40, 49))	('rs7628058', 'Mutation', 'rs7628058', (54, 63))	('Chr 3', 'Gene', (71, 76))
29415	27798627	Five of the seven SNPs were in high LD (r2>0.8) with the strongest eQTL of at least one of the genes within the corresponding loci, indicating that the SNP associated with AFB or NEB and the SNP most significantly associated with expression tag the same functional site, i.e., rs10908557 (associated with the expression of CRTC2 and SLC39A1), rs1160544 (AFF3), rs2777888 (RBM6, RNF123 and RBM5), rs2721195 (CYHR1, GPT, RECQL4 and PPP1R16A) and rs293566 (NOL4L).	('PPP1R16A', 'Gene', '84988', (430, 438))	('AFF3', 'Gene', '3899', (354, 358))	('rs1160544', 'Var', (343, 352))	('GPT', 'Gene', '2875', (414, 417))	('associated', 'Reg', (214, 224))	('rs293566', 'Var', (444, 452))	('rs10908557', 'Var', (277, 287))	('CRTC2', 'Gene', '200186', (323, 328))	('PPP1R16A', 'Gene', (430, 438))	('AFB', 'Chemical', '-', (172, 175))	('RBM6', 'Gene', (372, 376))	('SLC39A1', 'Gene', '27173', (333, 340))	('SLC39A1', 'Gene', (333, 340))	('rs293566', 'Mutation', 'rs293566', (444, 452))	('CRTC2', 'Gene', (323, 328))	('RBM6', 'Gene', '10180', (372, 376))	('rs2777888', 'Var', (361, 370))	('expression', 'MPA', (230, 240))	('AFF3', 'Gene', (354, 358))	('RECQL4', 'Gene', '9401', (419, 425))	('rs2721195', 'Mutation', 'rs2721195', (396, 405))	('rs2777888', 'Mutation', 'rs2777888', (361, 370))	('rs2721195', 'Var', (396, 405))	('NEB', 'Chemical', '-', (179, 182))	('RECQL4', 'Gene', (419, 425))	('rs1160544', 'Mutation', 'rs1160544', (343, 352))	('RNF123', 'Gene', (378, 384))	('NOL4L', 'Gene', '140688', (454, 459))	('RNF123', 'Gene', '63891', (378, 384))	('rs10908557', 'Mutation', 'rs10908557', (277, 287))	('RBM5', 'Gene', (389, 393))	('RBM5', 'Gene', '10181', (389, 393))	('NOL4L', 'Gene', (454, 459))	('GPT', 'Gene', (414, 417))
29417	27798627	Of these SNPs, only rs2777888 was in high LD (r2>0.8) with the strongest eQTL for three of its five associated genes: LRFN1, LAMP2 and FGD3.	('LAMP2', 'Gene', (125, 130))	('rs2777888', 'Mutation', 'rs2777888', (20, 29))	('LRFN1', 'Gene', (118, 123))	('LRFN1', 'Gene', '57622', (118, 123))	('FGD3', 'Gene', (135, 139))	('FGD3', 'Gene', '89846', (135, 139))	('rs2777888', 'Var', (20, 29))
29419	27798627	Seven of the 11 SNPs were in high LD (r2>0.8) with the strongest meQTL of one of the corresponding methylation sites, i.e., rs10908557 (associated with methylation of CRTC2, SLC39A1, CREB3L4, DENND4B and RAB13), rs1160544 (AFF3), rs2777888 (CAMKV), rs6885307 (C5orf34), rs10056247 (JADE2), rs2721195 (CYHR1) and rs13161115 (EFNA5).	('JADE2', 'Gene', '23338', (282, 287))	('rs2777888', 'Mutation', 'rs2777888', (230, 239))	('rs6885307', 'Mutation', 'rs6885307', (249, 258))	('rs1160544', 'Mutation', 'rs1160544', (212, 221))	('rs10056247', 'Var', (270, 280))	('CREB3L4', 'Gene', '148327', (183, 190))	('CAMKV', 'Gene', (241, 246))	('CRTC2', 'Gene', (167, 172))	('CAMKV', 'Gene', '79012', (241, 246))	('rs2721195', 'Mutation', 'rs2721195', (290, 299))	('JADE2', 'Gene', (282, 287))	('DENND4B', 'Gene', '9909', (192, 199))	('C5orf34', 'Gene', '375444', (260, 267))	('rs10908557', 'Mutation', 'rs10908557', (124, 134))	('AFF3', 'Gene', (223, 227))	('rs13161115', 'Var', (312, 322))	('rs2721195', 'Var', (290, 299))	('rs6885307', 'Var', (249, 258))	('rs1160544', 'Var', (212, 221))	('SLC39A1', 'Gene', '27173', (174, 181))	('SLC39A1', 'Gene', (174, 181))	('RAB13', 'Gene', '5872', (204, 209))	('RAB13', 'Gene', (204, 209))	('DENND4B', 'Gene', (192, 199))	('methylation', 'MPA', (152, 163))	('CREB3L4', 'Gene', (183, 190))	('rs10056247', 'Mutation', 'rs10056247', (270, 280))	('rs10908557', 'Var', (124, 134))	('rs13161115', 'Mutation', 'rs13161115', (312, 322))	('C5orf34', 'Gene', (260, 267))	('AFF3', 'Gene', '3899', (223, 227))	('CRTC2', 'Gene', '200186', (167, 172))	('rs2777888', 'Var', (230, 239))
29420	27798627	Three of the SNPs were associated with the same genes for both methylation and gene expression in cis: rs10908557 (CRTC2), rs1160544 (AFF3) and rs2721195 (CYHR1) (Supplementary Tables 7,9).	('rs2721195', 'Mutation', 'rs2721195', (144, 153))	('AFF3', 'Gene', (134, 138))	('CRTC2', 'Gene', (115, 120))	('men', 'Species', '9606', (169, 172))	('CRTC2', 'Gene', '200186', (115, 120))	('AFF3', 'Gene', '3899', (134, 138))	('rs2721195', 'Var', (144, 153))	('rs1160544', 'Mutation', 'rs1160544', (123, 132))	('rs10908557', 'Var', (103, 113))	('rs10908557', 'Mutation', 'rs10908557', (103, 113))	('rs1160544', 'Var', (123, 132))
29422	27798627	Of these SNPs, only rs2777888 was in high LD (r2>0.8) with the strongest meQTL of a corresponding methylation site (ASAP3).	('ASAP3', 'Gene', '55616', (116, 121))	('ASAP3', 'Gene', (116, 121))	('rs2777888', 'Mutation', 'rs2777888', (20, 29))	('rs2777888', 'Var', (20, 29))
29423	27798627	Of note: rs2777888 was also a trans eQTL.	('rs2777888', 'Mutation', 'rs2777888', (9, 18))	('rs2777888', 'Var', (9, 18))	('ran', 'Gene', (31, 34))	('ran', 'Gene', '5901', (31, 34))
29427	27798627	Amongst the genes that - at a protein level - bind at the site of one or more of the 18 variants in the locus on Chr 1 are CREBBP, HNF4A, CDX2 and ERG.	('Chr 1', 'Gene', (113, 118))	('HNF4A', 'Gene', '3172', (131, 136))	('CDX2', 'Gene', '1045', (138, 142))	('ERG', 'Gene', (147, 150))	('ERG', 'Gene', '2078', (147, 150))	('HNF4A', 'Gene', (131, 136))	('CREBBP', 'Gene', (123, 129))	('CREBBP', 'Gene', '1387', (123, 129))	('variants', 'Var', (88, 96))	('CDX2', 'Gene', (138, 142))
29429	27798627	Amongst the genes that - at a protein level - bind at rs2247510 and rs1800688 in the Chr 3 locus are ARID3A, REST and TFAP2C, as well as HNF4A and CDX2, which also bind at the Chr 1 locus.	('rs1800688', 'Var', (68, 77))	('TFAP2C', 'Gene', '7022', (118, 124))	('CDX2', 'Gene', '1045', (147, 151))	('HNF4A', 'Gene', (137, 142))	('HNF4A', 'Gene', '3172', (137, 142))	('CDX2', 'Gene', (147, 151))	('TFAP2C', 'Gene', (118, 124))	('ARID3A', 'Gene', (101, 107))	('rs2247510', 'Mutation', 'rs2247510', (54, 63))	('rs1800688', 'Mutation', 'rs1800688', (68, 77))	('ARID3A', 'Gene', '1820', (101, 107))	('rs2247510', 'Var', (54, 63))	('Chr 3', 'Gene', (85, 90))
29438	27798627	When we control for right-censored data using a survival model for AFB, we found that a 1SD increase in the AFB polygenic score is associated with an 8% (95% CI 7%-10%) reduction in the hazard ratio of reproduction in women and 3% (95% CI 1%-5%) in men (Supplementary Table 22).	('reduction', 'NegReg', (169, 178))	('women', 'Species', '9606', (218, 223))	('polygenic score', 'Var', (112, 127))	('increase', 'PosReg', (92, 100))	('AFB', 'Chemical', '-', (108, 111))	('AFB', 'Gene', (108, 111))	('men', 'Species', '9606', (249, 252))	('men', 'Species', '9606', (260, 263))	('reproduction', 'CPA', (202, 214))	('AFB', 'Chemical', '-', (67, 70))	('men', 'Species', '9606', (220, 223))
29439	27798627	As an additional test, we examined whether the aforementioned polygenic scores for AFB and NEB can predict related fertility traits such as age at menopause and age at menarche (Supplementary Table 23).	('men', 'Species', '9606', (52, 55))	('NEB', 'Gene', (91, 94))	('predict', 'Reg', (99, 106))	('men', 'Species', '9606', (184, 187))	('AFB', 'Gene', (83, 86))	('AFB', 'Chemical', '-', (83, 86))	('NEB', 'Chemical', '-', (91, 94))	('age at menopause', 'Phenotype', 'HP:0008209', (140, 156))	('polygenic scores', 'Var', (62, 78))	('men', 'Species', '9606', (147, 150))	('men', 'Species', '9606', (168, 171))
29440	27798627	Our estimates indicate that a 1SD increase of the AFB polygenic score is associated with a 3% decrease in age at natural menopause (95% CI 1%-5% ) and a 20 day increase in age at menarche (95% CI 0.4-40 days).	('men', 'Species', '9606', (179, 182))	('men', 'Species', '9606', (121, 124))	('age at natural menopause', 'CPA', (106, 130))	('polygenic score', 'Var', (54, 69))	('increase', 'PosReg', (160, 168))	('natural menopause', 'Phenotype', 'HP:0008209', (113, 130))	('increase', 'PosReg', (34, 42))	('AFB', 'Chemical', '-', (50, 53))	('AFB', 'Gene', (50, 53))	('decrease', 'NegReg', (94, 102))
29444	27798627	The lead SNPs for RBM6-SEMA3F (rs2188151) and ESR1 (rs67229052) are in LD with our lead SNPs for AFB on Chr 3 (r2= 0.44) and Chr 6 (r2=0.94), respectively.	('SEMA3F', 'Gene', '6405', (23, 29))	('rs67229052', 'Var', (52, 62))	('rs2188151', 'Var', (31, 40))	('RBM6', 'Gene', '10180', (18, 22))	('AFB', 'Chemical', '-', (97, 100))	('rs67229052', 'Mutation', 'rs67229052', (52, 62))	('rs2188151', 'Mutation', 'rs2188151', (31, 40))	('SEMA3F', 'Gene', (23, 29))	('RBM6', 'Gene', (18, 22))
29445	27798627	An in silico pleiotropy analysis showed that our lead SNP in the Chr 3 locus (rs2777888) is in LD (r2=0.59) with rs6762477 - which has been associated with age at menarche2 - while other SNPs in the same locus have been associated with HDL cholesterol (rs2013208; r2=0.81) and BMI (rs7613875; r2=0.81) (Supplementary Table 5).	('rs6762477 -', 'Var', (113, 124))	('men', 'Species', '9606', (309, 312))	('HDL cholesterol', 'Disease', (236, 251))	('rs2013208', 'Mutation', 'rs2013208', (253, 262))	('rs7613875', 'Mutation', 'rs7613875', (282, 291))	('men', 'Species', '9606', (163, 166))	('rs6762477', 'Mutation', 'rs6762477', (113, 122))	('rs7613875;', 'Var', (282, 292))	('rs2013208;', 'Var', (253, 263))	('cholesterol', 'Chemical', 'MESH:D002784', (240, 251))	('rs2777888', 'Var', (78, 87))	('rs2777888', 'Mutation', 'rs2777888', (78, 87))
29447	27798627	After controlling for multiple testing, we identified three AFB-associated SNPs near rs2777888 on Chr 3 (rs9589, rs6803222 and rs9858889) that are also associated with age at menarche (P<4.10x10-4).	('rs2777888', 'Mutation', 'rs2777888', (85, 94))	('P<4', 'Gene', (185, 188))	('rs9858889', 'Var', (127, 136))	('age at menarche', 'Disease', (168, 183))	('rs9589', 'Var', (105, 111))	('rs9858889', 'Mutation', 'rs9858889', (127, 136))	('rs6803222', 'Mutation', 'rs6803222', (113, 122))	('P<4', 'Gene', '201780', (185, 188))	('rs9589', 'Mutation', 'rs9589', (105, 111))	('associated', 'Reg', (152, 162))	('AFB-associated', 'Gene', (60, 74))	('rs6803222', 'Var', (113, 122))	('AFB', 'Chemical', '-', (60, 63))	('men', 'Species', '9606', (175, 178))
29454	27798627	We also observed significant genetic correlations of rg=0.86 (SE=0.052) for AFB and rg=0.97 (SE=0.095) for NEB between men and women, implying that most genetic effects on reproductive behavior resulting from common SNPs are shared across the sexes.	('rg=0.97', 'Var', (84, 91))	('NEB', 'Chemical', '-', (107, 110))	('women', 'Species', '9606', (127, 132))	('men', 'Species', '9606', (129, 132))	('men', 'Species', '9606', (119, 122))	('AFB', 'Gene', (76, 79))	('AFB', 'Chemical', '-', (76, 79))	('NEB', 'Gene', (107, 110))
29458	27798627	We identify ten novel and confirm two recently identified genetic loci that are robustly associated with AFB and NEB, as well as variants and genes within these loci that likely drive these associations.	('associated', 'Reg', (89, 99))	('variants', 'Var', (129, 137))	('AFB', 'Disease', (105, 108))	('NEB', 'Disease', (113, 116))	('NEB', 'Chemical', '-', (113, 116))	('AFB', 'Chemical', '-', (105, 108))
29460	27798627	The lead SNP and/or functional variants in LD with it are also associated with the methylation status of these two genes and expression of CRTC2 in whole blood and lymphocytes.	('variants', 'Var', (31, 39))	('CRTC2', 'Gene', (139, 144))	('associated', 'Reg', (63, 73))	('expression', 'MPA', (125, 135))	('CRTC2', 'Gene', '200186', (139, 144))	('methylation status', 'MPA', (83, 101))
29461	27798627	Three promising functional variants in the Chr 1 locus reside in binding sites of the transcriptional co-activator CREB binding protein (CREBBP).	('variants', 'Var', (27, 35))	('Chr 1', 'Gene', (43, 48))	('CREB binding protein', 'Gene', '1387', (115, 135))	('CREBBP', 'Gene', (137, 143))	('ran', 'Gene', (87, 90))	('ran', 'Gene', '5901', (87, 90))	('CREB binding protein', 'Gene', (115, 135))	('CREBBP', 'Gene', '1387', (137, 143))
29462	27798627	In addition to a direct effect of the above-mentioned non-synonymous SNPs on protein function, the associations of AFB and NEB with variants in the locus on Chr 1 may thus be mediated by alterations in cAMP responsive element binding in men and women.	('NEB', 'Chemical', '-', (123, 126))	('men', 'Species', '9606', (44, 47))	('cAMP responsive element binding', 'Interaction', (202, 233))	('alterations', 'Reg', (187, 198))	('women', 'Species', '9606', (245, 250))	('men', 'Species', '9606', (221, 224))	('cAMP', 'Chemical', 'MESH:D000242', (202, 206))	('NEB', 'Gene', (123, 126))	('variants', 'Var', (132, 140))	('AFB', 'Chemical', '-', (115, 118))	('AFB', 'Gene', (115, 118))	('associations', 'Interaction', (99, 111))	('men', 'Species', '9606', (247, 250))	('men', 'Species', '9606', (237, 240))
29465	27798627	The lead SNP of the locus on Chr 3 (rs2777888) is associated with methylation and expression of several genes - in cis and trans - that are known to play a role in cell cycle progression and/or sperm function.	('expression', 'MPA', (82, 92))	('sperm function', 'CPA', (194, 208))	('ran', 'Gene', (124, 127))	('methylation', 'Var', (66, 77))	('ran', 'Gene', '5901', (124, 127))	('rs2777888', 'Var', (36, 45))	('associated', 'Reg', (50, 60))	('rs2777888', 'Mutation', 'rs2777888', (36, 45))	('cell cycle progression', 'CPA', (164, 186))
29466	27798627	First, rs2777888 is associated with the expression of RNF123 (or KPC1) in cis, which plays a role in cellular transition from the quiescence to proliferative state.	('rs2777888', 'Var', (7, 16))	('KPC1', 'Gene', (65, 69))	('associated', 'Reg', (20, 30))	('RNF123', 'Gene', (54, 60))	('KPC1', 'Gene', '63891', (65, 69))	('RNF123', 'Gene', '63891', (54, 60))	('rs2777888', 'Mutation', 'rs2777888', (7, 16))	('ran', 'Gene', (111, 114))	('ran', 'Gene', '5901', (111, 114))
29467	27798627	Secondly, rs2777888 - or functional variants in LD with it - may influence the cell cycle by altering the expression of RBM5 and RBM6 (RNA binding motif proteins 5 and 6).	('RBM5', 'Gene', '10181', (120, 124))	('cell cycle', 'CPA', (79, 89))	('RBM6', 'Gene', (129, 133))	('RBM5', 'Gene', (120, 124))	('LD with it -', 'Gene', (48, 60))	('rs2777888', 'Mutation', 'rs2777888', (10, 19))	('rs2777888 -', 'Var', (10, 21))	('expression', 'MPA', (106, 116))	('RBM6', 'Gene', '10180', (129, 133))	('altering', 'Reg', (93, 101))	('influence', 'Reg', (65, 74))	('variants', 'Var', (36, 44))
29468	27798627	The former plays a role in cell cycle arrest and apoptosis induction and regulates haploid male germ cell pre-mRNA splicing and fertility in mice.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('arrest', 'Disease', (38, 44))	('haploid', 'Var', (83, 90))	('mice', 'Species', '10090', (141, 145))	('regulates', 'Reg', (73, 82))	('fertility', 'CPA', (128, 137))	('apoptosis', 'CPA', (49, 58))	('arrest', 'Disease', 'MESH:D006323', (38, 44))
29469	27798627	RMB5 mutant mice exhibit spermatid differentiation arrest, germ cell sloughing and apoptosis, leading to lack of sperm in ejaculation.	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('spermatid differentiation arrest', 'Phenotype', 'HP:0031038', (25, 57))	('RMB5', 'Gene', (0, 4))	('arrest', 'Disease', (51, 57))	('lack', 'NegReg', (105, 109))	('mutant', 'Var', (5, 11))	('apoptosis', 'CPA', (83, 92))	('mice', 'Species', '10090', (12, 16))	('germ cell sloughing', 'CPA', (59, 78))
29470	27798627	Thirdly, rs2777888 affects expression of LAMP2 in trans, which is located on the X chromosome and encodes a lysosomal membrane protein involved in the acrosome reaction, i.e.	('LAMP2', 'Gene', (41, 46))	('ran', 'Gene', (122, 125))	('ran', 'Gene', '5901', (122, 125))	('affects', 'Reg', (19, 26))	('ran', 'Gene', (51, 54))	('expression', 'MPA', (27, 37))	('ran', 'Gene', '5901', (51, 54))	('rs2777888', 'Var', (9, 18))	('rs2777888', 'Mutation', 'rs2777888', (9, 18))
29472	27798627	LAMP2 is expressed at the protein level in male and female reproductive organs with an effect size of rs2777888 for LAMP2 mRNA expression that is almost twice as large in women than in men (Supplementary Figure 4).	('men', 'Species', '9606', (185, 188))	('rs2777888', 'Mutation', 'rs2777888', (102, 111))	('men', 'Species', '9606', (196, 199))	('women', 'Species', '9606', (171, 176))	('men', 'Species', '9606', (173, 176))	('mRNA', 'MPA', (122, 126))	('LAMP2', 'Gene', (116, 121))	('rs2777888', 'Var', (102, 111))
29473	27798627	Finally, functional variants in the Chr 3 locus are associated with the mRNA expression of HYAL3 in monocytes (hyaluronoglucosaminidase 3).	('hyaluronoglucosaminidase 3', 'Gene', (111, 137))	('variants', 'Var', (20, 28))	('associated', 'Reg', (52, 62))	('HYAL3', 'Gene', '8372', (91, 96))	('HYAL3', 'Gene', (91, 96))	('mRNA expression', 'MPA', (72, 87))	('Chr 3', 'Gene', (36, 41))	('hyaluronoglucosaminidase 3', 'Gene', '8372', (111, 137))
29476	27798627	This can be extended to candidate genes in the remaining loci identified in the present study, some of which are relevant for fertility: mice lacking EFNA5 (Chr 5 NEB locus) are subfertile, ESR1 on Chr 6 encodes an estrogen receptor,  and CYHR1 on Chr 8 is involved in spermatogenesis.	('EFNA5', 'Gene', (150, 155))	('ESR1 on', 'Var', (190, 197))	('NEB', 'Chemical', '-', (163, 166))	('lacking', 'NegReg', (142, 149))	('mice', 'Species', '10090', (137, 141))
29477	27798627	Such experiments would help understand whether binding of estrogen receptor 1 - encoded by ESR1 in the locus on Chr 6 - at the site of functional variants in the locus on Chr 2 drives or mediates the association with AFB in the Chr 2 locus, as well as to identify and characterize causal genes.	('ESR1', 'Gene', (91, 95))	('estrogen receptor 1', 'Gene', '2099', (58, 77))	('estrogen receptor 1', 'Gene', (58, 77))	('AFB', 'Chemical', '-', (217, 220))	('association', 'Interaction', (200, 211))	('Chr 2', 'Gene', (171, 176))	('variants', 'Var', (146, 154))	('men', 'Species', '9606', (11, 14))
29496	27798627	As joint analysis of correlated traits may boost power for mapping functional loci, we applied a recently developed multi-trait analysis method to test the association between each variant and the two correlated traits AFB and NEB simultaneously using multivariate analysis of variance (MANOVA) (see Supplementary Note and Supplementary Table 29).	('test', 'Reg', (147, 151))	('men', 'Species', '9606', (306, 309))	('AFB', 'Chemical', '-', (219, 222))	('NEB', 'Chemical', '-', (227, 230))	('variant', 'Var', (181, 188))	('association', 'Interaction', (156, 167))	('men', 'Species', '9606', (329, 332))
29498	27798627	The analysis also provided a conditional association test of the genetic effect of each variant on AFB including NEB as a covariate, and on NEB including AFB as a covariate (Supplementary Figure 31) We used two methods to assess whether our GWAS results exhibited signs of population stratification (see Supplementary Note).	('AFB', 'Chemical', '-', (154, 157))	('AFB', 'Chemical', '-', (99, 102))	('NEB', 'Chemical', '-', (140, 143))	('variant', 'Var', (88, 95))	('men', 'Species', '9606', (310, 313))	('men', 'Species', '9606', (180, 183))	('AFB', 'Disease', (99, 102))	('NEB', 'Chemical', '-', (113, 116))
29504	27798627	Our estimates based on LD bivariate regression indicated a genetic correlation of rg=0.86 (SE=0.052) among the sexes for AFB and rg=0.97 (SE=0.095) for NEB.	('AFB', 'Chemical', '-', (121, 124))	('rg=0.97', 'Var', (129, 136))	('NEB', 'Chemical', '-', (152, 155))	('AFB', 'Disease', (121, 124))
29508	27798627	In addition, we tested how well our polygenic scores for NEB could predict childlessness at the end of the reproductive period (using age 45 for women and 55 for men), Supplementary Table 21.	('NEB', 'Chemical', '-', (57, 60))	('polygenic scores', 'Var', (36, 52))	('childlessness', 'Disease', (75, 88))	('tested', 'Reg', (16, 22))	('men', 'Species', '9606', (162, 165))	('predict', 'Reg', (67, 74))	('men', 'Species', '9606', (174, 177))	('women', 'Species', '9606', (145, 150))	('men', 'Species', '9606', (147, 150))
29511	27798627	Finally, we examined whether menopause variants are associated with AFB.	('AFB', 'Chemical', '-', (68, 71))	('associated', 'Reg', (52, 62))	('men', 'Species', '9606', (29, 32))	('AFB', 'Disease', (68, 71))	('variants', 'Var', (39, 47))
29518	27798627	Following the results on genetic overlap with other phenotypes we tested - in a quasi-phenotype replication setting - whether the SNPs strongly associated with AFB in women were empirically plausible candidate SNPs for age at menarche and age at menopause (see Supplementary Note).	('associated', 'Reg', (144, 154))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (226, 229))	('men', 'Species', '9606', (246, 249))	('SNPs', 'Var', (130, 134))	('women', 'Species', '9606', (167, 172))	('age at menopause', 'Phenotype', 'HP:0008209', (239, 255))	('men', 'Species', '9606', (267, 270))	('tested', 'Reg', (66, 72))	('AFB', 'Chemical', '-', (160, 163))	('AFB', 'Gene', (160, 163))
29529	27798627	We used RegulomeDB to identify variants amongst the 322 SNPs that reached P<5x10-08 for association with AFB and/or NEB in the meta-analysis of GWAS that likely influenced regulation of gene expression (see Supplementary Note).	('regulation', 'MPA', (172, 182))	('variants', 'Var', (31, 39))	('NEB', 'Chemical', '-', (116, 119))	('influenced', 'Reg', (161, 171))	('men', 'Species', '9606', (213, 216))	('association', 'Interaction', (88, 99))	('AFB', 'Chemical', '-', (105, 108))
29560	27798627	These SNPs are: 1) rs7628058 on chromosome 3 for AFB, an eQTLs for RBM6 in monocytes; 2) rs2247510 on chromosome 3 for AFB, an eQTL for RBM6 and HYAL3 in monocytes and binding site for a range of transcription factors; 3) rs2415984, the lead SNP in the chromosome 14 locus for NEB.	('AFB', 'Chemical', '-', (119, 122))	('RBM6', 'Gene', (67, 71))	('HYAL3', 'Gene', '8372', (145, 150))	('RBM6', 'Gene', '10180', (67, 71))	('rs7628058', 'Mutation', 'rs7628058', (19, 28))	('rs2415984', 'Var', (222, 231))	('rs2247510', 'Var', (89, 98))	('rs2247510', 'Mutation', 'rs2247510', (89, 98))	('RBM6', 'Gene', (136, 140))	('rs2415984', 'Mutation', 'rs2415984', (222, 231))	('RBM6', 'Gene', '10180', (136, 140))	('NEB', 'Chemical', '-', (277, 280))	('rs7628058', 'Var', (19, 28))	('HYAL3', 'Gene', (145, 150))	('ran', 'Gene', (197, 200))	('ran', 'Gene', '5901', (197, 200))	('AFB', 'Chemical', '-', (49, 52))	('ran', 'Gene', (187, 190))	('ran', 'Gene', '5901', (187, 190))
29573	26425644	The TEEs can result in higher morbidity rates, impaired quality of life, and, in some cases, may put the patient's life at risk.	('patient', 'Species', '9606', (105, 112))	('TEEs', 'Var', (4, 8))	('quality', 'MPA', (56, 63))	('put', 'Reg', (97, 100))	('higher', 'PosReg', (23, 29))	('impaired', 'NegReg', (47, 55))	('TEEs', 'Phenotype', 'HP:0001907', (4, 8))	('morbidity', 'CPA', (30, 39))
29629	26425644	It has been proposed that cisplatin is associated with vascular injury, platelet-aggregation alterations, augmented serum levels of vWF:Ag, and autonomic dysfunction.	('vascular injury', 'Disease', (55, 70))	('autonomic dysfunction', 'Phenotype', 'HP:0012332', (144, 165))	('platelet-aggregation alterations', 'Disease', (72, 104))	('cisplatin', 'Var', (26, 35))	('platelet-aggregation alterations', 'Disease', 'MESH:D001791', (72, 104))	('vWF', 'Gene', '7450', (132, 135))	('vWF', 'Gene', (132, 135))	('vascular injury', 'Disease', 'MESH:D057772', (55, 70))	('platelet-aggregation alterations', 'Phenotype', 'HP:0003540', (72, 104))	('associated', 'Reg', (39, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('men', 'Species', '9606', (109, 112))	('autonomic dysfunction', 'Disease', 'MESH:D001342', (144, 165))	('autonomic dysfunction', 'Disease', (144, 165))	('augmented', 'PosReg', (106, 115))
29631	26425644	Bleomicin, on the other hand, would cause endothelial alterations in capillaries and arterioles, such as vacuolization, necrosis, and occlusion.	('necrosis', 'Disease', (120, 128))	('cause', 'Reg', (36, 41))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('Bleomicin', 'Chemical', 'MESH:D001761', (0, 9))	('occlusion', 'Disease', (134, 143))	('vacuolization', 'Disease', (105, 118))	('Bleomicin', 'Var', (0, 9))	('endothelial', 'MPA', (42, 53))
29645	22901013	The residue Phe37 plays a critical role in stabilizing the binding complex of HMGB4 with the cisplatin-modified DNA, as it does for HMGB1.	('Phe37', 'Chemical', '-', (12, 17))	('binding', 'Interaction', (59, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('Phe37', 'Var', (12, 17))	('HMGB4', 'Gene', (78, 83))	('stabilizing', 'MPA', (43, 54))
29647	22901013	An in vitro repair assay revealed that HMGB4, at 1 microM concentration, interferes with repair of cisplatin 1,2-intrastrand cross-link damage by >90% compared to control, whereas HMGB1 at the same concentration inhibits repair by 45% This repair inhibition capability is highly dependent on both the binding affinity and size of the proteins.	('inhibits', 'NegReg', (212, 220))	('HMGB4', 'Var', (39, 44))	('rat', 'Species', '10116', (205, 208))	('interferes', 'NegReg', (73, 83))	('repair', 'MPA', (221, 227))	('repair', 'MPA', (89, 95))	('cross-link damage', 'Disease', (125, 142))	('cross-link damage', 'Disease', 'MESH:C537866', (125, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('rat', 'Species', '10116', (65, 68))
29679	22901013	Site-directed mutagenesis was performed according to the Strategene Quick change protocol to create an F37A variant of full-length HMGB4 and HMGB4a.	('HMGB4', 'Gene', (131, 136))	('HMGB4a', 'Gene', (141, 147))	('rat', 'Species', '10116', (59, 62))	('F37A', 'Mutation', 'p.F37A', (103, 107))	('F37A', 'Var', (103, 107))
29713	22901013	Moreover, the binding interaction of HMGB4a does not change in the presence of 1-10 mM DTT, unlike HMGB1 domain A, which has a redox-dependent binding affinity owing to the presence of adjacent cysteine residues that are lacking in HMGB4 proteins (Figure 4B).	('cysteine', 'Chemical', 'MESH:D003545', (194, 202))	('DTT', 'Chemical', 'MESH:D004229', (87, 90))	('binding', 'Interaction', (14, 21))	('HMGB4a', 'Var', (37, 43))
29715	22901013	To investigate the importance of Phe37 in modulating the interaction of cisplatin-modified DNA with full-length HMGB4 or HMGB4a, F37A variants were produced by site-directed mutagenesis.	('Phe37', 'Chemical', '-', (33, 38))	('variants', 'Var', (134, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('F37A', 'Mutation', 'p.F37A', (129, 133))	('interaction', 'Interaction', (57, 68))
29716	22901013	HMGB4a had significantly lower binding affinity for platinated DNA when Phe37 was replaced by alanine (Figure 5A); no protein/platinated DNA complex was observed up to concentrations of 20 microM, indicating that the binding affinity of this variant is > 2000-fold less than that of wild type HMGB4a.	('less', 'NegReg', (265, 269))	('variant', 'Var', (242, 249))	('binding', 'Interaction', (217, 224))	('binding', 'Interaction', (31, 38))	('Phe37 was replaced by alanine', 'Mutation', 'p.F37A', (72, 101))	('lower', 'NegReg', (25, 30))	('rat', 'Species', '10116', (175, 178))
29717	22901013	On the other hand, the dissociation constant of the F37A variant of full-length HMGB4 is only 2.7-fold greater than that of wild type protein (Figure 5B).	('F37A', 'Var', (52, 56))	('dissociation constant', 'MPA', (23, 44))	('HMGB4', 'Gene', (80, 85))	('greater', 'PosReg', (103, 110))	('F37A', 'Mutation', 'p.F37A', (52, 56))
29722	22901013	The footprinting patterns of wild type HMGB4 and its F37A variant under the same conditions are almost identical (Figure 7).	('F37A', 'Var', (53, 57))	('F37A', 'Mutation', 'p.F37A', (53, 57))	('HMGB4', 'Gene', (39, 44))
29727	22901013	At 1 microM concentration, HMGB1 reduces repair by 45% compared to control, whereas HMGB4 at the same concentration inhibits repair by > 90% (Table 2).	('repair', 'MPA', (41, 47))	('repair', 'MPA', (125, 131))	('HMGB1', 'Var', (27, 32))	('rat', 'Species', '10116', (19, 22))	('rat', 'Species', '10116', (109, 112))	('reduces', 'NegReg', (33, 40))	('inhibits', 'NegReg', (116, 124))
29728	22901013	In the presence of 125 nM HMGB4, repair is inhibited by 70%, whereas no significant decrease in the repair occurs in the presence of HMGB1 at the same concentration.	('repair', 'MPA', (33, 39))	('HMGB4', 'Var', (26, 31))	('inhibited', 'NegReg', (43, 52))	('rat', 'Species', '10116', (158, 161))
29730	22901013	There is no significant repair inhibition observed in the presence of the F37A variant of HMGB4a (Figure 10).	('F37A', 'Mutation', 'p.F37A', (74, 78))	('repair', 'MPA', (24, 30))	('F37A', 'Var', (74, 78))	('HMGB4a', 'Gene', (90, 96))
29739	22901013	Notably, the intercalating residue Phe37, which plays a significant role in the binding of HMGB1 to platinated DNA, is conserved in HMGB4.	('binding', 'Interaction', (80, 87))	('Phe37', 'Chemical', '-', (35, 40))	('HMGB1', 'Gene', (91, 96))	('Phe37', 'Var', (35, 40))
29740	22901013	However, the most remarkable feature is replacement of cysteine at position 22 in HMGB1 with phenylalanine in rat and mouse HMGB4, and a tyrosine in human HMGB4.	('rat', 'Species', '10116', (110, 113))	('cysteine', 'Chemical', 'MESH:D003545', (55, 63))	('phenylalanine', 'Chemical', 'MESH:D010649', (93, 106))	('human', 'Species', '9606', (149, 154))	('tyrosine', 'Chemical', 'MESH:D014443', (137, 145))	('mouse', 'Species', '10090', (118, 123))	('replacement', 'Var', (40, 51))	('HMGB1', 'Gene', (82, 87))
29751	22901013	A combination of pi-pi stacking and edge-to-face aromatic interactions between the phenyl ring side-chain and the two guanine bases significantly stabilizes the complex.	('stabilizes', 'Reg', (146, 156))	('pi-pi', 'Var', (17, 22))	('guanine', 'Chemical', 'MESH:D006147', (118, 125))
29754	22901013	Replacement of Phe37 with Ala37 decreases the binding affinity of domain A to the platinated DNA by more than a factor of 2x103, demonstrating its critical role in stabilizing the interaction.	('Ala37', 'Chemical', '-', (26, 31))	('Phe37', 'Gene', (15, 20))	('rat', 'Species', '10116', (136, 139))	('binding', 'Interaction', (46, 53))	('Replacement', 'Var', (0, 11))	('decreases', 'NegReg', (32, 41))	('Phe37', 'Chemical', '-', (15, 20))
29756	22901013	In HMGB4b, Leu100 is at the position corresponding to intercalating residue Phe102 of HMGB1 domain B and Ala16 in HMGB1 domain A (Figure 1A).	('Leu100', 'Chemical', '-', (11, 17))	('Leu100', 'Var', (11, 17))	('HMGB1', 'Gene', (86, 91))	('Phe102', 'Var', (76, 82))	('Phe102', 'Chemical', '-', (76, 82))	('Ala16', 'Chemical', '-', (105, 110))
29757	22901013	Another possible intercalating residue, corresponding to Phe37 of HMGB4 domain A and Ile121 of HMGB1 domain B, is Val119.	('Phe37', 'Chemical', '-', (57, 62))	('Ile121', 'Var', (85, 91))	('Ile121', 'Chemical', '-', (85, 91))	('Val119', 'Chemical', '-', (114, 120))	('Phe37', 'Var', (57, 62))
29759	22901013	This result suggests Leu100, rather than Val119, may function as an intercalating residue in HMGB4b when binding to platinated-DNA.	('rat', 'Species', '10116', (29, 32))	('Val119', 'Chemical', '-', (41, 47))	('Leu100', 'Var', (21, 27))	('HMGB4b', 'Gene', (93, 99))	('Leu100', 'Chemical', '-', (21, 27))	('binding', 'Interaction', (105, 112))
29765	22901013	The F37A variant of HMGB4a does not show any repair inhibition because it cannot bind to platinated lesions.	('HMGB4a', 'Gene', (20, 26))	('F37A', 'Var', (4, 8))	('F37A', 'Mutation', 'p.F37A', (4, 8))	('bind', 'Interaction', (81, 85))
29778	22901013	In particular, HMGB4: (i) binds to the 1,2-intrastrand cross-linked DNA with high preference; (ii) Interacts mainly through its HMG domain A; and (iii) binds more weakly when Phe37 is mutated to alanine, with the domain A exhibiting dramatically reduced binding affinity for platinated DNA.	('HMG', 'Chemical', 'MESH:D008596', (128, 131))	('Interacts', 'Interaction', (99, 108))	('Phe37', 'Gene', (175, 180))	('weakly', 'NegReg', (163, 169))	('binds', 'Interaction', (152, 157))	('HMGB4', 'Gene', (15, 20))	('mutated', 'Var', (184, 191))	('HMG', 'Chemical', 'MESH:D008596', (15, 18))	('Phe37 is mutated to alanine', 'Mutation', 'p.F37A', (175, 202))	('binds', 'Interaction', (26, 31))
29801	22096659	Aberrant expression patterns of miRNAs in cancer have been well documented in most tumor types (Figure 1B), and detailed work from many labs have shown that many miRNAs, including miR-10b, let-7, miR-101, and the miR-15a-16-1 cluster, possess oncogenic or tumor suppressive functions (Figure 1C).	('miR-101', 'Var', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-10b', 'Gene', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('oncogenic', 'CPA', (243, 252))	('let-7', 'Gene', (189, 194))	('miR-10b', 'Gene', '406903', (180, 187))	('miR-15a', 'Gene', '406948', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('men', 'Species', '9606', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miR-15a', 'Gene', (213, 220))
29802	22096659	While the nomenclature is still evolving, lncRNA typically refers to a polyadenylated long ncRNA that is transcribed by RNA polymerase II and associated with epigenetic signatures common to protein-coding genes, such as trimethylation of histone 3 lysine 4 (H3K4me3) at the transcriptional start site (TSS) and trimethylation of histone 3 lysine 36 (H3K36me3) throughout the gene body.	('lysine', 'Chemical', 'MESH:D008239', (248, 254))	('men', 'Species', '9606', (12, 15))	('H3K36me3', 'Protein', (350, 358))	('trimethylation', 'Var', (311, 325))	('lysine', 'Chemical', 'MESH:D008239', (339, 345))
29808	22096659	Dysregulated expression of lncRNAs in cancer marks the spectrum of disease progression and may serve as an independent predictor for patient outcomes.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('expression', 'MPA', (13, 23))	('patient', 'Species', '9606', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('Dysregulated', 'Var', (0, 12))	('lncRNAs', 'Protein', (27, 34))	('cancer', 'Disease', (38, 44))
29816	22096659	Aberrant expression of H19 is observed in numerous solid tumors, including hepatocellular and bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Aberrant', 'Var', (0, 8))	('numerous solid tumors', 'Disease', (42, 63))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('observed', 'Reg', (30, 38))	('H19', 'Gene', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('H19', 'Gene', '283120', (23, 26))	('hepatocellular', 'Disease', (75, 89))	('numerous solid tumors', 'Disease', 'MESH:D009369', (42, 63))
29819	22096659	In model systems, siRNA knockdown of H19 expression impairs cell growth and clonogenicity in lung cancer cell lines in vitro and decreased xenograft tumor growth of Hep3B hepatocellular carcinoma cells in vivo.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (171, 195))	('Hep3B', 'CellLine', 'CVCL:0326', (165, 170))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('impairs', 'NegReg', (52, 59))	('decreased xenograft tumor', 'Disease', 'MESH:D009369', (129, 154))	('decreased xenograft tumor', 'Disease', (129, 154))	('cell growth', 'CPA', (60, 71))	('clonogenicity', 'CPA', (76, 89))	('lung cancer', 'Disease', (93, 104))	('H19', 'Gene', (37, 40))	('H19', 'Gene', '283120', (37, 40))	('knockdown', 'Var', (24, 33))	('hepatocellular carcinoma', 'Disease', (171, 195))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (171, 195))
29824	22096659	Conversely, aberrant H19 methylation in BWS appears to predispose to cancer development more strongly  XIST, perhaps the most well studied lncRNA, is transcribed from the inactivated X chromosome, in order to facilitate that chromosome's inactivation, and manifests as multiple isoforms.	('H19', 'Gene', '283120', (21, 24))	('inactivation', 'MPA', (238, 250))	('predispose', 'Reg', (55, 65))	('men', 'Species', '9606', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('BWS', 'Disease', 'MESH:D001506', (40, 43))	('BWS', 'Disease', (40, 43))	('methylation', 'Var', (25, 36))	('XIST', 'Gene', '7503', (103, 107))	('aberrant', 'Var', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('XIST', 'Gene', (103, 107))	('facilitate', 'PosReg', (209, 219))	('H19', 'Gene', (21, 24))
29826	22096659	XIST contains a double-hairpin RNA motif in the RepA domain, located in the first exon, which is crucial for its ability to bind Polycomb Repressive Complex 2 (PRC2) and propagate epigenetic silencing of an individual X chromosome (Figure 2B).	('bind', 'Interaction', (124, 128))	('XIST', 'Gene', '7503', (0, 4))	('Polycomb', 'Gene', (129, 137))	('epigenetic silencing', 'Var', (180, 200))	('XIST', 'Gene', (0, 4))	('Polycomb', 'Gene', '12416', (129, 137))	('propagate', 'Reg', (170, 179))
29830	22096659	There have also been surprising accounts of aberrant XIST regulation in other cancers, including lymphoma and male testicular germ-cell tumors, where XIST hypomethylation is, unexpectedly, a biomarker.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('XIST', 'Gene', '7503', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('XIST', 'Gene', (53, 57))	('hypomethylation', 'Var', (155, 170))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('XIST', 'Gene', '7503', (150, 154))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('lymphoma', 'Disease', (97, 105))	('cancers', 'Disease', (78, 85))	('XIST', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('aberrant', 'Var', (44, 52))	('lymphoma', 'Disease', 'MESH:D008223', (97, 105))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))
29832	22096659	Located on Ch9p21 in the INK4A/ARF tumor suppressor locus, ANRIL was initially described by examining the deletion of this region in hereditary neural system tumors, which predispose for hereditary cutaneous malignant melanoma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('neural system tumors', 'Phenotype', 'HP:0004375', (144, 164))	('hereditary neural system tumors', 'Disease', 'MESH:C536149', (133, 164))	('ANRIL', 'Gene', '100048912', (59, 64))	('ARF tumor', 'Disease', 'MESH:D009369', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('hereditary cutaneous malignant melanoma', 'Disease', (187, 226))	('ARF tumor', 'Disease', (31, 40))	('INK4A/ARF', 'Gene', '1029', (25, 34))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (198, 226))	('deletion', 'Var', (106, 114))	('malignant melanoma', 'Phenotype', 'HP:0002861', (208, 226))	('ANRIL', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('hereditary cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (187, 226))	('INK4A/ARF', 'Gene', (25, 34))	('hereditary neural system tumors', 'Disease', (133, 164))
29838	22096659	Through GWAS, ANRIL has also been identified by single nucleotide polymorphisms (SNPs) correlated with a higher risk of atherosclerosis and coronary artery disease, and ANRIL expression has been noted in many tissues.	('single nucleotide polymorphisms', 'Var', (48, 79))	('correlated', 'Reg', (87, 97))	('ANRIL', 'Gene', (169, 174))	('coronary artery disease', 'Disease', 'MESH:D003324', (140, 163))	('ANRIL', 'Gene', '100048912', (14, 19))	('atherosclerosis', 'Disease', 'MESH:D050197', (120, 135))	('atherosclerosis', 'Phenotype', 'HP:0002621', (120, 135))	('coronary artery disease', 'Disease', (140, 163))	('ANRIL', 'Gene', '100048912', (169, 174))	('atherosclerosis', 'Disease', (120, 135))	('ANRIL', 'Gene', (14, 19))
29850	22096659	Moreover, HoxA genes are broadly known to be important for many cancers, particularly HOXA9, which is essential for oncogenesis in leukemias harboring MLL rearrangements.	('leukemias', 'Disease', (131, 140))	('rearrangements', 'Var', (155, 169))	('MLL', 'Gene', (151, 154))	('HoxA', 'Gene', (10, 14))	('MLL', 'Gene', '4297', (151, 154))	('HOXA9', 'Gene', '3205', (86, 91))	('leukemias', 'Disease', 'MESH:D007938', (131, 140))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('HOXA9', 'Gene', (86, 91))	('HoxA', 'Gene', '3197', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('men', 'Species', '9606', (164, 167))	('leukemias', 'Phenotype', 'HP:0001909', (131, 140))
29853	22096659	First described in fibroblasts, HOTAIR is located in the HoxC cluster; but unlike HOTTIP and HOTAIRM1, HOTAIR was found to regulate HoxD cluster genes in a trans-regulatory mechanism (Figure 2C).	('HoxD cluster genes', 'Gene', (132, 150))	('HOTTIP', 'Gene', (82, 88))	('regulate', 'Reg', (123, 131))	('HOTAIR', 'Var', (103, 109))	('HOTTIP', 'Gene', '100316868', (82, 88))	('HOTAIRM1', 'Gene', '100506311', (93, 101))	('HOTAIRM1', 'Gene', (93, 101))
29857	22096659	In breast cancer, HOTAIR overexpression facilitates aberrant PRC2 function by increasing PRC2 recruitment to the genomic positions of target genes.	('recruitment', 'MPA', (94, 105))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('increasing', 'PosReg', (78, 88))	('men', 'Species', '9606', (101, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('function', 'MPA', (66, 74))	('aberrant', 'Var', (52, 60))	('PRC2', 'Protein', (89, 93))	('facilitates', 'PosReg', (40, 51))	('PRC2', 'Gene', (61, 65))
29859	22096659	Supporting this, in benign immortalized breast cells overexpressing EZH2, a core component of PRC2, knockdown of HOTAIR mitigated EZH2-induced invasion in vitro.	('EZH2', 'Gene', (68, 72))	('EZH2', 'Gene', (130, 134))	('EZH2', 'Gene', '2146', (130, 134))	('knockdown', 'Var', (100, 109))	('HOTAIR', 'Gene', (113, 119))	('mitigated', 'NegReg', (120, 129))	('EZH2', 'Gene', '2146', (68, 72))
29868	22096659	Intriguingly, because loss of BRCA2 function is known to increase cell sensitivity to small molecule inhibitors of PARP1, these data may suggest that PCAT-1 may impact cellular response to these drugs as well.	('cell sensitivity to small molecule inhibitors', 'MPA', (66, 111))	('cellular response to these drugs', 'MPA', (168, 200))	('PARP1', 'Gene', '142', (115, 120))	('PCAT-1', 'Gene', '100750225', (150, 156))	('PARP1', 'Gene', (115, 120))	('impact', 'Reg', (161, 167))	('BRCA2', 'Gene', (30, 35))	('increase', 'PosReg', (57, 65))	('PCAT-1', 'Gene', (150, 156))	('loss', 'Var', (22, 26))	('BRCA2', 'Gene', '675', (30, 35))
29873	22096659	recently described an intriguing mechanism by which GAS5 modulates cell survival and metabolism by antagonizing the glucocorticoid receptor (GR).	('antagonizing', 'NegReg', (99, 111))	('GR', 'Gene', '2908', (141, 143))	('glucocorticoid receptor', 'Gene', '2908', (116, 139))	('glucocorticoid receptor', 'Gene', (116, 139))	('cell survival', 'CPA', (67, 80))	('GAS5', 'Var', (52, 56))	('metabolism', 'CPA', (85, 95))	('modulates', 'Reg', (57, 66))
29906	22096659	While the mechanism of their action is still unclear, in prostate cancer cells, induction of AR signaling increased eRNA synthesis at AR-regulated gene enhancers, suggesting that eRNAs facilitate active transcription upon induction of a signaling pathway.	('prostate cancer', 'Disease', (57, 72))	('AR', 'Gene', '367', (93, 95))	('active transcription', 'MPA', (196, 216))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('AR', 'Gene', '367', (134, 136))	('induction', 'Var', (80, 89))	('eRNA synthesis', 'MPA', (116, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('increased', 'PosReg', (106, 115))
29916	22096659	In human tumors, MEG3 downregulation is widely noted, with frequent hypermethylation of its promoter observed in pituitary tumors and leukemias.	('leukemias', 'Disease', 'MESH:D007938', (134, 143))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('human', 'Species', '9606', (3, 8))	('leukemias', 'Phenotype', 'HP:0001909', (134, 143))	('MEG3', 'Gene', '55384', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('downregulation', 'NegReg', (22, 36))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('promoter', 'MPA', (92, 100))	('leukemias', 'Disease', (134, 143))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('pituitary tumors', 'Disease', 'MESH:D010911', (113, 129))	('hypermethylation', 'Var', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('MEG3', 'Gene', (17, 21))	('tumors', 'Disease', (9, 15))	('pituitary tumors', 'Disease', (113, 129))
29924	22096659	CTN-RNA is longer than mCAT2, and under stress conditions, cleavage of CTN-RNA to the mCAT2 coding transcript resulted in increased mCAT2 protein.	('mCAT2', 'Gene', '111335', (23, 28))	('mCAT2', 'Gene', '111335', (132, 137))	('CTN', 'Gene', (71, 74))	('CTN', 'Gene', '12310', (71, 74))	('cleavage', 'Var', (59, 67))	('CTN', 'Gene', (0, 3))	('mCAT2', 'Gene', (86, 91))	('CTN', 'Gene', '12310', (0, 3))	('mCAT2', 'Gene', (23, 28))	('mCAT2', 'Gene', (132, 137))	('increased', 'PosReg', (122, 131))	('mCAT2', 'Gene', '111335', (86, 91))
29947	22096659	This approach could potentially target aberrant ncRNAs, mutant mRNAs, as well as nucleotide triplet-repeat expansions seen in several neurological diseases (such as Huntington's disease).	('neurological diseases', 'Disease', (134, 155))	('mutant', 'Var', (56, 62))	("Huntington's disease", 'Disease', (165, 185))	("Huntington's disease", 'Disease', 'MESH:D006816', (165, 185))	('neurological diseases', 'Disease', 'MESH:D019636', (134, 155))	('mRNAs', 'Gene', (63, 68))	('nucleotide triplet-repeat expansions', 'Var', (81, 117))
29952	22096659	Of the 14 genomic loci, the most prominent by far is the "gene desert" region upstream of the cMYC oncogene on chromosome 8q24, which harbors 10 of the 31 reproducible SNPs associated with prostate cancer (Figure 4C).	('prostate cancer', 'Disease', 'MESH:D011471', (189, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (189, 204))	('cMYC', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('associated with', 'Reg', (173, 188))	('prostate cancer', 'Disease', (189, 204))	('SNPs', 'Var', (168, 172))	('cMYC', 'Gene', '4609', (94, 98))
29955	22096659	Although the relationship between PCAT-1 and the 8q24 SNPs is not clear at this time, this discovery suggests that previously-termed "gene deserts" may, in fact, harbor critical lncRNA genes, and that SNPs found in these regions may impact uncovered aspects of biology.	('uncovered aspects of biology', 'CPA', (240, 268))	('lncRNA genes', 'Gene', (178, 190))	('PCAT-1', 'Gene', '100750225', (34, 40))	('impact', 'Reg', (233, 239))	('PCAT-1', 'Gene', (34, 40))	('SNPs', 'Var', (201, 205))
29972	22096659	While numerous lncRNAs display altered expression levels in cancer, it is unclear to what extent cancers specifically target lncRNAs for genomic amplification/deletion, somatic point mutations, or other targeted aberrations.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('altered', 'Reg', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Disease', (97, 103))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('expression levels', 'MPA', (39, 56))	('point mutations', 'Var', (177, 192))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
29974	22096659	For example, approximately half of prostate cancers harbor gene fusions of the ETS family transcription factors (ERG, ETV1, ETV4, ETV5), which generally result in the translocation of an androgen-regulated promoter to drive upregulation of the ETS gene.	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('prostate cancers', 'Phenotype', 'HP:0012125', (35, 51))	('prostate cancers', 'Disease', (35, 51))	('ETV1', 'Gene', '2115', (118, 122))	('androgen-regulated promoter', 'MPA', (187, 214))	('ETV4', 'Gene', (124, 128))	('ETV5', 'Gene', (130, 134))	('ERG', 'Gene', (113, 116))	('gene fusions', 'Var', (59, 71))	('translocation', 'MPA', (167, 180))	('result in', 'Reg', (153, 162))	('ERG', 'Gene', '2078', (113, 116))	('ETV4', 'Gene', '2118', (124, 128))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('prostate cancers', 'Disease', 'MESH:D011471', (35, 51))	('ETS gene', 'Gene', (244, 252))	('ETV5', 'Gene', '2119', (130, 134))	('ETV1', 'Gene', (118, 122))	('upregulation', 'PosReg', (224, 236))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
29975	22096659	One patient was initially found to have an ETV1 translocation to an intergenic androgen-regulated region which was subsequently found to encode a prostate-specific lncRNA (PCAT-14), thereby creating a gene fusion between the lncRNA and ETV1.	('ETV1', 'Gene', (43, 47))	('PCAT-14', 'Gene', (172, 179))	('ETV1', 'Gene', (236, 240))	('ETV1', 'Gene', '2115', (236, 240))	('ETV1', 'Gene', '2115', (43, 47))	('patient', 'Species', '9606', (4, 11))	('gene fusion', 'Var', (201, 212))	('creating', 'Reg', (190, 198))	('PCAT-14', 'Gene', '101978785', (172, 179))
29978	22096659	These initial data suggest that somatic aberrations of lncRNAs do contribute to their dysregulated function in cancer, although most studies to date identify gene expression changes as the primary alteration in lncRNA function.	('lncRNAs', 'Gene', (55, 62))	('dysregulated function', 'MPA', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('aberrations', 'Var', (40, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
29979	22096659	Yet, the study of mutated lncRNAs in cancer will be an area of high importance in future investigations, as several prominent oncogenes, such as KRAS, show no substantial change in protein expression level in mutated compared to non-mutated cases.	('protein expression level', 'MPA', (181, 205))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('KRAS', 'Gene', (145, 149))	('KRAS', 'Gene', '3845', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutated', 'Var', (209, 216))
29985	22096659	In cancer, dysregulated lncRNA expression characterizes the entire spectrum of disease and aberrant lncRNA function drives cancer through disruption of normal cell processes, typically by facilitating epigenetic repression of downstream target genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disruption', 'NegReg', (138, 148))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('dysregulated', 'MPA', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('epigenetic repression', 'MPA', (201, 222))	('cancer', 'Disease', (123, 129))	('lncRNA', 'Protein', (100, 106))	('cancer', 'Disease', (3, 9))	('lncRNA expression', 'MPA', (24, 41))	('aberrant', 'Var', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
29988	22096659	Epigenetic marks consistent with a transcribed gene (H3K4me3 at the gene promoter, H3K36me3 throughout the gene body Transcription via RNA polymerase II Polyadenylation Often exhibit splicing of multiple exons via canonical genomic splice site motifs Regulation by well-established transcription factors Frequently expressed in a tissue-specific manner Long noncoding RNAs (lncRNAs) are now emerging as a fundamental aspect of biology.	('exhibit', 'Reg', (175, 182))	('Polyadenylation', 'Var', (153, 168))	('H3K36me3', 'Var', (83, 91))	('men', 'Species', '9606', (410, 413))	('splicing', 'MPA', (183, 191))
29996	21515368	Disruption of Androgen Receptor Signaling in Males by Environmental Chemicals Androgen-disruptors are environmental chemicals in that interfere with the biosynthesis, metabolism or action of endogenous androgens resulting in a deflection from normal male developmental programming and reproductive tract growth and function.	('reproductive tract growth', 'CPA', (285, 310))	('biosynthesis', 'MPA', (153, 165))	('men', 'Species', '9606', (262, 265))	('interfere', 'NegReg', (134, 143))	('Androgen Receptor', 'Gene', '367', (14, 31))	('deflection', 'MPA', (227, 237))	('men', 'Species', '9606', (61, 64))	('male developmental programming', 'CPA', (250, 280))	('metabolism', 'MPA', (167, 177))	('Androgen Receptor', 'Gene', (14, 31))	('men', 'Species', '9606', (109, 112))	('Disruption', 'Var', (0, 10))
30028	21515368	Studies have raised the possibility that EDCs may be contributing to a decline in the human sperm count that has been observed over the last 50-60 years.	('decline', 'NegReg', (71, 78))	('human sperm count', 'CPA', (86, 103))	('human', 'Species', '9606', (86, 91))	('EDCs', 'Var', (41, 45))
30040	21515368	In utero diethylstilbestrol exposure has been associated with an increased risk of testicular cancers while maternal levels of chlorinated chemicals suggests a link for these compounds with mixed estrogenic and antiandrogenic activity to testicular cancer rates in sons.	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (9, 27))	('testicular cancers', 'Phenotype', 'HP:0010788', (83, 101))	('testicular cancer', 'Phenotype', 'HP:0010788', (238, 255))	('diethylstilbestrol', 'Var', (9, 27))	('rat', 'Species', '10116', (256, 259))	('testicular cancer', 'Disease', 'MESH:D013736', (238, 255))	('testicular cancers', 'Disease', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('testicular cancer', 'Phenotype', 'HP:0010788', (83, 100))	('testicular cancer', 'Disease', (238, 255))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('testicular cancers', 'Disease', 'MESH:D013736', (83, 101))	('testicular cancer', 'Disease', 'MESH:D013736', (83, 100))
30041	21515368	Further, a rabbit model for testicular cancer identified exposure to di-n-butylphthalates with antiandrogenic action to testicular carcinoma in situ.	('rabbit', 'Species', '9986', (11, 17))	('testicular cancer', 'Disease', (28, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('antiandrogenic action', 'MPA', (95, 116))	('testicular carcinoma', 'Disease', 'MESH:D013736', (120, 140))	('testicular carcinoma', 'Disease', (120, 140))	('di-n-butylphthalates', 'Var', (69, 89))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (131, 148))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (120, 140))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('testicular cancer', 'Phenotype', 'HP:0010788', (28, 45))	('testicular cancer', 'Disease', 'MESH:D013736', (28, 45))	('di-n-butylphthalates', 'Chemical', 'MESH:D003993', (69, 89))
30071	21515368	While methoxychlor exposure of neonatal rats did not affect male puberty, reproductive organ weights or functions in adulthood, exposure throughout gestation, weaning, and lactation resulted in multiple effects including inhibition of somatic growth and accessory sex gland weight, elevated pituitary and serum prolactin levels, delayed puberty, suppression of Leydig cell function, reduced sperm counts and decreased DNA content of the accessory sex glands in the male offspring.	('delayed puberty', 'CPA', (329, 344))	('decreased', 'NegReg', (408, 417))	('somatic growth', 'CPA', (235, 249))	('reduced', 'NegReg', (383, 390))	('accessory sex gland weight', 'CPA', (254, 280))	('DNA content of the accessory sex glands', 'MPA', (418, 457))	('methoxychlor', 'Var', (6, 18))	('elevated', 'PosReg', (282, 290))	('inhibition', 'NegReg', (221, 231))	('sperm counts', 'CPA', (391, 403))	('Leydig cell function', 'CPA', (361, 381))	('rats', 'Species', '10116', (40, 44))	('lactation', 'Disease', (172, 181))	('elevated pituitary and serum prolactin levels', 'Phenotype', 'HP:0000870', (282, 327))	('lactation', 'Disease', 'MESH:D007775', (172, 181))	('suppression', 'NegReg', (346, 357))	('reduced sperm', 'Phenotype', 'HP:0012207', (383, 396))	('delayed puberty', 'Phenotype', 'HP:0000823', (329, 344))	('exposure', 'Var', (128, 136))	('methoxychlor', 'Chemical', 'MESH:D008731', (6, 18))	('male puberty', 'Phenotype', 'HP:0008185', (60, 72))
30077	21515368	BPA exposures have been linked to reduced sperm counts in a rodent model and a human epidemiology study.	('human', 'Species', '9606', (79, 84))	('reduced', 'NegReg', (34, 41))	('reduced sperm', 'Phenotype', 'HP:0012207', (34, 47))	('BPA', 'Chemical', 'MESH:C006780', (0, 3))	('sperm counts', 'CPA', (42, 54))	('exposures', 'Var', (4, 13))
30082	21515368	They first observed that 1 nM BPA activates AR-T877A in transcriptional assays and leads to unscheduled cell cycle progression and cellular proliferation in vitro in the absence of androgen.	('cellular proliferation', 'CPA', (131, 153))	('leads to', 'Reg', (83, 91))	('AR-T877A', 'Var', (44, 52))	('rat', 'Species', '10116', (147, 150))	('unscheduled cell cycle progression', 'CPA', (92, 126))	('activates', 'PosReg', (34, 43))	('T877A', 'Mutation', 'c.877T>A', (47, 52))	('BPA', 'Chemical', 'MESH:C006780', (30, 33))
30083	21515368	Since BPA had no impact on wild-type AR, these data indicate that this gain-of-function AR mutant attained the ability to utilize BPA as agonist.	('gain-of-function', 'PosReg', (71, 87))	('BPA', 'Chemical', 'MESH:C006780', (130, 133))	('BPA', 'Chemical', 'MESH:C006780', (6, 9))	('mutant', 'Var', (91, 97))
30084	21515368	Subsequent in vivo analyses of the impact of BPA on human prostate tumor growth and recurrence were performed using a mouse xenograft of human cells containing the AR-T877A mutation.	('human', 'Species', '9606', (137, 142))	('prostate tumor', 'Disease', 'MESH:D011471', (58, 72))	('human', 'Species', '9606', (52, 57))	('BPA', 'Chemical', 'MESH:C006780', (45, 48))	('AR-T877A mutation', 'Var', (164, 181))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mouse', 'Species', '10090', (118, 123))	('prostate tumor', 'Disease', (58, 72))	('prostate tumor', 'Phenotype', 'HP:0100787', (58, 72))	('T877A', 'Mutation', 'c.877T>A', (167, 172))
30232	26089923	Patients with GD who have Y-chromosome material are at increased risk for the development of type II germ cell tumors (GCT), including dysgerminoma (DG) and seminoma arising from their precursor lesions gonadoblastoma (GB) and carcinoma in situ (CIS)/intratubular germ cell neoplasia unclassified (ITGCNU), respectively.	('gonadoblastoma', 'Phenotype', 'HP:0000150', (203, 217))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('seminoma', 'Disease', (157, 165))	('GD', 'Phenotype', 'HP:0000133', (14, 16))	('neoplasia', 'Phenotype', 'HP:0002664', (274, 283))	('DG', 'Phenotype', 'HP:0100621', (149, 151))	('seminoma', 'Disease', 'MESH:D018239', (157, 165))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (227, 244))	('dysgerminoma', 'Disease', 'MESH:D004407', (135, 147))	('lesions gonadoblastoma', 'Disease', (195, 217))	('Patients', 'Species', '9606', (0, 8))	('Y-chromosome material', 'Var', (26, 47))	('type II germ cell tumors', 'Disease', (93, 117))	('carcinoma in situ', 'Disease', 'MESH:D002278', (227, 244))	('GCT', 'Phenotype', 'HP:0100728', (119, 122))	('lesions gonadoblastoma', 'Disease', 'MESH:D018238', (195, 217))	('CIS', 'Phenotype', 'HP:0030075', (246, 249))	('dysgerminoma', 'Phenotype', 'HP:0100621', (135, 147))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (264, 283))	('germ cell tumors', 'Phenotype', 'HP:0100728', (101, 117))	('dysgerminoma', 'Disease', (135, 147))	('neoplasia', 'Disease', 'MESH:D009369', (274, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('GB', 'Phenotype', 'HP:0000150', (219, 221))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('neoplasia', 'Disease', (274, 283))	('GD', 'Disease', 'MESH:D005776', (14, 16))	('type II germ cell tumors', 'Disease', 'MESH:D009373', (93, 117))	('germ cell tumor', 'Phenotype', 'HP:0100728', (101, 116))	('carcinoma in situ', 'Disease', (227, 244))
30242	26089923	Abnormal regulation of OCT 3/4 leads to inappropriate cell survival and has been shown to be present in precursor cells of type II GCTs.	('OCT 3/4', 'Gene', '5460', (23, 30))	('inappropriate cell survival', 'CPA', (40, 67))	('GCT', 'Phenotype', 'HP:0100728', (131, 134))	('Abnormal', 'Var', (0, 8))	('OCT 3/4', 'Gene', (23, 30))
30289	26089923	In patients who are older than 1 year of age, the presence of OCT 3/4-positive immature germ cells located along the basal lamina in dysgenetic testes or undifferentiated gonadal tissue confers a high risk for development of germ cell neoplasia and should lead to gonadectomy.	('gonadectomy', 'Disease', (264, 275))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (225, 244))	('lead to', 'Reg', (256, 263))	('dysgenetic testes', 'Disease', (133, 150))	('neoplasia', 'Disease', (235, 244))	('presence', 'Var', (50, 58))	('OCT 3/4', 'Gene', '5460', (62, 69))	('patients', 'Species', '9606', (3, 11))	('neoplasia', 'Disease', 'MESH:D009369', (235, 244))	('neoplasia', 'Phenotype', 'HP:0002664', (235, 244))	('dysgenetic testes', 'Phenotype', 'HP:0008733', (133, 150))	('dysgenetic testes', 'Disease', 'MESH:D013736', (133, 150))	('OCT 3/4', 'Gene', (62, 69))
30391	23626723	Cells were transiently transfected with either GPER (200 nM of the duplex) or scrambled siRNAs by using the Oligofectamine  Reagent (Invitrogen) according to the manufacturer's instructions.	('GPER', 'Gene', (47, 51))	('Oligofectamine', 'Chemical', 'MESH:C484027', (108, 122))	('200 nM', 'Var', (53, 59))	('GPER', 'Gene', '2852', (47, 51))	('man', 'Species', '9606', (162, 165))
30402	23626723	Notably, It is noteworthy that NT2/D1 cells knocked down for ERalpha36 are not viable.	('ERalpha', 'Gene', (61, 68))	('ERalpha', 'Gene', '2099', (61, 68))	('knocked down', 'Var', (44, 56))
30404	23626723	Since we previously demonstrated that E2 and E2BSA both trigger CREB phosphorylation and in TCam-2 cells through GPER- ERalpha36 dependent mechanisms, we tested the potential estrogenicity of M4 by assessing phosphorylated CREB level.	('GPER', 'Gene', (113, 117))	('ERalpha', 'Gene', '2099', (119, 126))	('E2BSA', 'Var', (45, 50))	('CREB', 'Gene', '1385', (64, 68))	('CREB', 'Gene', (223, 227))	('tested', 'Reg', (154, 160))	('phosphorylated', 'MPA', (208, 222))	('CREB', 'Gene', '1385', (223, 227))	('phosphorylation', 'MPA', (69, 84))	('GPER', 'Gene', '2852', (113, 117))	('CREB', 'Gene', (64, 68))	('trigger', 'Reg', (56, 63))	('ERalpha', 'Gene', (119, 126))
30405	23626723	Western blot analysis clearly indicated an increase of CREB phosphorylation level (Figure 2A) after a 20 minute exposure to 1.0 nM M4.	('1.0', 'Var', (124, 127))	('increase', 'PosReg', (43, 51))	('CREB', 'Gene', (55, 59))	('CREB', 'Gene', '1385', (55, 59))
30411	23626723	As previously demonstrated, GPER knockdown prevented E2-dependent CREB phosphorylation, which suggests that the mechanisms involved in M4 signaling do not fully mimic those of estrogens.	('knockdown', 'Var', (33, 42))	('GPER', 'Gene', '2852', (28, 32))	('CREB', 'Gene', (66, 70))	('GPER', 'Gene', (28, 32))	('CREB', 'Gene', '1385', (66, 70))	('prevented', 'NegReg', (43, 52))
30425	23626723	Among the functional classes of genes whose expression is significantly up- or down-regulated (top list provided in Table S5), we focused on those involved in epigenetic modifications which seemed related to PI3K/CREB and estrogen receptor signaling in Ingenuity sorting (Figure S3).	('expression', 'MPA', (44, 54))	('down-regulated', 'NegReg', (79, 93))	('CREB', 'Gene', (213, 217))	('epigenetic modifications', 'Var', (159, 183))	('up-', 'PosReg', (72, 75))	('CREB', 'Gene', '1385', (213, 217))	('estrogen receptor', 'Gene', (222, 239))	('estrogen receptor', 'Gene', '2099', (222, 239))
30434	23626723	High doses of tert-octylphenol or nonylphenol ranging from 25 to 200 mg/kg bw were previously shown to significantly decreased sperm count and quality in male mice, and affect uterine weight, vaginal opening and reproductive ability in female rats.	('tert-octylphenol', 'Chemical', '-', (14, 30))	('uterine weight', 'CPA', (176, 190))	('rats', 'Species', '10116', (243, 247))	('reproductive ability', 'CPA', (212, 232))	('nonylphenol', 'Chemical', 'MESH:C025256', (34, 45))	('decreased sperm count', 'Phenotype', 'HP:0000798', (117, 138))	('affect', 'Reg', (169, 175))	('mice', 'Species', '10090', (159, 163))	('decreased', 'NegReg', (117, 126))	('tert-octylphenol', 'Var', (14, 30))	('decreased sperm count and quality', 'Phenotype', 'HP:0012207', (117, 150))	('sperm count', 'CPA', (127, 138))	('vaginal opening', 'Disease', 'MESH:D014627', (192, 207))	('vaginal opening', 'Disease', (192, 207))	('nonylphenol', 'Var', (34, 45))	('quality', 'CPA', (143, 150))
30445	23626723	We focused on M4-dependent down-regulation of DNMT3 expression because (i) other estrogeno-mimetic such as genistein and resveratrol or anti-androgenic compounds such as vinclozolin that are present in food have been previously demonstrated to modulate tumor suppressor gene expression through epigenetic mechanisms, (ii) DNMT3 proteins have been shown to be involved in germ cell proliferation and differentiation control during a developmental window when neoplastic germ cells (CIS) are believed to emerge, (iii) polymorphism of these genes is clearly associated with gastric and breast cancer, as well as ovarian endometriosis susceptibility.	('ovarian endometriosis', 'Disease', 'MESH:D004715', (609, 630))	('DNMT', 'Gene', '1786', (322, 326))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('DNMT', 'Gene', (322, 326))	('endometriosis', 'Phenotype', 'HP:0030127', (617, 630))	('associated with', 'Reg', (555, 570))	('ovarian endometriosis', 'Disease', (609, 630))	('breast cancer', 'Phenotype', 'HP:0003002', (583, 596))	('vinclozolin', 'Chemical', 'MESH:C025643', (170, 181))	('gastric', 'Disease', (571, 578))	('tumor', 'Disease', (253, 258))	('breast cancer', 'Disease', 'MESH:D001943', (583, 596))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('DNMT', 'Gene', '1786', (46, 50))	('polymorphism', 'Var', (516, 528))	('DNMT', 'Gene', (46, 50))	('breast cancer', 'Disease', (583, 596))	('gastric', 'Disease', 'MESH:D013274', (571, 578))	('men', 'Species', '9606', (439, 442))	('CIS', 'Phenotype', 'HP:0030075', (481, 484))	('cancer', 'Phenotype', 'HP:0002664', (590, 596))
30448	23626723	Hence, our results indicate that either wortmanin treatment or ERalpha36 knockdown can impair M4-dependent Dnmt3 repression while ERalpha36 expression appears to be necessary for M4-dependent enhanced proliferation.	('men', 'Species', '9606', (55, 58))	('wortmanin', 'Chemical', '-', (40, 49))	('ERalpha', 'Gene', '2099', (63, 70))	('M4-dependent Dnmt3 repression', 'MPA', (94, 123))	('ERalpha', 'Gene', (63, 70))	('impair', 'NegReg', (87, 93))	('ERalpha', 'Gene', (130, 137))	('ERalpha', 'Gene', '2099', (130, 137))	('knockdown', 'Var', (73, 82))
30453	23626723	This point was already addressed by others who demonstrated that downregulation of DNMT3A and DNMT3B led to regulation of ESR1 or ESR2 via promoter DNA aberrant methylation in acute myeloid leukemia, endometriosis, prostate and ovarian cancer.	('endometriosis, prostate and ovarian cancer', 'Disease', 'MESH:D004715', (200, 242))	('regulation', 'MPA', (108, 118))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (176, 198))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (182, 198))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (176, 198))	('ovarian cancer', 'Phenotype', 'HP:0100615', (228, 242))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('aberrant methylation', 'Var', (152, 172))	('ESR1', 'Gene', '2099', (122, 126))	('DNMT3A', 'Gene', (83, 89))	('ESR1', 'Gene', (122, 126))	('DNMT3B', 'Gene', (94, 100))	('DNMT3B', 'Gene', '1789', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('acute myeloid leukemia', 'Disease', (176, 198))	('ESR2', 'Gene', '2100', (130, 134))	('ESR2', 'Gene', (130, 134))	('downregulation', 'NegReg', (65, 79))	('endometriosis', 'Phenotype', 'HP:0030127', (200, 213))	('DNMT3A', 'Gene', '1788', (83, 89))
30491	19709439	Moreover, it has been shown that VEGF expression is correlated with metastases in these tumors.	('correlated', 'Reg', (52, 62))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('VEGF', 'Protein', (33, 37))	('expression', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('metastases', 'Disease', (68, 78))	('tumors', 'Disease', (88, 94))	('metastases', 'Disease', 'MESH:D009362', (68, 78))
30530	19709439	hCG median and mean serum levels were 25.0 (range, 0-479000) and 14772 +- 71503, respectively.	('14772 +- 71503', 'Var', (65, 79))	('hCG', 'Gene', '93659', (0, 3))	('hCG', 'Gene', (0, 3))
30559	19709439	Concerning these results, there is a possibility that angiogenic factors other than VEGF are relevant in the development of this neoplasm's vascularization, taking into account the fact that modulation of the angiopoietin family has been previously described in non-tumor models, as well as fibroblast growth factor, metalloprotease induction, and cellular adhesion-molecule expression.	('non-tumor', 'Disease', (262, 271))	('non-tumor', 'Disease', 'MESH:D009369', (262, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('modulation', 'Var', (191, 201))	('neoplasm', 'Phenotype', 'HP:0002664', (129, 137))
30598	17805427	The B6C3F1/N mouse has a very low incidence of spontaneous Leydig cell tumors (< 1%) but also appears to be resistant to developing chemically induced testicular tumors, as none have been identified in NTP studies.	('mouse', 'Species', '10090', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('testicular tumors', 'Disease', (151, 168))	('testicular tumors', 'Phenotype', 'HP:0010788', (151, 168))	('Leydig cell tumors', 'Disease', (59, 77))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (59, 77))	('B6C3F1/N', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('testicular tumors', 'Disease', 'MESH:D013736', (151, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('testicular tumor', 'Phenotype', 'HP:0010788', (151, 167))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (59, 77))	('NTP', 'Chemical', '-', (202, 205))
30604	17805427	Familial male precocious puberty (FMPP) stems from a mutation in the LH receptor, resulting in constitutive activation.	('constitutive activation', 'MPA', (95, 118))	('male precocious puberty', 'Phenotype', 'HP:0008185', (9, 32))	('stems from', 'Reg', (40, 50))	('mutation', 'Var', (53, 61))	('Familial male precocious puberty', 'Disease', (0, 32))	('precocious puberty', 'Phenotype', 'HP:0000826', (14, 32))	('LH receptor', 'Gene', (69, 80))	('LH receptor', 'Gene', '3973', (69, 80))
30613	17805427	The incidence of Leydig cell tumors in men who have a defective androgen receptor that makes them insensitive to androgens is considerably higher than for men without this syndrome (2.3% vs. ~ 0.00004%).	('Leydig cell tumors', 'Disease', 'MESH:D007984', (17, 35))	('androgen receptor', 'Gene', '367', (64, 81))	('men', 'Species', '9606', (155, 158))	('defective androgen', 'Phenotype', 'HP:0008226', (54, 72))	('insensitive to androgens', 'Phenotype', 'HP:0008226', (98, 122))	('Leydig cell tumors', 'Disease', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('androgen receptor', 'Gene', (64, 81))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (17, 35))	('defective', 'Var', (54, 63))	('men', 'Species', '9606', (39, 42))	('higher', 'PosReg', (139, 145))
30645	17805427	Factors that lead to greater lifetime exposure to endogenous estrogens (i.e., early menses, late menopause, nulliparity, post-menopausal obesity) are associated with elevated risk.	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (97, 100))	('-menopausal obesity', 'Phenotype', 'HP:0008209', (125, 144))	('obesity', 'Disease', 'MESH:D009765', (137, 144))	('men', 'Species', '9606', (84, 87))	('obesity', 'Disease', (137, 144))	('nulliparity', 'Var', (108, 119))	('late menopause', 'Phenotype', 'HP:0008209', (92, 106))	('obesity', 'Phenotype', 'HP:0001513', (137, 144))
30652	17805427	The breakout group noted that tumors may arise from endocrine alterations and genotoxicity as well as epigenetic effects.	('tumors', 'Disease', (30, 36))	('toxicity', 'Disease', (82, 90))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('arise from', 'Reg', (41, 51))	('endocrine alterations', 'Phenotype', 'HP:0000818', (52, 73))	('epigenetic effects', 'Var', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('rat', 'Species', '10116', (66, 69))	('toxicity', 'Disease', 'MESH:D064420', (82, 90))
30697	17805427	The breakout group also identified several preneoplastic events that NTP could consider evaluating for predictiveness of human response, including loss of contact inhibition, stratification of the surface epithelium, loss of p53, loss of phosphatase and tensin homolog (PTEN), and overexpression of phospho-AKT in epithelial cells.	('loss', 'Var', (217, 221))	('NTP', 'Chemical', '-', (69, 72))	('rat', 'Species', '10116', (177, 180))	('AKT', 'Gene', (307, 310))	('p53', 'Gene', (225, 228))	('PTEN', 'Gene', (270, 274))	('overexpression', 'PosReg', (281, 295))	('PTEN', 'Gene', '5728', (270, 274))	('contact', 'Interaction', (155, 162))	('p53', 'Gene', '7157', (225, 228))	('human', 'Species', '9606', (121, 126))	('loss', 'NegReg', (147, 151))	('AKT', 'Gene', '207', (307, 310))	('loss', 'NegReg', (230, 234))
30698	17805427	The group discussed several recently developed genetically engineered models [i.e., p53 and retinoblastoma (Rb) conditional knock-out, K-ras activation, and PTEN loss] that may be useful but have not been evaluated for their predictiveness for human risk.	('knock-out', 'Var', (124, 133))	('human', 'Species', '9606', (244, 249))	('loss', 'NegReg', (162, 166))	('K-ras', 'Gene', (135, 140))	('K-ras', 'Gene', '3845', (135, 140))	('retinoblastoma', 'Gene', '5925', (92, 106))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('PTEN', 'Gene', (157, 161))	('Rb', 'Phenotype', 'HP:0009919', (108, 110))	('retinoblastoma', 'Phenotype', 'HP:0009919', (92, 106))	('PTEN', 'Gene', '5728', (157, 161))	('retinoblastoma', 'Gene', (92, 106))	('activation', 'PosReg', (141, 151))	('Rb', 'Gene', '5925', (108, 110))
30724	17805427	The participants in that workshop strongly recommended that the NTP discontinues use of the F344/N because of its high background incidences of certain types of tumors (i.e., Leydig cell tumors and mononuclear cell leukemia), unresolved issues regarding its declining fertility, occurrence of sporadic seizures, and chylothorax.	('tumors', 'Disease', (161, 167))	('F344/N', 'Var', (92, 98))	('chylothorax', 'Disease', (316, 327))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (175, 193))	('participants', 'Species', '9606', (4, 16))	('declining fertility', 'Phenotype', 'HP:0000144', (258, 277))	('leukemia', 'Disease', 'MESH:D007938', (215, 223))	('NTP', 'Chemical', '-', (64, 67))	('leukemia', 'Disease', (215, 223))	('Leydig cell tumors', 'Disease', (175, 193))	('Leydig cell tumors', 'Disease', 'MESH:D007984', (175, 193))	('sporadic seizures', 'Disease', 'MESH:D012640', (293, 310))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('sporadic seizures', 'Disease', (293, 310))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('sporadic seizures', 'Phenotype', 'HP:0007359', (293, 310))	('men', 'Species', '9606', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('chylothorax', 'Phenotype', 'HP:0010310', (316, 327))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Disease', (187, 193))	('seizures', 'Phenotype', 'HP:0001250', (302, 310))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('discontinues', 'NegReg', (68, 80))	('leukemia', 'Phenotype', 'HP:0001909', (215, 223))	('tumors', 'Disease', 'MESH:D009369', (187, 193))
30767	17805427	The NTP is confident that these changes will strengthen its research and testing activities and enhance the scientific information available for making sound decisions that protect public health.	('enhance', 'PosReg', (96, 103))	('strengthen', 'PosReg', (45, 55))	('testing', 'MPA', (73, 80))	('NTP', 'Chemical', '-', (4, 7))	('research', 'MPA', (60, 68))	('changes', 'Var', (32, 39))
30768	32942548	Dysregulation of Key Proteins Associated with Sperm Motility and Fertility Potential in Cancer Patients Cancer has adverse effects on male reproductive health.	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Dysregulation', 'Var', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('male reproductive', 'CPA', (134, 151))	('Cancer', 'Disease', (104, 110))	('Proteins', 'Protein', (21, 29))	('Cancer', 'Disease', (88, 94))	('effects', 'Reg', (123, 130))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
30805	32942548	Functional analysis revealed that the upstream regulators (RICTOR, KDM5A, MAP4K4, and TRAP1) were activated due to the aberrant expression of sperm proteins in the cancer group compared to fertile men (Table 3).	('aberrant', 'Var', (119, 127))	('MAP4K4', 'Gene', '9448', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('RICTOR', 'Gene', '253260', (59, 65))	('activated', 'PosReg', (98, 107))	('KDM5A', 'Gene', (67, 72))	('MAP4K4', 'Gene', (74, 80))	('sperm proteins', 'Protein', (142, 156))	('men', 'Species', '9606', (197, 200))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('expression', 'MPA', (128, 138))	('TRAP1', 'Gene', '10131', (86, 91))	('RICTOR', 'Gene', (59, 65))	('TRAP1', 'Gene', (86, 91))	('KDM5A', 'Gene', '5927', (67, 72))
30822	32942548	Although it is expressed in several tissues, including testis, the inactivation of mesothelin gene in experimental mice model did not affect the normal fertility, pregnancy and offspring delivery.	('pregnancy', 'CPA', (163, 172))	('inactivation', 'Var', (67, 79))	('mesothelin', 'Gene', (83, 93))	('mesothelin', 'Gene', '56047', (83, 93))	('men', 'Species', '9606', (108, 111))	('mice', 'Species', '10090', (115, 119))
30836	32942548	In the current study, molecular functions associated with mitochondria were dysregulated in the spermatozoa of cancer patients, mainly due to the aberrant expression of the mitochondrial proteins.	('dysregulated', 'Reg', (76, 88))	('molecular functions', 'MPA', (22, 41))	('mitochondrial proteins', 'Protein', (173, 195))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('expression', 'MPA', (155, 165))	('aberrant', 'Var', (146, 154))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))
30847	32942548	UQCRC2 is reportedly involved in the TCA cycle and its underexpression has been correlated with poor fertilization rates and male infertility conditions, such as varicocele.	('correlated', 'Reg', (80, 90))	('varicocele', 'Phenotype', 'HP:0012871', (162, 172))	('UQCRC2', 'Gene', '7385', (0, 6))	('infertility conditions', 'Disease', (130, 152))	('varicocele', 'Disease', (162, 172))	('poor fertilization rates', 'CPA', (96, 120))	('infertility', 'Phenotype', 'HP:0000789', (130, 141))	('underexpression', 'Var', (55, 70))	('male infertility', 'Phenotype', 'HP:0003251', (125, 141))	('male infertility', 'Disease', (125, 141))	('male infertility', 'Disease', 'MESH:D007248', (125, 141))	('infertility conditions', 'Disease', 'MESH:D007247', (130, 152))	('TCA', 'Chemical', 'MESH:D014233', (37, 40))	('UQCRC2', 'Gene', (0, 6))
30849	32942548	In the current study, several DEPs identified in the spermatozoa of cancer patients can affect the normal sperm physiological functions, especially motility or fertilizing ability.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('affect', 'Reg', (88, 94))	('DEPs', 'Var', (30, 34))	('patients', 'Species', '9606', (75, 83))	('motility', 'CPA', (148, 156))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('sperm physiological functions', 'CPA', (106, 135))	('fertilizing ability', 'CPA', (160, 179))
30851	32942548	SOD1 is an enzyme involved in the antioxidant defense mechanism during a state of oxidative stress, hence, underexpression of SOD1 suggests a dysfunctional mechanism to counteract oxidative stress in cancer patients.	('SOD1', 'Gene', (0, 4))	('patients', 'Species', '9606', (207, 215))	('SOD1', 'Gene', '6647', (0, 4))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('dysfunctional', 'Disease', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('dysfunctional', 'Disease', 'MESH:D009461', (142, 155))	('underexpression', 'Var', (107, 122))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('oxidative stress', 'Phenotype', 'HP:0025464', (180, 196))	('SOD1', 'Gene', (126, 130))	('SOD1', 'Gene', '6647', (126, 130))	('cancer', 'Disease', (200, 206))
30858	32942548	While it is well-known that cryopreservation can reduce semen quality, we cannot exclude the influence of the freezing/thawing processes on the sperm proteome, which has been previously suggested by Wang et al., who observed a differential expression of proteins involved in physiological sperm pathways following cryopreservation.	('proteins', 'Protein', (254, 262))	('reduce', 'NegReg', (49, 55))	('expression', 'MPA', (240, 250))	('semen quality', 'CPA', (56, 69))	('cryopreservation', 'Var', (28, 44))	('men', 'Species', '9606', (58, 61))
30889	32942548	Moreover, altered expression of proteins (NDUFS1, SOD1, SERPINA5, and UQCRC2) involved in sperm fertility potential and motility suggests that the fertility of cancer patients may be at risk due to the aberrant expression of critical sperm proteins.	('UQCRC2', 'Gene', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('altered', 'Reg', (10, 17))	('aberrant', 'Var', (202, 210))	('NDUFS1', 'Gene', '4719', (42, 48))	('SERPINA5', 'Gene', (56, 64))	('cancer', 'Disease', (160, 166))	('UQCRC2', 'Gene', '7385', (70, 76))	('SOD1', 'Gene', (50, 54))	('proteins', 'Protein', (32, 40))	('SOD1', 'Gene', '6647', (50, 54))	('patients', 'Species', '9606', (167, 175))	('fertility', 'CPA', (147, 156))	('expression', 'MPA', (18, 28))	('SERPINA5', 'Gene', '5104', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('NDUFS1', 'Gene', (42, 48))	('expression', 'MPA', (211, 221))
30903	31583563	Human CDKN2A is induced in response to senescence and many oncogenic signals, and its deletion is one of the most frequent events in human cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('CDKN2A', 'Gene', (6, 12))	('human', 'Species', '9606', (133, 138))	('deletion', 'Var', (86, 94))	('cancer', 'Disease', (139, 145))
30908	31583563	A broader role for CDKN2A in human disease is suggested by the fact that polymorphisms in a gene-poor region lying upstream of CDKN2A and the flanking CDKN2B confer risk for coronary artery disease (CAD) and Type 2 diabetes mellitus.	('CDKN2B', 'Gene', '1030', (151, 157))	('Type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (208, 232))	('coronary artery disease', 'Disease', 'MESH:D003324', (174, 197))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (215, 232))	('Type 2 diabetes mellitus', 'Disease', (208, 232))	('risk', 'Reg', (165, 169))	('coronary artery disease', 'Disease', (174, 197))	('polymorphisms', 'Var', (73, 86))	('Type 2 diabetes', 'Phenotype', 'HP:0005978', (208, 223))	('CDKN2A', 'Gene', (127, 133))	('CDKN2B', 'Gene', (151, 157))	('human', 'Species', '9606', (29, 34))
30909	31583563	Knocking out the orthologous gene-poor region in the mouse reproduced elements of the human phenotype in that the mutant animals were overweight and displayed increased mortality when fed a high-fat, high-cholesterol diet.	('overweight', 'PosReg', (134, 144))	('mortality', 'Disease', (169, 178))	('overweight', 'Phenotype', 'HP:0025502', (134, 144))	('increased', 'PosReg', (159, 168))	('human', 'Species', '9606', (86, 91))	('mutant', 'Var', (114, 120))	('high-cholesterol', 'Phenotype', 'HP:0003124', (200, 216))	('mouse', 'Species', '10090', (53, 58))	('mortality', 'Disease', 'MESH:D003643', (169, 178))	('cholesterol', 'Chemical', 'MESH:D002784', (205, 216))
30910	31583563	That phenotype correlated with decreased expression of both Cdkn2a and Cdkn2b in the heart and in the eye, Absence of this so-called CAD risk interval in mouse embryo fibroblasts (MEFs) impairs Arf induction by TGFbeta.	('mouse', 'Species', '10090', (154, 159))	('Absence', 'Var', (107, 114))	('Cdkn2b', 'Gene', '12579', (71, 77))	('expression', 'MPA', (41, 51))	('Cdkn2a', 'Gene', '12578', (60, 66))	('decreased', 'NegReg', (31, 40))	('Cdkn2a', 'Gene', (60, 66))	('Cdkn2b', 'Gene', (71, 77))	('Arf induction', 'MPA', (194, 207))	('impairs', 'NegReg', (186, 193))
30927	31583563	chr4Delta70kb/Delta70kb mice were obtained from Mouse Models of Human Cancer Consortium Repository (MMHCC) and maintained on a mixed C57BL/6 x 129/Sv genetic background.	('mice', 'Species', '10090', (24, 28))	('Human', 'Species', '9606', (64, 69))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('chr4Delta70kb/Delta70kb', 'Var', (0, 23))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('Mouse', 'Species', '10090', (48, 53))	('129/Sv', 'Species', '10090', (143, 149))
30952	31583563	Sequencing of genomic DNA derived from the transgenic mouse showed that lack of fluorescence was not due to a deleterious mutation in the nhrGFPII altering the coding sequence or disrupting translation initiation (Fig.	('altering', 'Reg', (147, 155))	('transgenic', 'Species', '10090', (43, 53))	('mutation', 'Var', (122, 130))	('disrupting', 'NegReg', (179, 189))	('nhrGFPII', 'Gene', (138, 146))	('mouse', 'Species', '10090', (54, 59))	('translation initiation', 'MPA', (190, 212))
30961	31583563	The aforementioned gene-poor segment orthologous to the human CAD risk interval could serve as that distant enhancer because it is essential for Arf expression in the Chr4 Delta70kb/Delta70kb eye but was not included in the BACik-p16G-p19T construct.	('Chr4', 'Gene', (167, 171))	('p16', 'Gene', '12578', (230, 233))	('p16', 'Gene', (230, 233))	('human', 'Species', '9606', (56, 61))	('p19', 'Gene', (235, 238))	('Delta70kb/Delta70kb', 'Var', (172, 191))	('p19', 'Gene', '12581', (235, 238))
30962	31583563	It should be emphasized that Arf expression in the mouse eye depends on TGFbeta, and deletion of the distant regulatory element in Chr4 Delta70kb/Delta70kb MEFs specifically impairs TGFbeta-dependent induction of this gene in cultured MEFs.	('impairs', 'NegReg', (174, 181))	('mouse', 'Species', '10090', (51, 56))	('Delta70kb/Delta70kb', 'Var', (136, 155))	('deletion', 'Var', (85, 93))	('Chr4', 'Gene', (131, 135))
30977	31583563	Finally, the growing use of CRISPR/Cas9 to edit the mammalian genome will enable the generation of reporters knocked into a native locus; however, the inactivation of the native gene product in the process can result in a phenotype and possibly alter the expression of the promoter.	('alter', 'Reg', (245, 250))	('mammalian', 'Species', '9606', (52, 61))	('inactivation', 'Var', (151, 163))	('expression', 'MPA', (255, 265))	('phenotype', 'MPA', (222, 231))	('promoter', 'MPA', (273, 281))	('result in', 'Reg', (210, 219))
30978	31583563	Indeed, Arf expressing cells are more easily visualized of Arf lacZ/lacZ and Arf Gfp/Gfp animals than in heterozygous animals retaining native p19Arf expression.	('p19Arf', 'Gene', '12578', (143, 149))	('p19Arf', 'Gene', (143, 149))	('Gfp/Gfp', 'Var', (81, 88))
30996	23510634	Y chromosome gr/gr deletion and PDE11A gene mutations have been suggested to modify the risk of familial testicular germ cell tumor (FTGCT).	('familial testicular germ cell tumor', 'Disease', (96, 131))	('PDE11A', 'Gene', (32, 38))	('germ cell tumor', 'Phenotype', 'HP:0100728', (116, 131))	('modify', 'Reg', (77, 83))	('deletion', 'Var', (19, 27))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('familial testicular germ cell tumor', 'Disease', 'MESH:C563236', (96, 131))	('PDE11A', 'Gene', '50940', (32, 38))
31032	23059747	The CTGCT patients had a 2.3-fold (95% CI 1.3-4.1) increased risk to develop a subsequent non-TGCT cancer and, consequently, a 1.8-fold (95% CI 1.1-2.9) higher risk of death than patients without a CTGCT.	('CTGCT', 'Chemical', '-', (198, 203))	('TGCT', 'Phenotype', 'HP:0010788', (94, 98))	('TGCT', 'Phenotype', 'HP:0010788', (5, 9))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('develop', 'PosReg', (69, 76))	('CTGCT', 'Chemical', '-', (4, 9))	('cancer', 'Disease', (99, 105))	('death', 'Disease', (168, 173))	('death', 'Disease', 'MESH:D003643', (168, 173))	('patients', 'Species', '9606', (179, 187))	('CTGCT', 'Var', (4, 9))	('TGCT', 'Phenotype', 'HP:0010788', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (10, 18))
31096	23059747	Although only based on two CTGCT, non-platinum regimens appeared also associated with lower CTGCT risk.	('CTGCT', 'Chemical', '-', (92, 97))	('CTGCT', 'Disease', (92, 97))	('TGCT', 'Phenotype', 'HP:0010788', (28, 32))	('lower', 'NegReg', (86, 91))	('non-platinum', 'Var', (34, 46))	('CTGCT', 'Chemical', '-', (27, 32))	('platinum', 'Chemical', 'MESH:D010984', (38, 46))	('TGCT', 'Phenotype', 'HP:0010788', (93, 97))
31101	23059747	Patients with a metachronous CTGCT had a 2.3 times (95% CI 1.3-4.1, P=0.006) higher risk of developing a subsequent non-TGCT invasive cancer (adjusted for age, chemotherapy and radiotherapy for primary TGCT; data not shown).	('CTGCT', 'Chemical', '-', (29, 34))	('metachronous', 'Var', (16, 28))	('TGCT', 'Phenotype', 'HP:0010788', (120, 124))	('invasive cancer', 'Disease', (125, 140))	('Patients', 'Species', '9606', (0, 8))	('TGCT', 'Phenotype', 'HP:0010788', (202, 206))	('TGCT', 'Phenotype', 'HP:0010788', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('invasive cancer', 'Disease', 'MESH:D009362', (125, 140))
31130	23059747	This may partly reflect the impact of additional CTGCT treatment on late treatment complications, especially non-testis second cancers, as suggested by the two-fold risk increase for a non-testis second cancer among patients with a CTGCT compared with patients without a CTGCT in our study.	('CTGCT', 'Chemical', '-', (232, 237))	('TGCT', 'Phenotype', 'HP:0010788', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (127, 134))	('patients', 'Species', '9606', (252, 260))	('TGCT', 'Phenotype', 'HP:0010788', (233, 237))	('CTGCT', 'Var', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('CTGCT', 'Chemical', '-', (271, 276))	('CTGCT', 'Chemical', '-', (49, 54))	('cancer', 'Disease', (127, 133))	('patients', 'Species', '9606', (216, 224))	('TGCT', 'Phenotype', 'HP:0010788', (272, 276))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
31224	26226633	We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling.	('NODAL signaling', 'MPA', (152, 167))	('BMP', 'Gene', (34, 37))	('pluripotency', 'Disease', (118, 130))	('inhibition', 'Var', (20, 30))	('pluripotency', 'Disease', 'None', (118, 130))	('BMP', 'Gene', '649', (34, 37))	('activation', 'PosReg', (100, 110))
31229	26226633	In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes and epigenetically fixes the EC state.	('silences', 'NegReg', (47, 55))	('seminoma', 'Disease', 'MESH:D018239', (56, 64))	('EC state', 'MPA', (111, 119))	('epigenetically', 'Var', (86, 100))	('DNMT3B', 'Gene', (13, 19))	('fixes', 'Reg', (101, 106))	('methylation', 'Var', (35, 46))	('DNMT3B', 'Gene', '1789', (13, 19))	('seminoma', 'Disease', (56, 64))
31249	26226633	RNAi-mediated knock down of the pluripotency factor ZIC3 in murine and human ESCs induced SOX17, demonstrating that SOX17 is normally repressed by ZIC3.	('SOX17', 'Gene', '64321', (90, 95))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('pluripotency', 'Disease', (32, 44))	('knock down', 'Var', (14, 24))	('murine', 'Species', '10090', (60, 66))	('SOX17', 'Gene', '64321', (116, 121))	('induced', 'Reg', (82, 89))	('SOX17', 'Gene', (90, 95))	('pluripotency', 'Disease', 'None', (32, 44))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('SOX17', 'Gene', (116, 121))	('human', 'Species', '9606', (71, 76))
31264	26226633	A Zebrafish model carrying a mutation in an ortholog of the human BMPR1B develops a seminoma-like tumor.	('seminoma', 'Disease', (84, 92))	('mutation', 'Var', (29, 37))	('BMPR1B', 'Gene', '658', (66, 72))	('BMPR1B', 'Gene', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Zebrafish', 'Species', '7955', (2, 11))	('tumor', 'Disease', (98, 103))	('seminoma', 'Disease', 'MESH:D018239', (84, 92))	('human', 'Species', '9606', (60, 65))
31285	26226633	The DNA of ECs is hypermethylated compared to seminomas.	('ECs', 'Disease', (11, 14))	('seminomas', 'Disease', 'MESH:D018239', (46, 55))	('seminomas', 'Disease', (46, 55))	('hypermethylated', 'Var', (18, 33))
31286	26226633	In line to this finding, the DNA of 2102EP cells is highly methylated compared to TCam-2 cells.	('methylated', 'MPA', (59, 69))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('2102EP', 'Var', (36, 42))	('TCam-2', 'Chemical', '-', (82, 88))
31287	26226633	A common feature of GCCs, the gain of chromosome 12p can also be found in 2102EP.	('2102EP', 'Var', (74, 80))	('gain', 'PosReg', (30, 34))	('P', 'Chemical', 'MESH:D010758', (79, 80))
31292	26226633	We demonstrate that interference with the BMP signaling pathway leads to upregulation of NODAL signaling as well as pluripotency- and epigenetic reprogramming factors, which drive the reprogramming and epigenetic remodeling of TCam-2 cells during growth in the somatic microenvironment of the murine flank.	('murine', 'Species', '10090', (293, 299))	('BMP', 'Gene', (42, 45))	('interference', 'Var', (20, 32))	('pluripotency', 'Disease', (116, 128))	('TCam-2', 'Chemical', '-', (227, 233))	('BMP', 'Gene', '649', (42, 45))	('NODAL', 'MPA', (89, 94))	('pluripotency', 'Disease', 'None', (116, 128))	('upregulation', 'PosReg', (73, 85))
31309	26226633	Following xenografting of TCam-2, numbers of medium (41-80%) and highly (> 81%) methylated CpGs showed a strong increase on all chromosomes, except chromosomes Y and 19 (S1A Data).	('TCam-2', 'Chemical', '-', (26, 32))	('TCam-2', 'Gene', (26, 32))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('increase', 'PosReg', (112, 120))	('methylated', 'Var', (80, 90))	('CpGs', 'Chemical', 'MESH:C015772', (91, 95))	('CpGs', 'Gene', (91, 95))
31310	26226633	Strongly reduced methylation on the Y chromosome can be explained by the fact that complete arms of this chromosome are deleted TCam-2 (purple arrow in S1A Data).	('TCam-2', 'Gene', (128, 134))	('methylation', 'MPA', (17, 28))	('deleted', 'Var', (120, 127))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('reduced', 'NegReg', (9, 16))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('TCam-2', 'Chemical', '-', (128, 134))
31336	26226633	From them, EC-, pluripotency- and reprogramming-associated genes REX1 (ZFP42), DND1, JARID2 and PRDM14 were hypomethylated and upregulated, while seminoma-related genes PRDM1, PROM1 and IGF1 became hypermethylated and were downregulated.	('JARID2', 'Gene', '3720', (85, 91))	('PROM1', 'Gene', '8842', (176, 181))	('PRDM1', 'Gene', '639', (169, 174))	('ZFP42', 'Gene', '132625', (71, 76))	('PRDM1', 'Gene', (169, 174))	('ZFP42', 'Gene', (71, 76))	('PRDM1', 'Gene', '639', (96, 101))	('DND1', 'Gene', (79, 83))	('PRDM1', 'Gene', (96, 101))	('downregulated', 'NegReg', (223, 236))	('seminoma', 'Disease', (146, 154))	('JARID2', 'Gene', (85, 91))	('REX1', 'Gene', (65, 69))	('hypomethylated', 'Var', (108, 122))	('pluripotency', 'Disease', (16, 28))	('EC-', 'Gene', (11, 14))	('IGF1', 'Gene', '3479', (186, 190))	('seminoma', 'Disease', 'MESH:D018239', (146, 154))	('upregulated', 'PosReg', (127, 138))	('DND1', 'Gene', '373863', (79, 83))	('pluripotency', 'Disease', 'None', (16, 28))	('PRDM14', 'Gene', (96, 102))	('REX1', 'Gene', '132625', (65, 69))	('PRDM14', 'Gene', '63978', (96, 102))	('PROM1', 'Gene', (176, 181))	('IGF1', 'Gene', (186, 190))
31339	26226633	Additionally, we confirmed demethylation of the GDF3 locus in TCam-2 4 weeks after xenografting by sodium-bisfulfite-sequencing (S4C Fig).	('sodium-bisfulfite', 'Chemical', '-', (99, 116))	('GDF3', 'Gene', '9573', (48, 52))	('TCam-2', 'Chemical', '-', (62, 68))	('GDF3', 'Gene', (48, 52))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('demethylation', 'Var', (27, 40))
31358	26226633	We found that DPPA3, AK3L1, DNMT3B and NODAL are hypermethylated at analyzed loci in seminomas and parental TCam-2 compared to TCam-2 in vivo 6w and the EC samples (Fig 3D).	('hypermethylated', 'Var', (49, 64))	('AK3L1', 'Gene', '205', (21, 26))	('seminomas', 'Disease', 'MESH:D018239', (85, 94))	('TCam-2', 'Chemical', '-', (127, 133))	('DPPA3', 'Gene', '359787', (14, 19))	('DNMT3B', 'Gene', '1789', (28, 34))	('DNMT3B', 'Gene', (28, 34))	('DPPA3', 'Gene', (14, 19))	('AK3L1', 'Gene', (21, 26))	('TCam-2', 'Chemical', '-', (108, 114))	('seminomas', 'Disease', (85, 94))
31360	26226633	GDF3 hypermethylation is restricted to parental TCam-2, but not seen in seminomas or EC cells (Fig 3D).	('seminomas', 'Disease', 'MESH:D018239', (72, 81))	('seminomas', 'Disease', (72, 81))	('GDF3', 'Gene', '9573', (0, 4))	('GDF3', 'Gene', (0, 4))	('TCam-2', 'Chemical', '-', (48, 54))	('hypermethylation', 'Var', (5, 21))
31382	26226633	Inhibition of BMP signaling leads to derepression of NODAL signaling as well as upregulation of pluripotency- and reprogramming-associated factors.	('pluripotency', 'Disease', 'None', (96, 108))	('NODAL signaling', 'MPA', (53, 68))	('upregulation', 'PosReg', (80, 92))	('derepression', 'PosReg', (37, 49))	('BMP', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('BMP', 'Gene', '649', (14, 17))	('pluripotency', 'Disease', (96, 108))	('reprogramming-associated', 'CPA', (114, 138))
31416	26226633	We show that inhibition of BMP signaling leads to induction of NODAL signaling and pluripotency- as well as epigenetic reprogramming factors comparable to the reprogramming of TCam-2 in vivo.	('BMP', 'Gene', (27, 30))	('pluripotency', 'Disease', (83, 95))	('inhibition', 'Var', (13, 23))	('pluripotency', 'Disease', 'None', (83, 95))	('BMP', 'Gene', '649', (27, 30))	('TCam-2', 'Chemical', '-', (176, 182))	('NODAL signaling', 'MPA', (63, 78))
31419	26226633	Hence, we propose that inhibition of BMP signaling is the initial event triggering SET-reprogramming.	('inhibition', 'Var', (23, 33))	('S', 'Chemical', 'MESH:D013455', (83, 84))	('BMP', 'Gene', '649', (37, 40))	('BMP', 'Gene', (37, 40))
31434	26226633	So, during SET, inhibition of BMP signaling leads to derepression of SOX2, restoring the classical pluripotency circuitry found in ECs and ESCs, subsequently leading to upregulation of ZIC3, which in turn helps to maintain NODAL signaling.	('SOX2', 'Gene', (69, 73))	('ZIC3', 'MPA', (185, 189))	('ECs', 'Disease', (131, 134))	('S', 'Chemical', 'MESH:D013455', (11, 12))	('SOX2', 'Gene', '6657', (69, 73))	('upregulation', 'PosReg', (169, 181))	('pluripotency circuitry', 'Disease', 'None', (99, 121))	('BMP', 'Gene', '649', (30, 33))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('pluripotency circuitry', 'Disease', (99, 121))	('NODAL signaling', 'MPA', (223, 238))	('BMP', 'Gene', (30, 33))	('ESCs', 'Disease', (139, 143))	('restoring', 'PosReg', (75, 84))	('S', 'Chemical', 'MESH:D013455', (140, 141))	('derepression', 'MPA', (53, 65))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('inhibition', 'Var', (16, 26))
31460	26226633	During this time, markers of pluripotency and reprogramming become upregulated and induction of DNMT3B initiates epigenetic remodeling.	('initiates', 'Reg', (103, 112))	('epigenetic', 'MPA', (113, 123))	('reprogramming', 'CPA', (46, 59))	('pluripotency', 'Disease', (29, 41))	('induction', 'Var', (83, 92))	('DNMT3B', 'Gene', '1789', (96, 102))	('pluripotency', 'Disease', 'None', (29, 41))	('DNMT3B', 'Gene', (96, 102))	('upregulated', 'PosReg', (67, 78))
31605	31555759	Mice with targeted disruption of the estrogen receptor alpha are not subject to well-described detrimental influences of DES on development of both male and female urogenital structures, indicating that this estrogen receptor mediates at least some teratogenic effects of DES on the reproductive tract.	('estrogen receptor', 'Gene', '13982', (208, 225))	('DES', 'Chemical', 'MESH:D004054', (121, 124))	('men', 'Species', '9606', (100, 103))	('estrogen receptor', 'Gene', '13982', (37, 54))	('estrogen receptor alpha', 'Gene', (37, 60))	('disruption', 'Var', (19, 29))	('DES on the reproductive tract', 'Phenotype', 'HP:0000078', (272, 301))	('men', 'Species', '9606', (135, 138))	('estrogen receptor', 'Gene', (208, 225))	('estrogen receptor alpha', 'Gene', '13982', (37, 60))	('Mice', 'Species', '10090', (0, 4))	('male and female urogenital structures', 'Phenotype', 'HP:0000119', (148, 185))	('DES', 'Chemical', 'MESH:D004054', (272, 275))
31612	31555759	This work was supported by grants from the National Cancer Institute (CA17054, CA136967, CA102042, and 5P30CA014089) U.S. Public Health Service and the California Cancer Research Program (03-00174-30021 and 99-0050-V-10260), and by the Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine.	('99-0050-V-10260', 'Chemical', 'MESH:C545472', (207, 222))	('CA102042', 'Var', (89, 97))	('California Cancer', 'Disease', 'MESH:D009369', (152, 169))	('CA17054', 'Var', (70, 77))	('CA136967', 'Chemical', 'MESH:D015295', (79, 87))	('CA17054', 'Chemical', 'MESH:D015295', (70, 77))	('men', 'Species', '9606', (242, 245))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('California Cancer', 'Disease', (152, 169))	('CA136967', 'Var', (79, 87))	('5P30CA014089', 'Chemical', 'MESH:C036512', (103, 115))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CA102042', 'Chemical', 'MESH:D015295', (89, 97))
31662	21938584	Polychemotherapy elicited a reduction of the retroperitoneal metastases with a mean factor of 0.6, resulting in a median postchemotherapy tumor size of 21 mm (range, 11-47 mm) (Table 2).	('Polychemotherapy', 'Var', (0, 16))	('tumor', 'Disease', (138, 143))	('retroperitoneal metastases', 'Disease', (45, 71))	('retroperitoneal metastases', 'Disease', 'MESH:D009362', (45, 71))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('reduction', 'NegReg', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
31730	20372076	Here we show that disruption of p53-mdm2 binding using the MDM2-specific inhibitor Nutlin activates p53 in TGCT cells and is sufficient to induce strong apoptosis.	('TG', 'Disease', 'None', (107, 109))	('activates', 'PosReg', (90, 99))	('binding', 'Interaction', (41, 48))	('MDM2', 'Gene', '4193', (59, 63))	('mdm2', 'Gene', '4193', (36, 40))	('Nutlin', 'Chemical', '-', (83, 89))	('MDM2', 'Gene', (59, 63))	('induce', 'Reg', (139, 145))	('disruption', 'Var', (18, 28))	('p53', 'Protein', (100, 103))	('mdm2', 'Gene', (36, 40))	('apoptosis', 'CPA', (153, 162))
31747	20372076	Interestingly, p53 mutation does not seem to be a major cause of drug resistance in TGCTs.	('mutation', 'Var', (19, 27))	('TG', 'Disease', 'None', (84, 86))	('drug resistance', 'Phenotype', 'HP:0020174', (65, 80))	('p53', 'Gene', (15, 18))	('cause', 'Reg', (56, 61))
31750	20372076	Because germ cell tumors rarely suffer p53 mutation in both untreated cases and after relapse, this unusual phenomenon led to the hypothesis that p53 in TGCT may be inactivated by a mechanism specific to this tumor type, much like the bypass of p53 mutation in HPV-positive cervical carcinomas by E6-mediated degradation of p53.	('HPV-positive cervical carcinomas', 'Disease', (261, 293))	('tumors', 'Disease', (18, 24))	('germ cell tumors', 'Phenotype', 'HP:0100728', (8, 24))	('men', 'Species', '9606', (113, 116))	('mutation', 'Var', (249, 257))	('tumor', 'Disease', (209, 214))	('TG', 'Disease', 'None', (153, 155))	('tumor', 'Disease', (18, 23))	('germ cell tumor', 'Phenotype', 'HP:0100728', (8, 23))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('p53', 'Gene', (245, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('carcinomas', 'Phenotype', 'HP:0030731', (283, 293))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('HPV-positive cervical carcinomas', 'Disease', 'MESH:D030361', (261, 293))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))
31755	20372076	This is often caused by overexpression of MDM2 and MDMX, and silencing of the MDM2 regulator ARF.	('ARF', 'Disease', (93, 96))	('MDM2', 'Gene', '4193', (78, 82))	('MDM2', 'Gene', (78, 82))	('overexpression', 'PosReg', (24, 38))	('silencing', 'Var', (61, 70))	('MDM2', 'Gene', '4193', (42, 46))	('MDM2', 'Gene', (42, 46))	('caused by', 'Reg', (14, 23))	('ARF', 'Disease', 'MESH:D058186', (93, 96))
31757	20372076	Genomic analysis of mutations in human glioblastomas showed that MDM2 or MDMX overexpression in combination with ARF deletion are important alternative mechanisms to p53 mutation.	('glioblastomas', 'Phenotype', 'HP:0012174', (39, 52))	('glioblastomas', 'Disease', 'MESH:D005909', (39, 52))	('p53', 'Gene', (166, 169))	('ARF', 'Disease', 'MESH:D058186', (113, 116))	('glioblastomas', 'Disease', (39, 52))	('ARF', 'Disease', (113, 116))	('MDM2', 'Gene', '4193', (65, 69))	('deletion', 'Var', (117, 125))	('human', 'Species', '9606', (33, 38))	('MDM2', 'Gene', (65, 69))	('mutations', 'Var', (20, 29))	('mutation', 'Var', (170, 178))
31761	20372076	Furthermore, the INK4a/ARF locus is frequently altered in TGCT, suggesting that hyperactivation of MDM2 plays a role in suppressing p53 function.	('p53', 'Protein', (132, 135))	('function', 'MPA', (136, 144))	('hyperactivation', 'Var', (80, 95))	('suppressing', 'NegReg', (120, 131))	('INK4a', 'Gene', (17, 22))	('MDM2', 'Gene', (99, 103))	('INK4a', 'Gene', '1029', (17, 22))	('MDM2', 'Gene', '4193', (99, 103))	('ARF', 'Disease', 'MESH:D058186', (23, 26))	('ARF', 'Disease', (23, 26))	('TG', 'Disease', 'None', (58, 60))
31764	20372076	We also found that MDMX expression is inducible by p53 in TGCT cells, and that MDMX also contributes to p53 inactivation in TGCT.	('TG', 'Disease', 'None', (124, 126))	('inactivation', 'NegReg', (108, 120))	('inducible', 'PosReg', (38, 47))	('p53', 'Var', (51, 54))	('MDMX', 'Gene', (19, 23))	('TG', 'Disease', 'None', (58, 60))
31766	20372076	Furthermore, TGCT cells have efficient apoptosis response to activated p53 that is unrelated to their sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('p53', 'Protein', (71, 74))	('apoptosis response', 'CPA', (39, 57))	('activated', 'Var', (61, 70))	('TG', 'Disease', 'None', (13, 15))
31788	20372076	Furthermore, MDMX siRNA cooperated with Nutlin to induce higher levels of p21 than Nutlin alone (Fig.	('Nutlin', 'Chemical', '-', (40, 46))	('higher', 'PosReg', (57, 63))	('p21', 'Gene', '1026', (74, 77))	('levels', 'MPA', (64, 70))	('p21', 'Gene', (74, 77))	('Nutlin', 'Chemical', '-', (83, 89))	('MDMX', 'Var', (13, 17))
31799	20372076	Analysis of human MDMX intron 1 sequence (8,974 bp) for p53 binding site revealed a low scoring site (4505-GGG GAT GTT AGT GCT TGT CT-4524, deviation from PuPuPuC(A/T)(T/A)GPyPyPy consensus underlined) located near the midpoint and a high scoring site (8537-AGA CAT GTT CCA ACA TGT TG-8556) near the boundary with exon 2 (Table 1).	('TG', 'Disease', 'None', (282, 284))	('AT', 'Disease', 'None', (263, 265))	('TGT', 'Gene', (127, 130))	('GAT', 'Gene', (111, 114))	('AT', 'Disease', 'None', (112, 114))	('GAT', 'Gene', '10249', (111, 114))	('AGT', 'Gene', (119, 122))	('TGT', 'Gene', (278, 281))	('8537-AGA', 'Var', (253, 261))	('TGT', 'Gene', '9097', (127, 130))	('human', 'Species', '9606', (12, 17))	('AGT', 'Gene', '183', (119, 122))	('TGT', 'Gene', '9097', (278, 281))	('TG', 'Disease', 'None', (127, 129))	('TG', 'Disease', 'None', (278, 280))	('4505-GGG', 'Var', (102, 110))
31804	20372076	In comparison, the MDM2 intron 1 promoter construct BP100-luciferase was activated more significantly under the same conditions (Fig.	('MDM2', 'Gene', '4193', (19, 23))	('BP100-luciferase', 'Var', (52, 68))	('MDM2', 'Gene', (19, 23))
31806	20372076	The results showed that Nutlin induced up to 3-fold increase in p53 binding to intron 1 in cells expressing p53, but not in HCT116-p53-/- cells (Fig.	('binding', 'Interaction', (68, 75))	('increase', 'PosReg', (52, 60))	('Nutlin', 'Chemical', '-', (24, 30))	('p53', 'Protein', (64, 67))	('intron 1', 'Protein', (79, 87))	('HCT116', 'CellLine', 'CVCL:0291', (124, 130))	('p53', 'Var', (108, 111))
31807	20372076	However, the p53 response capability of the MDMX P2 promoter is weaker than the MDM2 P2 promoter.	('MDM2', 'Gene', (80, 84))	('weaker', 'NegReg', (64, 70))	('MDMX P2', 'Var', (44, 51))	('p53 response capability', 'MPA', (13, 36))	('MDM2', 'Gene', '4193', (80, 84))
31816	20372076	As expected, we found that treatment of HCT116 with Nutlin resulted in p53-dependent cell cycle arrest with near complete depletion of S phase population (Fig.	('depletion', 'NegReg', (122, 131))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('men', 'Species', '9606', (32, 35))	('S phase population', 'MPA', (135, 153))	('Nutlin', 'Chemical', '-', (52, 58))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('HCT116', 'Var', (40, 46))	('p53-dependent cell cycle arrest', 'CPA', (71, 102))
31825	20372076	MDMX knockdown also caused a 2-fold stimulation of apoptosis by Nutlin in NT2/D1 cells (data not shown).	('MDMX', 'Gene', (0, 4))	('Nutlin', 'Chemical', '-', (64, 70))	('knockdown', 'Var', (5, 14))	('apoptosis', 'CPA', (51, 60))	('stimulation', 'PosReg', (36, 47))
31829	20372076	The presence of wt p53 is thought to contribute to favorable response to therapy, although other specific features of this cell type such as inability to repair damage induced by chemotherapy may be the main reason for its excellent response.	('presence', 'Var', (4, 12))	('inability', 'Disease', (141, 150))	('inability', 'Disease', 'MESH:D016388', (141, 150))
31861	20372076	Our finding is consistent with an emerging theme that tumors with infrequent p53 mutation achieve p53 functional inactivation using the MDM2 and MDMX proteins.	('functional', 'MPA', (102, 112))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('MDM2', 'Gene', '4193', (136, 140))	('mutation', 'Var', (81, 89))	('MDM2', 'Gene', (136, 140))	('p53', 'Gene', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p53', 'Gene', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
31862	20372076	This is often accomplished by gene amplification or overexpression of MDM2 and MDMX, or inactivation of the INK4a/ARF locus.	('ARF', 'Disease', (114, 117))	('MDM2', 'Gene', '4193', (70, 74))	('MDMX', 'Var', (79, 83))	('gene amplification', 'Var', (30, 48))	('INK4a', 'Gene', (108, 113))	('INK4a', 'Gene', '1029', (108, 113))	('overexpression', 'PosReg', (52, 66))	('ARF', 'Disease', 'MESH:D058186', (114, 117))	('MDM2', 'Gene', (70, 74))	('inactivation', 'Var', (88, 100))
31879	20372076	However, Nutlin treatment of TGCT cells 833KE and 2102EP resulted in significant increase of MDMX expression at protein and mRNA levels.	('TG', 'Disease', 'None', (29, 31))	('2102EP', 'Var', (50, 56))	('MDMX', 'Gene', (93, 97))	('increase', 'PosReg', (81, 89))	('men', 'Species', '9606', (21, 24))	('Nutlin', 'Chemical', '-', (9, 15))
31881	20372076	Luciferase assay showed that p53 activates MDMX P2 promoter in a dose-dependent manner, although to a lesser degree than the MDM2 P2 promoter.	('MDMX P2', 'Gene', (43, 50))	('p53', 'Var', (29, 32))	('activates', 'PosReg', (33, 42))	('MDM2', 'Gene', '4193', (125, 129))	('MDM2', 'Gene', (125, 129))
31885	20372076	These results are consistent with the observation that MDMX knockout in mice caused severe proliferation defect during early embryogenesis, but has less effect in adult tissues, probably reflecting its important role in stem cells but not in terminally differentiated tissues.	('knockout', 'Var', (60, 68))	('MDMX', 'Gene', (55, 59))	('proliferation defect', 'Disease', (91, 111))	('mice', 'Species', '10090', (72, 76))	('proliferation defect', 'Disease', 'MESH:D065703', (91, 111))
31886	20372076	It is noteworthy that compared to the large induction of MDM2 by p53, the magnitude of MDMX induction by p53 (~2-fold) appears quite moderate.	('MDM2', 'Gene', '4193', (57, 61))	('MDM2', 'Gene', (57, 61))	('p53', 'Var', (105, 108))
31887	20372076	However, recent observations of MDMX gene dosage effect using mouse model suggest that a 2-fold difference in MDMX expression level caused by heterozygous MDMX knockout can lead to significantly increased radiation sensitivity and altered tumor development timing.	('radiation sensitivity', 'CPA', (205, 226))	('expression level', 'MPA', (115, 131))	('knockout', 'Var', (160, 168))	('mouse', 'Species', '10090', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('MDMX', 'Gene', (110, 114))	('men', 'Species', '9606', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('MDMX', 'Gene', (155, 159))	('altered', 'Reg', (231, 238))	('tumor', 'Disease', (239, 244))	('increased', 'PosReg', (195, 204))	('lead to', 'Reg', (173, 180))
31888	20372076	Furthermore, studies of MDM2 gene dosage effect and expression level due to SNP309 polymorphism also revealed an exquisite sensitivity of p53 function to small changes in MDM2 expression level.	('SNP309', 'Gene', (76, 82))	('polymorphism', 'Var', (83, 95))	('SNP309', 'Chemical', '-', (76, 82))	('MDM2', 'Gene', '4193', (171, 175))	('MDM2', 'Gene', '4193', (24, 28))	('MDM2', 'Gene', (171, 175))	('MDM2', 'Gene', (24, 28))
31914	28039263	Variants in WFS1 and other Mendelian deafness genes are associated with cisplatin-associated ototoxicity Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic.	('ototoxic', 'Disease', 'MESH:D006311', (93, 101))	('deafness', 'Phenotype', 'HP:0000365', (37, 45))	('Variants', 'Var', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('WFS1', 'Gene', '7466', (12, 16))	('ototoxic', 'Disease', 'MESH:D006311', (197, 205))	('Cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('associated', 'Reg', (56, 66))	('Mendelian deafness', 'Disease', 'MESH:D003638', (27, 45))	('Mendelian deafness', 'Disease', (27, 45))	('ototoxicity', 'Disease', 'MESH:D006311', (93, 104))	('ototoxicity', 'Disease', (93, 104))	('ototoxic', 'Disease', (93, 101))	('ototoxic', 'Disease', (197, 205))	('WFS1', 'Gene', (12, 16))
31915	28039263	We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).	('variants', 'Var', (30, 38))	('ototoxicity', 'Disease', (74, 85))	('CAO', 'Chemical', '-', (87, 90))	('modulate', 'Reg', (44, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('ototoxicity', 'Disease', 'MESH:D006311', (74, 85))
31917	28039263	One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4x10-8).	('CAO', 'Chemical', '-', (224, 227))	('WFS1', 'Gene', '7466', (169, 173))	('WFS1', 'Gene', (68, 72))	('Mendelian deafness gene WFS1', 'Disease', 'MESH:D014929', (44, 72))	('deafness', 'Phenotype', 'HP:0000365', (54, 62))	('Mendelian deafness gene WFS1', 'Disease', (44, 72))	('CAO', 'Disease', (224, 227))	('wolframin', 'Gene', (74, 83))	('wolframin', 'Gene', '7466', (74, 83))	('WFS1', 'Gene', '7466', (68, 72))	('association', 'Interaction', (207, 218))	('rs62283056', 'Var', (9, 19))	('WFS1', 'Gene', (169, 173))	('rs62283056', 'Mutation', 'rs62283056', (9, 19))
31918	28039263	A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035).	('patients', 'Species', '9606', (163, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('hearing loss', 'Phenotype', 'HP:0000365', (147, 159))	('rs62283056', 'Var', (64, 74))	('rs62283056', 'Mutation', 'rs62283056', (64, 74))	('hearing loss', 'Disease', (147, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('hearing loss', 'Disease', 'MESH:D034381', (147, 159))	('exacerbate', 'PosReg', (136, 146))
31920	28039263	Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048).	('Mendelian deafness', 'Disease', 'MESH:D003638', (92, 110))	('Mendelian deafness', 'Disease', (92, 110))	('SNPs in', 'Var', (66, 73))	('CAO', 'Chemical', '-', (32, 35))	('CAO', 'Disease', (32, 35))	('deafness', 'Phenotype', 'HP:0000365', (102, 110))
31921	28039263	We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype.	('CAO', 'Disease', (47, 50))	('rs62283056', 'Mutation', 'rs62283056', (153, 163))	('WFS1', 'Gene', (39, 43))	('WFS1', 'Gene', '7466', (39, 43))	('CAO', 'Chemical', '-', (47, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('rs62283056', 'Var', (153, 163))	('men', 'Species', '9606', (59, 62))
31930	28039263	In 2011, the FDA amended the cisplatin label to recommend TPMT (thiopurine S-methyltransferase) genotyping in children prior to cisplatin administration, based on the findings of Ross et al..	('thiopurine S-methyltransferase', 'Gene', '7172', (64, 94))	('thiopurine S-methyltransferase', 'Gene', (64, 94))	('children', 'Species', '9606', (110, 118))	('men', 'Species', '9606', (18, 21))	('TPMT', 'Gene', (58, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('genotyping', 'Var', (96, 106))	('TPMT', 'Gene', '7172', (58, 62))	('men', 'Species', '9606', (53, 56))
31932	28039263	A recent GWAS for CAO in pediatric patients identified a variant in ACYP2, which has since been replicated, highlighting the potential utility of genome-wide approaches.	('ACYP2', 'Gene', '98', (68, 73))	('CAO', 'Chemical', '-', (18, 21))	('variant', 'Var', (57, 64))	('patients', 'Species', '9606', (35, 43))	('ACYP2', 'Gene', (68, 73))
31949	28039263	For the top SNP, we also tested for interaction between SNP genotype and cisplatin dose using the following model:   The dose term is a binary variable of those with <=300 mg/m2 (n = 217) or >300 mg/m2 (n = 294).	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('tested', 'Reg', (25, 31))	('>300 mg/m2', 'Var', (191, 201))
31953	28039263	We conducted a permutation resampling analysis to test for an enrichment of the 34,095 SNPs within 50kb of 84 Mendelian nonsyndromic deafness genes among the CAO-associated SNPs (GWAS).	('Mendelian nonsyndromic deafness', 'Disease', 'MESH:C580334', (110, 141))	('Mendelian nonsyndromic deafness', 'Disease', (110, 141))	('deafness', 'Phenotype', 'HP:0000365', (133, 141))	('CAO', 'Chemical', '-', (158, 161))	('SNPs', 'Var', (87, 91))	('men', 'Species', '9606', (68, 71))
31970	28039263	One SNP, rs62283056, in the first intron of WFS1, which encodes wolframin ER transmembrane glycoprotein, met genome-wide significance for association with CAO (beta = -0.34 +- 0.06, P = 1.4 x 10-8, Fig.	('WFS1', 'Gene', (44, 48))	('CAO', 'Chemical', '-', (155, 158))	('CAO', 'Disease', (155, 158))	('WFS1', 'Gene', '7466', (44, 48))	('association', 'Interaction', (138, 149))	('wolframin', 'Gene', (64, 73))	('wolframin', 'Gene', '7466', (64, 73))	('rs62283056', 'Var', (9, 19))	('rs62283056', 'Mutation', 'rs62283056', (9, 19))
31971	28039263	Mutations in WFS1 can cause DFNA6 (deafness, autosomal dominant 6) and the recessive Wolfram syndrome, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness).	('DIDMOAD', 'Disease', (117, 124))	('recessive Wolfram syndrome', 'Disease', 'MESH:D014929', (75, 101))	('WFS1', 'Gene', (13, 17))	('deafness', 'Phenotype', 'HP:0000365', (35, 43))	('deafness', 'Disease', (35, 43))	('deafness', 'Disease', 'MESH:D003638', (35, 43))	('WFS1', 'Gene', '7466', (13, 17))	('Mutations', 'Var', (0, 9))	('recessive Wolfram syndrome', 'Disease', (75, 101))	('Diabetes Mellitus', 'Disease', 'MESH:D003920', (146, 163))	('Optic Atrophy', 'Phenotype', 'HP:0000648', (165, 178))	('cause', 'Reg', (22, 27))	('Diabetes Mellitus', 'Disease', (146, 163))	('Deafness', 'Disease', (184, 192))	('DIDMOAD', 'Disease', 'MESH:D014929', (117, 124))	('Diabetes Insipidus', 'Phenotype', 'HP:0000873', (126, 144))	('Diabetes Insipidus', 'Disease', (126, 144))	('Optic Atrophy', 'Disease', (165, 178))	('Deafness', 'Phenotype', 'HP:0000365', (184, 192))	('Diabetes Insipidus', 'Disease', 'MESH:D003919', (126, 144))	('Optic Atrophy', 'Disease', 'MESH:D009896', (165, 178))	('Diabetes Mellitus', 'Phenotype', 'HP:0000819', (146, 163))	('Deafness', 'Disease', 'MESH:D003638', (184, 192))
31972	28039263	While single variant analysis revealed one genome-wide significant signal in a plausible gene, we also explored the possibility that many variants are involved in CAO by estimating the heritability explained by all common SNPs.	('CAO', 'Disease', (163, 166))	('involved', 'Reg', (151, 159))	('variants', 'Var', (138, 146))	('CAO', 'Chemical', '-', (163, 166))
31973	28039263	As mutations in WFS1 are known to cause deafness, and to test our hypothesis that related phenotypes share genetic liability with adverse drug events, we examined additional Mendelian genes that cause deafness for enrichment in the top GWAS signals.	('WFS1', 'Gene', (16, 20))	('deafness', 'Disease', 'MESH:D003638', (201, 209))	('adverse drug event', 'Phenotype', 'HP:0020172', (130, 148))	('deafness', 'Disease', 'MESH:D003638', (40, 48))	('deafness', 'Phenotype', 'HP:0000365', (201, 209))	('cause', 'Reg', (34, 39))	('adverse drug events', 'Phenotype', 'HP:0020172', (130, 149))	('WFS1', 'Gene', '7466', (16, 20))	('deafness', 'Disease', (201, 209))	('deafness', 'Phenotype', 'HP:0000365', (40, 48))	('mutations', 'Var', (3, 12))	('deafness', 'Disease', (40, 48))	('men', 'Species', '9606', (220, 223))
31974	28039263	We found that SNPs within 50kb of 84 genes known to cause Mendelian nonsyndromic deafness are significantly enriched for low P-values, as indicated by the departure from the null in the quantile-quantile plot and a permutation resampling analysis of the GWAS data (P = 0.048, Fig.	('deafness', 'Phenotype', 'HP:0000365', (81, 89))	('SNPs within', 'Var', (14, 25))	('cause', 'Reg', (52, 57))	('Mendelian nonsyndromic deafness', 'Disease', 'MESH:C580334', (58, 89))	('low', 'NegReg', (121, 124))	('Mendelian nonsyndromic deafness', 'Disease', (58, 89))	('P-values', 'MPA', (125, 133))
31978	28039263	The minor allele of rs62283056 (frequency 0.21 in the GWAS cohort) associates with both increased hearing loss (Fig.	('hearing loss', 'Phenotype', 'HP:0000365', (98, 110))	('rs62283056', 'Var', (20, 30))	('rs62283056', 'Mutation', 'rs62283056', (20, 30))	('hearing loss', 'Disease', (98, 110))	('increased', 'PosReg', (88, 97))	('hearing loss', 'Disease', 'MESH:D034381', (98, 110))
31986	28039263	Importantly, we found a significant interaction between rs62283056 genotype and cumulative cisplatin dose, indicating higher doses may further increase hearing loss in patients with the minor allele (P = 0.035, Fig.	('hearing loss', 'Phenotype', 'HP:0000365', (152, 164))	('hearing loss', 'Disease', (152, 164))	('hearing loss', 'Disease', 'MESH:D034381', (152, 164))	('rs62283056', 'Mutation', 'rs62283056', (56, 66))	('patients', 'Species', '9606', (168, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('rs62283056', 'Var', (56, 66))	('increase', 'PosReg', (143, 151))
31994	28039263	The GWAS of cisplatin-associated hearing loss among the 238 patients treated at St. Jude Children's Hospital found that rs1872328 in ACYP2 met genome-wide significance, a finding which was replicated in 68 children and in an independent cohort of 156 pediatric and adult osteosarcoma patients.	('Children', 'Species', '9606', (89, 97))	('hearing loss', 'Phenotype', 'HP:0000365', (33, 45))	('adult osteosarcoma', 'Disease', 'MESH:D012516', (265, 283))	('hearing loss', 'Disease', (33, 45))	('patients', 'Species', '9606', (284, 292))	('osteosarcoma', 'Phenotype', 'HP:0002669', (271, 283))	('rs1872328', 'Mutation', 'rs1872328', (120, 129))	('patients', 'Species', '9606', (60, 68))	('adult osteosarcoma', 'Disease', (265, 283))	('ACYP2', 'Gene', (133, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('hearing loss', 'Disease', 'MESH:D034381', (33, 45))	('children', 'Species', '9606', (206, 214))	('ACYP2', 'Gene', '98', (133, 138))	('rs1872328', 'Var', (120, 129))
32001	28039263	In the first GWAS of CAO in adults, we found that rs62283056 in the plausible gene WFS1 was significantly associated with CAO (P = 1.4 x 10-8), a relationship exacerbated by increased cumulative cisplatin dose.	('rs62283056', 'Var', (50, 60))	('CAO', 'Disease', (122, 125))	('rs62283056', 'Mutation', 'rs62283056', (50, 60))	('associated', 'Reg', (106, 116))	('WFS1', 'Gene', (83, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))	('CAO', 'Chemical', '-', (21, 24))	('CAO', 'Chemical', '-', (122, 125))	('WFS1', 'Gene', '7466', (83, 87))
32009	28039263	Mutations in WFS1 cause both autosomal dominant low-frequency sensorineural hearing loss and Wolfram syndrome, characterized by autosomal recessive hearing loss, diabetes mellitus, diabetes insipidus and optic atrophy.	('Wolfram syndrome', 'Disease', 'MESH:D014929', (93, 109))	('WFS1', 'Gene', (13, 17))	('sensorineural hearing', 'Phenotype', 'HP:0000407', (62, 83))	('diabetes mellitus', 'Disease', 'MESH:D003920', (162, 179))	('sensorineural hearing loss', 'Disease', 'MESH:D006313', (62, 88))	('autosomal recessive hearing loss', 'Disease', (128, 160))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (162, 179))	('optic atrophy', 'Disease', 'MESH:D009896', (204, 217))	('sensorineural hearing loss', 'Disease', (62, 88))	('low-frequency sensorineural hearing loss', 'Phenotype', 'HP:0008573', (48, 88))	('diabetes insipidus', 'Disease', (181, 199))	('Mutations', 'Var', (0, 9))	('WFS1', 'Gene', '7466', (13, 17))	('hearing loss', 'Phenotype', 'HP:0000365', (148, 160))	('Wolfram syndrome', 'Disease', (93, 109))	('hearing loss', 'Phenotype', 'HP:0000365', (76, 88))	('diabetes insipidus', 'Disease', 'MESH:D003919', (181, 199))	('optic atrophy', 'Disease', (204, 217))	('autosomal recessive hearing loss', 'Disease', 'MESH:D034381', (128, 160))	('diabetes mellitus', 'Disease', (162, 179))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (181, 199))	('optic atrophy', 'Phenotype', 'HP:0000648', (204, 217))	('cause', 'Reg', (18, 23))
32012	28039263	Dominant mutations that cause low-frequency hearing loss are nearly always found in the 3' end of WFS1 and are usually non-inactivating.	('hearing loss', 'Phenotype', 'HP:0000365', (44, 56))	('WFS1', 'Gene', (98, 102))	('hearing loss', 'Disease', (44, 56))	('mutations', 'Var', (9, 18))	('WFS1', 'Gene', '7466', (98, 102))	('-frequency hearing', 'Phenotype', 'HP:0005101', (33, 51))	('low-frequency hearing loss', 'Phenotype', 'HP:0008542', (30, 56))	('hearing loss', 'Disease', 'MESH:D034381', (44, 56))
32013	28039263	On the other hand, WFS1 mutations causing the recessive Wolfram syndrome are numerous, usually loss-of-function, and distributed along the entire gene.	('loss-of-function', 'NegReg', (95, 111))	('WFS1', 'Gene', (19, 23))	('recessive Wolfram syndrome', 'Disease', 'MESH:D014929', (46, 72))	('causing', 'Reg', (34, 41))	('WFS1', 'Gene', '7466', (19, 23))	('recessive Wolfram syndrome', 'Disease', (46, 72))	('mutations', 'Var', (24, 33))
32015	28039263	The top GWAS SNP, rs62283056, is in the first intron of WFS1 (5' end) and the risk allele is associated with lower expression (loss-of-function) of the gene.	('WFS1', 'Gene', '7466', (56, 60))	('lower', 'NegReg', (109, 114))	('expression', 'MPA', (115, 125))	('WFS1', 'Gene', (56, 60))	('rs62283056', 'Mutation', 'rs62283056', (18, 28))	('rs62283056', 'Var', (18, 28))
32017	28039263	As shown in pancreatic beta-cells from Wfs1-/- mice and human lymphocytes from Wolfram syndrome patients, dysfunction of wolframin in inner ear cells likely results in increased expression of the ER stress response genes and apoptosis.	('increased', 'PosReg', (168, 177))	('apoptosis', 'CPA', (225, 234))	('dysfunction', 'Var', (106, 117))	('wolframin', 'Gene', (121, 130))	('Wolfram syndrome', 'Disease', (79, 95))	('wolframin', 'Gene', '7466', (121, 130))	('expression', 'MPA', (178, 188))	('human', 'Species', '9606', (56, 61))	('Wfs1', 'Gene', '22393', (39, 43))	('patients', 'Species', '9606', (96, 104))	('Wolfram syndrome', 'Disease', 'MESH:D014929', (79, 95))	('mice', 'Species', '10090', (47, 51))	('Wfs1', 'Gene', (39, 43))
32018	28039263	In addition to causing DNA damage, cisplatin also induces ER stress and nucleus-independent apoptosis.	('nucleus-independent apoptosis', 'CPA', (72, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('ER stress', 'CPA', (58, 67))	('cisplatin', 'Var', (35, 44))	('induces', 'Reg', (50, 57))
32019	28039263	Because both cisplatin and WFS1 loss-of-function induce ER stress, increased ER stress is likely one potential mechanism for the significant interaction we found between cumulative cisplatin dose and rs62283056 genotype, with higher cisplatin dose exacerbating hearing loss in patients carrying the minor allele.	('hearing loss', 'Disease', 'MESH:D034381', (261, 273))	('exacerbating', 'PosReg', (248, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))	('WFS1', 'Gene', (27, 31))	('hearing loss', 'Phenotype', 'HP:0000365', (261, 273))	('patients', 'Species', '9606', (277, 285))	('loss-of-function', 'NegReg', (32, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('WFS1', 'Gene', '7466', (27, 31))	('hearing loss', 'Disease', (261, 273))	('rs62283056', 'Var', (200, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('ER stress', 'MPA', (56, 65))	('rs62283056', 'Mutation', 'rs62283056', (200, 210))
32023	28039263	In addition to WFS1, we found that SNPs mapping to other genes implicated in Mendelian forms of hearing impairment were also associated with CAO more often than expected by chance.	('CAO', 'Chemical', '-', (141, 144))	('WFS1', 'Gene', '7466', (15, 19))	('CAO', 'Disease', (141, 144))	('hearing impairment', 'Disease', (96, 114))	('hearing impairment', 'Disease', 'MESH:D034381', (96, 114))	('associated with', 'Reg', (125, 140))	('SNPs mapping', 'Var', (35, 47))	('hearing impairment', 'Phenotype', 'HP:0000365', (96, 114))	('WFS1', 'Gene', (15, 19))
32025	28039263	Rather, a subset of these SNPs are likely to affect expression of the local gene, thereby leading to an increased risk of CAO and general hearing loss.	('affect', 'Reg', (45, 51))	('local gene', 'Gene', (70, 80))	('CAO', 'Disease', (122, 125))	('hearing loss', 'Disease', 'MESH:D034381', (138, 150))	('CAO', 'Chemical', '-', (122, 125))	('SNPs', 'Var', (26, 30))	('expression', 'MPA', (52, 62))	('hearing loss', 'Phenotype', 'HP:0000365', (138, 150))	('hearing loss', 'Disease', (138, 150))
32026	28039263	Future GWAS of CAO with larger sample sizes may reveal additional variants in deafness gene loci that meet genome-wide significance.	('deafness', 'Disease', (78, 86))	('deafness', 'Disease', 'MESH:D003638', (78, 86))	('CAO', 'Chemical', '-', (15, 18))	('variants', 'Var', (66, 74))	('deafness', 'Phenotype', 'HP:0000365', (78, 86))
32027	28039263	Consistent with the enrichment results in these loci, the heritability estimate for CAO (0.92 +- 0.62, P = 0.039) using a variance-component approach provides preliminary support to the hypothesis that many common variants with small effect sizes underlie CAO; thus, it is a polygenic trait.	('CAO', 'Chemical', '-', (256, 259))	('CAO', 'Chemical', '-', (84, 87))	('men', 'Species', '9606', (26, 29))	('variants', 'Var', (214, 222))	('underlie', 'Reg', (247, 255))	('CAO', 'Disease', (256, 259))
32028	28039263	Lack of replication of candidate genes reported in previous smaller studies of CAO (n = 130-254 patients) also supports the hypothesis that large-effect variants for ototoxicity are unlikely.	('ototoxicity', 'Disease', (166, 177))	('CAO', 'Chemical', '-', (79, 82))	('patients', 'Species', '9606', (96, 104))	('variants', 'Var', (153, 161))	('ototoxicity', 'Disease', 'MESH:D006311', (166, 177))
32033	28039263	SNPs in FGD4, a Mendelian gene for congenital peripheral neuropathy (Charcot-Marie-Tooth disease), associated with paclitaxel-induced peripheral neuropathy.	('Charcot-Marie-Tooth disease', 'Disease', (69, 96))	('FGD4', 'Gene', (8, 12))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (46, 67))	('FGD4', 'Gene', '121512', (8, 12))	('associated with', 'Reg', (99, 114))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('peripheral neuropathy', 'Disease', (134, 155))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (134, 155))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (134, 155))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (46, 67))	('SNPs', 'Var', (0, 4))	('congenital peripheral neuropathy', 'Disease', 'MESH:D010523', (35, 67))	('congenital peripheral neuropathy', 'Phenotype', 'HP:0006903', (35, 67))	('congenital peripheral neuropathy', 'Disease', (35, 67))	('Tooth disease', 'Phenotype', 'HP:0000164', (83, 96))	('Charcot-Marie-Tooth disease', 'Disease', 'MESH:D000699', (69, 96))
32034	28039263	SNPs in VAC14 associated with docetaxel-induced peripheral neuropathy, and the gene was recently shown to be mutated in pediatric-onset neurological disease.	('neurological disease', 'Disease', 'MESH:D019636', (136, 156))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (48, 69))	('associated with', 'Reg', (14, 29))	('SNPs', 'Var', (0, 4))	('VAC14', 'Gene', '55697', (8, 13))	('VAC14', 'Gene', (8, 13))	('peripheral neuropathy', 'Disease', (48, 69))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (48, 69))	('neurological disease', 'Disease', (136, 156))	('docetaxel', 'Chemical', 'MESH:D000077143', (30, 39))	('neurological disease', 'Phenotype', 'HP:0000707', (136, 156))
32035	28039263	Beyond chemotherapy studies, genetic variants that associate with the euphoric effects of d-amphetamine significantly overlap with variants that decrease risk for schizophrenia and attention deficit hyperactivity disorder.	('attention deficit', 'Phenotype', 'HP:0007018', (181, 198))	('d-amphetamine', 'Chemical', 'MESH:D003913', (90, 103))	('schizophrenia', 'Phenotype', 'HP:0100753', (163, 176))	('schizophrenia and attention deficit hyperactivity disorder', 'Disease', 'MESH:D001289', (163, 221))	('variants', 'Var', (37, 45))	('decrease', 'NegReg', (145, 153))	('hyperactivity', 'Phenotype', 'HP:0000752', (199, 212))
32042	28039263	WFS1 mutations can cause the Mendelian disorders DFNA6 (deafness, autosomal dominant 6) and Wolfram Syndrome (with hearing loss).	('cause', 'Reg', (19, 24))	('deafness', 'Disease', 'MESH:D003638', (56, 64))	('hearing loss', 'Disease', (115, 127))	('Wolfram Syndrome', 'Disease', (92, 108))	('hearing loss', 'Disease', 'MESH:D034381', (115, 127))	('WFS1', 'Gene', '7466', (0, 4))	('deafness', 'Phenotype', 'HP:0000365', (56, 64))	('mutations', 'Var', (5, 14))	('Mendelian disorders DFNA6', 'Disease', (29, 54))	('WFS1', 'Gene', (0, 4))	('deafness', 'Disease', (56, 64))	('hearing loss', 'Phenotype', 'HP:0000365', (115, 127))	('Wolfram Syndrome', 'Disease', 'MESH:D014929', (92, 108))	('Mendelian disorders DFNA6', 'Disease', 'MESH:C563421', (29, 54))
32118	12782494	In cases only the concentration on lipid basis of cis-nonachlordane was significantly increased, whereas case mothers showed significantly increased concentrations of the sum of PCBs, HCB, trans- and cis-nonachlordane, and the sum of chlordanes.	('PCBs', 'Chemical', 'MESH:D011078', (178, 182))	('trans- and cis-nonachlordane', 'Chemical', '-', (189, 217))	('cis-nonachlordane', 'Var', (200, 217))	('increased', 'PosReg', (86, 95))	('concentrations', 'MPA', (149, 163))	('increased', 'PosReg', (139, 148))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('cis-nonachlordane', 'Chemical', 'MESH:C001870', (200, 217))	('cis-nonachlordane', 'Chemical', 'MESH:C001870', (50, 67))	('chlordanes', 'Chemical', 'MESH:D002706', (234, 244))	('HCB', 'Chemical', 'MESH:D006581', (184, 187))
32120	12782494	For HCB, OR = 4.4 (95% CI, 1.7-12); for trans-nonachlordane, OR = 4.1 (95% CI, 1.5-11); for cis-nonachlordane, OR = 3.1 (95% CI, 1.2-7.8); and for sum of chlordanes, OR = 1.9 (95% CI, 0.7-5.0).	('HCB', 'Chemical', 'MESH:D006581', (4, 7))	('chlordanes', 'Chemical', 'MESH:D002706', (154, 164))	('cis-nonachlordane', 'Var', (92, 109))	('trans-nonachlordane', 'Var', (40, 59))	('cis-nonachlordane', 'Chemical', 'MESH:C001870', (92, 109))	('trans-nonachlordane', 'Chemical', 'MESH:C001870', (40, 59))
32179	33434070	In the pure seminoma subgroup, retroperitoneal lymph node dissection was statistically significantly associated with an increased risk of death.	('retroperitoneal', 'Var', (31, 46))	('death', 'Disease', 'MESH:D003643', (138, 143))	('death', 'Disease', (138, 143))	('seminoma', 'Disease', 'MESH:D018239', (12, 20))	('associated', 'Reg', (101, 111))	('seminoma', 'Disease', (12, 20))
32309	32627997	These authors reported that fetal exposure decreased due to the pegylated formulation with lower cellular intake and toxicity of PLD compared to doxorubicin.	('lower', 'NegReg', (91, 96))	('cellular intake', 'MPA', (97, 112))	('pegylated', 'Var', (64, 73))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('fetal exposure', 'Phenotype', 'HP:0031437', (28, 42))	('toxicity', 'Disease', (117, 125))	('doxorubicin', 'Chemical', 'MESH:D004317', (145, 156))	('fetal', 'CPA', (28, 33))	('decreased', 'NegReg', (43, 52))
32328	32627997	A further study reported that melatonin increases the efficacy of CIS and 5-FU in HT-29 cells.	('HT-29', 'CellLine', 'CVCL:0320', (82, 87))	('efficacy', 'MPA', (54, 62))	('melatonin', 'Chemical', 'MESH:D008550', (30, 39))	('CIS', 'Var', (66, 69))	('increases', 'PosReg', (40, 49))	('5-FU', 'Chemical', 'MESH:D005472', (74, 78))
32335	32627997	Studies have shown that the molecular protective mechanisms of carotenoids in isolated human cell culture include: stopping the cell cycle in G1/G0 phase by decreasing cycline D1 levels; apoptosis induction downregulating survivin levels; increase in cellular gap junction communication and angiogenic effect through modulation of various cytokines including decreased interleukin-6 (IL-6), IL-1b, tumour necrosis factor alpha and granulocyte-macrophage colony-stimulating factor levels and increased IL-2 and TIMP metallopeptidase inhibitor 1 (TIMP-1) levels.	('interleukin-6', 'Gene', '3569', (369, 382))	('increased', 'PosReg', (491, 500))	('IL-1b', 'Gene', '3553', (391, 396))	('decreasing', 'NegReg', (157, 167))	('decreased', 'NegReg', (359, 368))	('angiogenic effect', 'CPA', (291, 308))	('IL-1b', 'Gene', (391, 396))	('TIMP metallopeptidase inhibitor 1', 'Gene', (510, 543))	('interleukin-6', 'Gene', (369, 382))	('IL-2', 'Gene', (501, 505))	('human', 'Species', '9606', (87, 92))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (431, 479))	('carotenoids', 'Chemical', 'MESH:D002338', (63, 74))	('cycline D1 levels', 'MPA', (168, 185))	('TIMP-1', 'Gene', '7076', (545, 551))	('TIMP-1', 'Gene', (545, 551))	('IL-6', 'Gene', '3569', (384, 388))	('tumour', 'Phenotype', 'HP:0002664', (398, 404))	('apoptosis', 'CPA', (187, 196))	('IL-6', 'Gene', (384, 388))	('IL-2', 'Gene', '3558', (501, 505))	('tumour necrosis', 'Disease', 'MESH:D009336', (398, 413))	('tumour necrosis', 'Disease', (398, 413))	('modulation', 'Var', (317, 327))	('downregulating', 'NegReg', (207, 221))	('cellular gap junction communication', 'MPA', (251, 286))	('increase', 'PosReg', (239, 247))	('decreased interleukin-6', 'Phenotype', 'HP:0030783', (359, 382))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (431, 479))	('mole', 'Phenotype', 'HP:0003764', (28, 32))	('TIMP metallopeptidase inhibitor 1', 'Gene', '7076', (510, 543))	('survivin levels', 'MPA', (222, 237))
32373	27336212	The FDRs and SDRs of azoospermic men had a significantly increased risk of thyroid cancer compared with fertile population control subjects.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('azoospermic', 'Var', (21, 32))	('thyroid cancer', 'Phenotype', 'HP:0002890', (75, 89))	('thyroid cancer', 'Disease', (75, 89))	('men', 'Species', '9606', (33, 36))	('thyroid cancer', 'Disease', 'MESH:D013964', (75, 89))
32375	27336212	This highlights the possibilities of shared biologic mechanisms between the two diseases, exposure to environmental factors, and an increased level of genetic and/or epigenetic burden in subfertile men and their relatives that may be associated with risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('associated', 'Reg', (234, 244))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('epigenetic burden', 'Var', (166, 183))	('cancer', 'Disease', (258, 264))	('men', 'Species', '9606', (109, 112))	('men', 'Species', '9606', (198, 201))
32396	27336212	A sperm concentration of 0 M/mL was categorized as azoospermia, <15 M/mL as oligozoospermia, 15-178 M/mL as normozoospermia, and >178 M/mL as hyperzoospermia (based on the 90th percentile of data).	('oligozoospermia', 'Disease', (76, 91))	('hyperzoospermia', 'Disease', 'None', (142, 157))	('azoospermia', 'Disease', 'MESH:D053713', (51, 62))	('hyperzoospermia', 'Disease', (142, 157))	('>178 M/mL', 'Var', (129, 138))	('azoospermia', 'Disease', (51, 62))	('<15 M/mL', 'Var', (64, 72))	('oligozoospermia', 'Disease', 'MESH:D009845', (76, 91))	('azoospermia', 'Phenotype', 'HP:0000027', (51, 62))	('15-178 M/mL', 'Var', (93, 104))
32397	27336212	Total sperm count was categorized as follows: 0 M as azoospermia, <39 M as oligozoospermia, 39-579 M as normozoospermia, and >579 M as hyperzoospermia (based on the 90th percentile).	('oligozoospermia', 'Disease', 'MESH:D009845', (75, 90))	('39-579 M', 'Var', (92, 100))	('azoospermia', 'Phenotype', 'HP:0000027', (53, 64))	('hyperzoospermia', 'Disease', 'None', (135, 150))	('hyperzoospermia', 'Disease', (135, 150))	('oligozoospermia', 'Disease', (75, 90))	('azoospermia', 'Disease', 'MESH:D053713', (53, 64))	('>579 M', 'Var', (125, 131))	('normozoospermia', 'Disease', (104, 119))	('azoospermia', 'Disease', (53, 64))
32398	27336212	Sperm motility and vitality cut points were made based on quartiles and were as follows: azoospermia, >0-49%, 50%-59%, 60%-69%, and 70%-100%.	('azoospermia', 'Disease', (89, 100))	('>0-49%', 'Var', (102, 108))	('azoospermia', 'Phenotype', 'HP:0000027', (89, 100))	('azoospermia', 'Disease', 'MESH:D053713', (89, 100))	('Sperm motility', 'CPA', (0, 14))
32419	27336212	To determine the risk of cancer in relatives of men with male-factor infertility and men with normal semen parameters, case-case analyses were also completed in which relatives of men with abnormal semen parameters were compared with relatives of men with normal semen parameters.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('men', 'Species', '9606', (48, 51))	('infertility', 'Disease', 'MESH:D007247', (69, 80))	('men', 'Species', '9606', (265, 268))	('abnormal', 'Var', (189, 197))	('infertility', 'Phenotype', 'HP:0000789', (69, 80))	('infertility', 'Disease', (69, 80))	('men', 'Species', '9606', (103, 106))	('men', 'Species', '9606', (180, 183))	('men', 'Species', '9606', (200, 203))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('men', 'Species', '9606', (85, 88))	('cancer', 'Disease', (25, 31))	('men', 'Species', '9606', (247, 250))
32435	27336212	For individual semen parameters, we found that both normozoospermic count (HR 1.67, 95% CI 1.13-2.45) and normozoospermic concentration (HR 1.90, 95% CI 1.26-2.85) were associated with increased risk of testicular cancer.	('normozoospermic', 'Var', (52, 67))	('normozoospermic concentration', 'Var', (106, 135))	('testicular cancer', 'Disease', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('testicular cancer', 'Phenotype', 'HP:0010788', (203, 220))	('testicular cancer', 'Disease', 'MESH:D013736', (203, 220))	('men', 'Species', '9606', (17, 20))
32448	27336212	The FDRs of azoospermic men had a twofold increased risk of being diagnosed with thyroid cancer compared with FDRs of fertile population control subjects (HR 2.12, 95% CI 1.26-3.57; Fig.	('men', 'Species', '9606', (24, 27))	('thyroid cancer', 'Disease', (81, 95))	('azoospermic', 'Var', (12, 23))	('thyroid cancer', 'Phenotype', 'HP:0002890', (81, 95))	('thyroid cancer', 'Disease', 'MESH:D013964', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
32460	27336212	Evidence from rodent models demonstrates that deletions of meiotic regulators in the DNA-mismatch repair proteins leads to infertility and tumorigenesis, and these same deletions have been identified in some infertile men.	('tumorigenesis', 'CPA', (139, 152))	('infertility', 'Disease', (123, 134))	('leads to', 'Reg', (114, 122))	('infertility', 'Disease', 'MESH:D007247', (123, 134))	('men', 'Species', '9606', (218, 221))	('deletions', 'Var', (46, 55))	('infertility', 'Phenotype', 'HP:0000789', (123, 134))
32461	27336212	Additionally, epigenetic factors may contribute to genitourinary cancers as well as to normal sperm function.	('contribute', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('genitourinary cancers', 'Disease', 'MESH:D014565', (51, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('epigenetic factors', 'Var', (14, 32))	('genitourinary cancer', 'Phenotype', 'HP:0007379', (51, 71))	('genitourinary cancers', 'Disease', (51, 72))
32462	27336212	We sought to determine if the genetic and epigenetic factors that predispose men to infertility and cancer would also predispose their relatives to cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('predispose', 'Reg', (118, 128))	('men', 'Species', '9606', (77, 80))	('infertility', 'Phenotype', 'HP:0000789', (84, 95))	('epigenetic', 'Var', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('infertility and cancer', 'Disease', 'MESH:D007247', (84, 106))
32468	27336212	It is unclear why FDRs of azoospermic men do not demonstrate this elevated cancer risk, but it may be that the germline DNA in these families have severe mutations that lead to spermatogenic arrest and do not elevate cancer risk, because they result in severe mutations that stop cell division.	('men', 'Species', '9606', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('spermatogenic arrest', 'Phenotype', 'HP:0031038', (177, 197))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (154, 163))	('mutations', 'Var', (260, 269))	('lead to', 'Reg', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('spermatogenic arrest', 'CPA', (177, 197))
32484	27336212	For example, mutations in thyroid receptors are associated with increased risk of papillary thyroid cancer, and aberrant alpha subunits have displayed an infertile phenotype.	('thyroid receptors', 'Protein', (26, 43))	('aberrant', 'Var', (112, 120))	('papillary thyroid cancer', 'Disease', (82, 106))	('associated', 'Reg', (48, 58))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (82, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('thyroid cancer', 'Phenotype', 'HP:0002890', (92, 106))	('alpha subunits', 'Protein', (121, 135))	('mutations', 'Var', (13, 22))
32485	27336212	We do not have the ability to investigate if the thyroid cancers in our database were papillary subtype, and it is unclear if the infertile phenotype identified with some alpha-receptor subtype mutations resulted in azoospermia.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('azoospermia', 'Disease', (216, 227))	('thyroid cancers', 'Disease', (49, 64))	('mutations', 'Var', (194, 203))	('thyroid cancers', 'Disease', 'MESH:D013964', (49, 64))	('azoospermia', 'Phenotype', 'HP:0000027', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('azoospermia', 'Disease', 'MESH:D053713', (216, 227))	('resulted in', 'Reg', (204, 215))
32552	24788853	In contrast to other malignancies, the relapse rate here is not indicative of treatment quality, since overtreatment, for example, may increase toxicity and long-term morbidity without affecting the relapse rate.	('overtreatment', 'Var', (103, 116))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('increase', 'PosReg', (135, 143))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (144, 152))	('malignancies', 'Disease', (21, 33))
32564	22815844	In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA.	('mutations', 'Var', (72, 81))	('Swyer syndrome', 'Disease', 'MESH:D006061', (51, 65))	('46,XY gonadal dysgenesis', 'Phenotype', 'HP:0008668', (13, 37))	('SRY', 'Gene', (68, 71))	('binding to', 'Interaction', (174, 184))	('bending', 'MPA', (189, 196))	('Swyer syndrome', 'Disease', (51, 65))	('gonadal dysgenesis', 'Disease', (19, 37))	('affect', 'Reg', (146, 152))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (19, 37))	('DNA', 'Protein', (200, 203))	('nuclear transport', 'MPA', (153, 170))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (19, 37))
32565	22815844	Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1).	('splice site mutation in', 'Var', (182, 205))	('Frasier syndrome', 'Disease', 'MESH:D052159', (0, 16))	('gonadal dysgenesis', 'Disease', (42, 60))	('WT1', 'Gene', (243, 246))	('chronic renal failure', 'Disease', 'MESH:D007676', (111, 132))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (42, 60))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (222, 234))	("Wilms' tumor 1", 'Gene', '7490', (222, 236))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('chronic renal failure', 'Phenotype', 'HP:0003774', (111, 132))	("Wilms' tumor 1", 'Gene', (222, 236))	('WT1', 'Gene', '7490', (243, 246))	('Frasier syndrome', 'Disease', (0, 16))	('renal failure', 'Phenotype', 'HP:0000083', (119, 132))	('chronic renal failure', 'Disease', (111, 132))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (42, 60))
32566	22815844	Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development.	('Sertoli cell', 'Phenotype', 'HP:0100619', (129, 141))	('Sertoli cell formation', 'Phenotype', 'HP:0100619', (129, 151))	('SOX9', 'Gene', (112, 116))	('SOX9', 'Gene', '6662', (112, 116))	('SRY', 'Gene', (82, 85))	('diminished', 'NegReg', (44, 54))	('WT1', 'Gene', '7490', (28, 31))	('expression', 'MPA', (55, 65))	('WT1', 'Gene', (28, 31))	('function', 'MPA', (70, 78))	('Mutations', 'Var', (0, 9))	('Sertoli cell formation', 'CPA', (129, 151))	('lack', 'NegReg', (167, 171))	('SRY', 'Gene', (13, 16))
32567	22815844	Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY.	('hypergonadotropic hypogonadism', 'Gene', (137, 167))	('missense mutation', 'Var', (221, 238))	('gonadal dygenesis', 'Phenotype', 'HP:0000133', (190, 207))	('SRY', 'Gene', (242, 245))	('hypergonadotropic hypogonadism', 'Phenotype', 'HP:0000815', (137, 167))	('hypergonadotropic hypogonadism', 'Gene', '3973', (137, 167))	('primary amenorrhoea', 'Disease', 'MESH:C537962', (97, 116))	('hypogonadism', 'Phenotype', 'HP:0000135', (155, 167))	('primary amenorrhoea', 'Phenotype', 'HP:0000786', (97, 116))	('primary amenorrhoea', 'Disease', (97, 116))
32570	22815844	Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9.	('WT1', 'Gene', '7490', (112, 115))	('focal segmental glomerular sclerosis', 'Phenotype', 'HP:0000097', (52, 88))	('WT1', 'Gene', (112, 115))	('kidney failure', 'Disease', 'MESH:D051437', (36, 50))	('glomerular sclerosis', 'Phenotype', 'HP:0000096', (68, 88))	('progressive kidney failure', 'Phenotype', 'HP:0012622', (24, 50))	('kidney failure', 'Disease', (36, 50))	('pathogenic', 'Reg', (129, 139))	('kidney failure', 'Phenotype', 'HP:0000083', (36, 50))	('focal segmental glomerular sclerosis', 'Disease', 'MESH:D005923', (52, 88))	('splice-site mutation in', 'Var', (140, 163))	('focal segmental glomerular sclerosis', 'Disease', (52, 88))
32582	22815844	The two major WT1 isoforms are produced by alternative splicing, resulting in an insertion (+KTS) or exclusion (-KTS) of lysine, threonine and serine between zinc fingers three and four.	('lysine', 'Chemical', 'MESH:D008239', (121, 127))	('insertion', 'Var', (81, 90))	('exclusion', 'NegReg', (101, 110))	('lysine', 'MPA', (121, 127))	('serine', 'Chemical', 'MESH:D012694', (143, 149))	('WT1', 'Gene', '7490', (14, 17))	('serine', 'MPA', (143, 149))	('threonine', 'Chemical', 'MESH:D013912', (129, 138))	('threonine', 'MPA', (129, 138))	('WT1', 'Gene', (14, 17))
32585	22815844	SRY mutations residing in the HMG (High Mobility Group) domains are found in 10-15% of the 46,XY gonadal dysgenesis cases and affect binding to and bending of DNA or nuclear transport.	('nuclear transport', 'CPA', (166, 183))	('binding to', 'Interaction', (133, 143))	('SRY', 'Gene', (0, 3))	('DNA', 'Protein', (159, 162))	('gonadal dysgenesis', 'Disease', (97, 115))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (97, 115))	('affect', 'Reg', (126, 132))	('bending', 'MPA', (148, 155))	('mutations', 'Var', (4, 13))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (97, 115))	('46,XY gonadal dysgenesis', 'Phenotype', 'HP:0008668', (91, 115))
32586	22815844	Specific intron 9 splice site mutations in WT1 resulting in a decreased WT1+KTS isoform are typically found in FS patients, leading to a diminished expression of SRY and subsequently SOX9, thereby disturbing testicular development.	('expression', 'MPA', (148, 158))	('WT1', 'Gene', (43, 46))	('decreased', 'NegReg', (62, 71))	('SOX9', 'Gene', (183, 187))	('testicular development', 'CPA', (208, 230))	('diminished', 'NegReg', (137, 147))	('WT1', 'Gene', '7490', (72, 75))	('SOX9', 'Gene', '6662', (183, 187))	('mutations', 'Var', (30, 39))	('disturbing', 'Reg', (197, 207))	('patients', 'Species', '9606', (114, 122))	('WT1', 'Gene', '7490', (43, 46))	('WT1', 'Gene', (72, 75))	('SRY', 'Protein', (162, 165))
32588	22815844	Thus both SRY and WT1 mutations can cause (complete) sex reversal.	('sex reversal', 'Phenotype', 'HP:0012245', (53, 65))	('cause', 'Reg', (36, 41))	('SRY', 'Gene', (10, 13))	('WT1', 'Gene', '7490', (18, 21))	('WT1', 'Gene', (18, 21))	('mutations', 'Var', (22, 31))
32595	22815844	Mutation analysis identified a novel missense mutation (c.383A>G, p.Lys128Arg) in the HMG domain of the SRY, which did not have a significant effect on transcriptional activation and nuclear import in vitro.	('c.383A>G', 'Mutation', 'rs375342012', (56, 64))	('p.Lys128Arg', 'Mutation', 'rs375342012', (66, 77))	('c.383A>G', 'Var', (56, 64))	('p.Lys128Arg', 'Var', (66, 77))
32599	22815844	Sequence analysis of DNA from five additional FS patients with a proven WT1 mutation for SRY mutations did not reveal any variants, indicating that the presence of mutations in both genes in FS patients is rare.	('SRY', 'Gene', (89, 92))	('patients', 'Species', '9606', (194, 202))	('mutations', 'Var', (93, 102))	('WT1', 'Gene', '7490', (72, 75))	('patients', 'Species', '9606', (49, 57))	('WT1', 'Gene', (72, 75))
32600	22815844	To our knowledge this is the first case describing a patient with a mutation in both WT1 and SRY, and underlines the importance of proper diagnosis, especially in patients with an increased risk for GCC, allowing early diagnosis and treatment, thus preventing the development of invasive cancer.	('patients', 'Species', '9606', (163, 171))	('WT1', 'Gene', (85, 88))	('mutation', 'Var', (68, 76))	('SRY', 'Gene', (93, 96))	('invasive cancer', 'Disease', (279, 294))	('patient', 'Species', '9606', (163, 170))	('preventing', 'NegReg', (249, 259))	('WT1', 'Gene', '7490', (85, 88))	('invasive cancer', 'Disease', 'MESH:D009362', (279, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('GCC', 'Disease', (199, 202))	('patient', 'Species', '9606', (53, 60))
32609	22815844	DNA encoding wild type SRY, mutant SRY and SF1 were cloned into the pcDNA3 mammalian expression plasmid (Clontech, Mountain View, CA, USA), and sequence verified.	('mutant', 'Var', (28, 34))	('SF1', 'Gene', '7536', (43, 46))	('SRY', 'Gene', (35, 38))	('SF1', 'Gene', (43, 46))	('mammalian', 'Species', '9606', (75, 84))
32613	22815844	Cells in each well were co-transfected with the reporter constructs TESCO-E1b-Luc (10 ng) or the empty vector E1b-Luc (8 ng), together with 40 ng of each of the expression constructs pcDNA3-SF1 and either pcDNA3-hSRY (wild-type) or pcDNA3-SRY-K128R (mutant).	('pcDNA3-SRY-K128R', 'Var', (232, 248))	('E1b', 'Gene', (110, 113))	('SF1', 'Gene', (190, 193))	('E1b', 'Gene', '594', (110, 113))	('E1b', 'Gene', (74, 77))	('K128R', 'Mutation', 'rs375342012', (243, 248))	('E1b', 'Gene', '594', (74, 77))	('SF1', 'Gene', '7536', (190, 193))
32619	22815844	Fold change of the mutant SRY-K128R construct was then normalized against that of wild-type SRY.	('K128R', 'Mutation', 'rs375342012', (30, 35))	('mutant', 'Var', (19, 25))	('SRY-K128R', 'Gene', (26, 35))
32634	22815844	Chromosome analysis on peripheral blood lymphocytes showed the presence of a 46,XY karyotype, and mutational analysis of the SRY gene revealed an, at that time, unclassified variant K128R (c.383 A>G, p.Lys128Arg).	('p.Lys128Arg', 'Var', (200, 211))	('c.383 A>G', 'Var', (189, 198))	('p.Lys128Arg', 'Mutation', 'rs375342012', (200, 211))	('SRY', 'Gene', (125, 128))	('K128R', 'Mutation', 'rs375342012', (182, 187))	('c.383 A>G', 'Mutation', 'rs375342012', (189, 198))
32647	22815844	Direct sequencing of the SRY gene showed the presence of a single nucleotide change at position 383 (A to G, see Figure 2A), resulting in a missense substitution (Lysine (K) to Arginine (R) amino acid change) at position 128 in the SRY protein (hemizygous pattern).	('in a', 'Reg', (135, 139))	('SRY', 'Gene', (232, 235))	('Arginine', 'Chemical', 'MESH:D001120', (177, 185))	('Lysine', 'Var', (163, 169))	('Lysine', 'Chemical', 'MESH:D008239', (163, 169))
32648	22815844	A K128R missense mutation in SRY has not been reported to date.	('K128R', 'Mutation', 'rs375342012', (2, 7))	('K128R missense', 'Var', (2, 16))	('SRY', 'Gene', (29, 32))
32652	22815844	Results show that the K128R mutation of SRY did not significantly affect TESCO activity in vitro compared to wild-type SRY (Figure 2C), although a reduction of about 20% was observed.	('TESCO activity', 'MPA', (73, 87))	('K128R', 'Mutation', 'rs375342012', (22, 27))	('K128R', 'Var', (22, 27))	('reduction', 'NegReg', (147, 156))	('SRY', 'Gene', (40, 43))
32653	22815844	As the K128R substitution is located next to the cNLS, the effect on nuclear import was also investigated using expression plasmids encoding wild-type and mutants full-length SRY transfected in HEK293T cells.	('HEK293T', 'CellLine', 'CVCL:0063', (194, 201))	('K128R', 'Mutation', 'rs375342012', (7, 12))	('K128R', 'Var', (7, 12))	('mutants', 'Var', (155, 162))
32654	22815844	The mutant K128R also showed a slight reduced but non-significant difference in nuclear accumulation compared to the wild type protein, indicating that the K128R mutation does not affect the nuclear import function of SRY.	('K128R', 'Var', (11, 16))	('nuclear accumulation', 'MPA', (80, 100))	('K128R', 'Mutation', 'rs375342012', (156, 161))	('K128R', 'Var', (156, 161))	('K128R', 'Mutation', 'rs375342012', (11, 16))
32656	22815844	Direct sequencing of the WT1 gene showed a single nucleotide change at the start of intron 9 at the position +4 (IVS9+4C > T) in a heterozygous state (Figure 2F), characteristic for FS.	('WT1', 'Gene', (25, 28))	('IVS9+4C > T', 'Mutation', 'c.IVS9+4C>T', (113, 124))	('IVS9+4C > T', 'Var', (113, 124))	('WT1', 'Gene', '7490', (25, 28))
32657	22815844	To determine if SRY mutations together with WT1 mutations were present in other DSD cases with the same clinical characteristics a review of the literature was done (Tables S1 and S2), showing that this has not been investigated to date.	('WT1', 'Gene', (44, 47))	('DSD', 'Disease', 'MESH:D058533', (80, 83))	('DSD', 'Disease', (80, 83))	('SRY', 'Gene', (16, 19))	('mutations', 'Var', (20, 29))	('WT1', 'Gene', '7490', (44, 47))
32658	22815844	Therefore an additional five DNA samples from FS patients with a proven WT1 mutation were analyzed for SRY, showing no aberrations in SRY in addition to the WT1 mutation.	('WT1', 'Gene', '7490', (157, 160))	('WT1', 'Gene', (157, 160))	('WT1', 'Gene', '7490', (72, 75))	('patients', 'Species', '9606', (49, 57))	('mutation', 'Var', (76, 84))	('WT1', 'Gene', (72, 75))
32663	22815844	SRY mutations play a role in 46,XY sex reversal (46,XY DSD) and in about 15% of 46,XY gonadal dysgenesis cases mutations are found.	('DSD', 'Disease', (55, 58))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (86, 104))	('SRY', 'Gene', (0, 3))	('gonadal dysgenesis', 'Disease', (86, 104))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (86, 104))	('sex reversal', 'Phenotype', 'HP:0012245', (35, 47))	('DSD', 'Disease', 'MESH:D058533', (55, 58))	('46,XY gonadal dysgenesis', 'Phenotype', 'HP:0008668', (80, 104))	('mutations', 'Var', (4, 13))	('role', 'Reg', (21, 25))
32664	22815844	The K128R mutation described here does not lead to a statistically significant reduction in transactivational activity as ascertained by an in-vitro assay, although a minor reduction (about 20%) was observed.	('transactivational activity', 'MPA', (92, 118))	('K128R', 'Mutation', 'rs375342012', (4, 9))	('K128R', 'Var', (4, 9))
32666	22815844	Although the lysine on position 128 is conserved between man and mouse, mutation of lysine on position 128 to arginine does not affect regulation of SRY subcellular distribution by (de-)acetylation via p300.	('regulation', 'MPA', (135, 145))	('mouse', 'Species', '10090', (65, 70))	('man', 'Species', '9606', (57, 60))	('SRY subcellular distribution', 'MPA', (149, 177))	('lysine', 'Chemical', 'MESH:D008239', (84, 90))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))	('mutation', 'Var', (72, 80))
32668	22815844	Reviewing the literature shows that almost all gonadal dysgenesis cases with a proven SRY mutation (86 cases in total, Table S1) show a female phenotype (n = 81, 94%).	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (47, 65))	('SRY', 'Gene', (86, 89))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (47, 65))	('gonadal dysgenesis', 'Disease', (47, 65))	('mutation', 'Var', (90, 98))
32672	22815844	In some cases the mutations described are also present (in mosaic form) in male family members, with one showing hypospadias and cryptorchidism, one diagnosed with a testicular seminoma, and one without GCC and a normal male phenotype (refs 14, 15 and 54 in Table S1).	('mutations', 'Var', (18, 27))	('testicular seminoma', 'Phenotype', 'HP:0100617', (166, 185))	('hypospadias', 'Phenotype', 'HP:0000047', (113, 124))	('testicular seminoma', 'Disease', 'MESH:D018239', (166, 185))	('testicular seminoma', 'Disease', (166, 185))	('cryptorchidism', 'Disease', (129, 143))	('hypospadias', 'Disease', 'MESH:D007021', (113, 124))	('cryptorchidism', 'Phenotype', 'HP:0000028', (129, 143))	('hypospadias', 'Disease', (113, 124))
32674	22815844	The patient described here was initially diagnosed as a 46,XY DSD complete gonadal dysgenesis and a (until now unclassified) mutation in SRY was found (i.e.	('DSD', 'Disease', (62, 65))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (75, 93))	('SRY', 'Gene', (137, 140))	('patient', 'Species', '9606', (4, 11))	('DSD', 'Disease', 'MESH:D058533', (62, 65))	('gonadal dysgenesis', 'Disease', (75, 93))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (75, 93))	('mutation', 'Var', (125, 133))
32678	22815844	Mutations in WT1 play a role in 46,XY DSD (i.e.	('DSD', 'Disease', (38, 41))	('WT1', 'Gene', '7490', (13, 16))	('WT1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('DSD', 'Disease', 'MESH:D058533', (38, 41))	('role', 'Reg', (24, 28))
32683	22815844	Careful review of the literature revealed that this is the first patient described having both a WT1 as well as a SRY mutation; however in almost all cases described a mutation screen of both SRY and WT1 was not performed.	('WT1', 'Gene', (200, 203))	('WT1', 'Gene', '7490', (97, 100))	('patient', 'Species', '9606', (65, 72))	('mutation', 'Var', (118, 126))	('WT1', 'Gene', '7490', (200, 203))	('WT1', 'Gene', (97, 100))
32684	22815844	Analysis of five additional FS patient samples with a proven WT1 mutation by conventional Sanger sequencing of the SRY gene did not reveal any mutations.	('WT1', 'Gene', (61, 64))	('patient', 'Species', '9606', (31, 38))	('mutation', 'Var', (65, 73))	('SRY', 'Gene', (115, 118))	('WT1', 'Gene', '7490', (61, 64))
32690	22815844	It has been described that SRY and SOX9 expression can be diminished in FS and one could speculate that in the case presented here the effects from reduced SRY expression by a mutated WT1 were exacerbated by the presence of the SRY K128R mutation, although a reduced SRY function could not be shown conclusively in vitro.	('SOX9', 'Gene', '6662', (35, 39))	('K128R', 'Mutation', 'rs375342012', (232, 237))	('reduced', 'NegReg', (148, 155))	('mutated', 'Var', (176, 183))	('exacerbated', 'PosReg', (193, 204))	('diminished', 'NegReg', (58, 68))	('K128R', 'Var', (232, 237))	('SOX9', 'Gene', (35, 39))	('SRY', 'Gene', (228, 231))	('SRY', 'Gene', (156, 159))	('WT1', 'Gene', '7490', (184, 187))	('WT1', 'Gene', (184, 187))
32691	22815844	However, screening an additional five FS patients with a proven WT1 mutation did not reveal any sequence variants in SRY.	('mutation', 'Var', (68, 76))	('WT1', 'Gene', (64, 67))	('SRY', 'Gene', (117, 120))	('patients', 'Species', '9606', (41, 49))	('WT1', 'Gene', '7490', (64, 67))
32692	22815844	To our knowledge this is the first patient described with a mutation in SRY together with a classical FS WT1 mutation, and thus seems to be a rare condition.	('WT1', 'Gene', (105, 108))	('mutation', 'Var', (60, 68))	('patient', 'Species', '9606', (35, 42))	('SRY', 'Gene', (72, 75))	('WT1', 'Gene', '7490', (105, 108))
32693	22815844	Nonetheless, in this patient an optimal diagnosis could have been made, if a screening for WT1 mutation was performed at an earlier time point.	('WT1', 'Gene', (91, 94))	('WT1', 'Gene', '7490', (91, 94))	('patient', 'Species', '9606', (21, 28))	('mutation', 'Var', (95, 103))
32695	22815844	This case clearly demonstrates the significant role of proper diagnosis of the variants of DSD, especially in those with an increased risk for GCC, allowing early diagnosis and treatment, thus preventing the development of invasive cancer.	('DSD', 'Disease', 'MESH:D058533', (91, 94))	('invasive cancer', 'Disease', (223, 238))	('variants', 'Var', (79, 87))	('preventing', 'NegReg', (193, 203))	('DSD', 'Disease', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('GCC', 'Disease', (143, 146))	('invasive cancer', 'Disease', 'MESH:D009362', (223, 238))
32696	22815844	The presence and type of WT1 mutation has major consequences for the patient.	('mutation', 'Var', (29, 37))	('WT1', 'Gene', '7490', (25, 28))	('WT1', 'Gene', (25, 28))	('patient', 'Species', '9606', (69, 76))	('consequences', 'Reg', (48, 60))
32823	29250030	Intriguingly, inappropriate Phf7 expression in females is associated with the formation of germline tumors.	('Phf7', 'Gene', (28, 32))	('Phf7', 'Gene', '51533', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('associated with', 'Reg', (58, 73))	('inappropriate', 'Var', (14, 27))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('expression', 'MPA', (33, 43))	('formation', 'CPA', (78, 87))
32833	29250030	Somatic cell-production of CXCL12 facilitates the later stages of PGC migration into the genital ridge immediately prior to their sexual differentiation, and upon reaching the nascent gonad, CXCL12 supports gonocyte survival.	('PGC', 'Gene', (66, 69))	('rat', 'Species', '10116', (73, 76))	('gonocyte survival', 'CPA', (207, 224))	('supports', 'PosReg', (198, 206))	('PGC', 'Gene', '5225', (66, 69))	('facilitates', 'PosReg', (34, 45))	('CXCL12', 'Var', (191, 197))
32834	29250030	Mice lacking the CXCR4 receptor have fewer gonocytes, and the difference between wild type and mutant animals increases with developmental age, indicating that CXCL12 regulates the germline cell cycle in the fetal testis.	('gonocytes', 'CPA', (43, 52))	('regulates', 'Reg', (167, 176))	('fewer', 'NegReg', (37, 42))	('germline cell cycle', 'CPA', (181, 200))	('men', 'Species', '9606', (132, 135))	('fewer gonocytes', 'Phenotype', 'HP:0005563', (37, 52))	('mutant', 'Var', (95, 101))	('Mice', 'Species', '10090', (0, 4))
32878	29250030	Knowledge of rodent spermatogenesis (summarized in Section "CXCL12 Influences SSC Fate") led to the hypothesis that aberrant CXCL12 signaling may contribute to the "dedifferentiation" of PGCs into GCNIS cells.	('contribute', 'Reg', (146, 156))	('PGC', 'Gene', '5225', (187, 190))	('PGC', 'Gene', (187, 190))	('CXCL12 signaling', 'MPA', (125, 141))	('dedifferentiation', 'CPA', (165, 182))	('SSC Fate', 'CPA', (78, 86))	('GCNIS', 'Chemical', '-', (197, 202))	('aberrant', 'Var', (116, 124))
32879	29250030	CXCL12 is known to mediate normal cell migration and is implicated in many neoplasias, including the overexpression of its canonical receptor, CXCR4, in various cancers.	('neoplasias', 'Disease', 'MESH:D009369', (75, 85))	('overexpression', 'PosReg', (101, 115))	('neoplasias', 'Disease', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CXCR4', 'MPA', (143, 148))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('neoplasias', 'Phenotype', 'HP:0002664', (75, 85))	('CXCL12', 'Var', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('cancers', 'Disease', (161, 168))	('man', 'Species', '9606', (70, 73))	('implicated', 'Reg', (56, 66))	('rat', 'Species', '10116', (42, 45))
32886	29250030	A zebrafish model arising from genetic disruption of BMP signaling (inactivating mutation in the type IB BMP receptor, encoded by alk6b) exhibited impaired spermatogonial differentiation and overgrowth of undifferentiated germ cells, analogous to events considered to underpin human TGCT initiation.	('alk6b', 'Gene', '100149664', (130, 135))	('overgrowth', 'Phenotype', 'HP:0001548', (191, 201))	('alk6b', 'Gene', (130, 135))	('inactivating mutation', 'Var', (68, 89))	('BMP', 'Gene', '649;652;9573', (105, 108))	('BMP', 'Gene', '649;652;9573', (53, 56))	('BMP', 'Gene', (105, 108))	('human', 'Species', '9606', (277, 282))	('BMP', 'Gene', (53, 56))	('impaired', 'NegReg', (147, 155))	('overgrowth', 'CPA', (191, 201))	('zebrafish', 'Species', '7955', (2, 11))	('spermatogonial differentiation', 'CPA', (156, 186))
32891	29250030	Furthermore, elevated TGCT risk was associated with a SNP in the INHA gene, which encodes the inhibin alpha subunit, though its relationship to altering activin bioactivity remains to be elucidated.	('activin', 'Gene', (153, 160))	('INHA', 'Gene', (65, 69))	('TGCT', 'Disease', (22, 26))	('inhibin alpha subunit', 'Gene', (94, 115))	('activin', 'Gene', '83729', (153, 160))	('elevated', 'PosReg', (13, 21))	('SNP', 'Var', (54, 57))	('INHA', 'Gene', '3623', (65, 69))	('inhibin alpha subunit', 'Gene', '3623', (94, 115))
32895	29250030	GWAS identified that KITL polymorphisms represent one of the highest risk factors for testicular neoplasia, thus regulation of this signaling pathway may be a logical target for therapeutic intervention.	('polymorphisms', 'Var', (26, 39))	('KITL', 'Gene', '4254', (21, 25))	('testicular neoplasia', 'Disease', (86, 106))	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('testicular neoplasia', 'Disease', 'MESH:D009369', (86, 106))	('testicular neoplasia', 'Phenotype', 'HP:0010788', (86, 106))	('KITL', 'Gene', (21, 25))
32904	29250030	These findings from independent laboratories implicate TGFbeta superfamily signaling as central to controlling TGCT cell behavior, supporting the concept that dysregulated TGFbeta superfamily signaling may elevate the risk of TGCT emergence.	('dysregulated', 'Var', (159, 171))	('TGFbeta superfamily', 'Gene', (172, 191))	('elevate', 'PosReg', (206, 213))	('rat', 'Species', '10116', (36, 39))	('TGCT emergence', 'Disease', (226, 240))
32921	29250030	A pro-proliferative effect of IL6 in testis cancer was suggested, contrasting the outcomes of in vitro treatments of seminiferous tubules in which IL6 was shown to induce normal germ cell apoptosis.	('testis cancer', 'Phenotype', 'HP:0010788', (37, 50))	('pro-proliferative', 'PosReg', (2, 19))	('men', 'Species', '9606', (108, 111))	('IL6', 'Var', (147, 150))	('testis cancer', 'Disease', (37, 50))	('rat', 'Species', '10116', (13, 16))	('testis cancer', 'Disease', 'MESH:D013736', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
32938	29250030	Dysregulated IL6 production has been identified in several cancers, often positively correlated with tumor growth and invasive behaviors.	('invasive behaviors', 'CPA', (118, 136))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('IL6 production', 'MPA', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Dysregulated', 'Var', (0, 12))	('correlated', 'Reg', (85, 95))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
32965	29250030	Consistent with relevant animal models, infiltrating lymphocytes are primarily effector memory T cells (CD45R0+; CD4+>CD8+), which are accompanied by increased numbers of non-resident CD68+ macrophages and mast cells.	('memory T', 'Disease', (88, 96))	('rat', 'Species', '10116', (46, 49))	('CD4+>CD8+', 'Var', (113, 122))	('CD45R0+; CD4+>CD8+', 'Var', (104, 122))	('increased', 'PosReg', (150, 159))	('memory T', 'Disease', 'MESH:D008569', (88, 96))
33000	29250030	In patients with acute mumps orchitis, IFNalpha2B with putative antiviral activity was administered in order to prevent or minimize testicular damage.	('orchitis', 'Phenotype', 'HP:0100796', (29, 37))	('testicular', 'Disease', (132, 142))	('patients', 'Species', '9606', (3, 11))	('acute mumps orchitis', 'Disease', (17, 37))	('IFNalpha2B', 'Var', (39, 49))	('acute mumps orchitis', 'Disease', 'MESH:D009920', (17, 37))
33003	29250030	Early experiments using the adoptive transfer of EAO in mice revealed that recipient pre-treatment with neutralizing antibody to TNF, but not neutralizing antibody to IFNgamma, attenuated autoimmune orchitis.	('attenuated autoimmune orchitis', 'Disease', (177, 207))	('men', 'Species', '9606', (94, 97))	('orchitis', 'Phenotype', 'HP:0100796', (199, 207))	('men', 'Species', '9606', (12, 15))	('mice', 'Species', '10090', (56, 60))	('attenuated autoimmune orchitis', 'Disease', 'MESH:D009920', (177, 207))	('neutralizing', 'Var', (104, 116))	('TNF', 'Gene', (129, 132))
33018	29250030	Considering that alterations in the KITL/KIT system may cause disorders of the neuro-endocrine-immunological network, tyrosine kinases (mTOR inhibitors) such as imatinib should not be ignored.	('disorders', 'MPA', (62, 71))	('KITL', 'Gene', (36, 40))	('rat', 'Species', '10116', (21, 24))	('cause', 'Reg', (56, 61))	('KITL', 'Gene', '4254', (36, 40))	('imatinib', 'Chemical', 'MESH:D000068877', (161, 169))	('alterations', 'Var', (17, 28))	('neuro-endocrine-immunological network', 'MPA', (79, 116))
33027	27996046	The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('DNAAF1', 'Gene', (85, 91))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (112, 119))	('mutated', 'Var', (23, 30))	('loss', 'NegReg', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('expression', 'MPA', (92, 102))
33028	27996046	DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu255h(+/-) zebrafish model, which has a 94% risk of TGCT.	('TGCT', 'Disease', (30, 34))	('cause', 'Reg', (21, 26))	('mutation', 'Var', (7, 15))	('zebrafish', 'Species', '7955', (71, 80))	('DNAAF1', 'Gene', (0, 6))
33034	27996046	This is further supported by evidence of second somatic mutation in tumour tissue and functional data from zebrafish, which collectively suggest a model of cilia inactivation in promoting TGC tumorigenesis.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('TGC', 'Disease', (188, 191))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('zebrafish', 'Species', '7955', (107, 116))	('tumour', 'Disease', (68, 74))	('tumorigenesis', 'CPA', (192, 205))	('inactivation', 'Var', (162, 174))	('promoting', 'PosReg', (178, 187))
33037	27996046	We searched in familial cases for genes that were recurrently affected by rare variants with presumptive damaging effects (nonsense, splice acceptor/donor and indel frameshift changes) that had a low burden of comparable variants in controls.	('splice acceptor/donor', 'Var', (133, 154))	('donor', 'Species', '9606', (149, 154))	('nonsense', 'Var', (123, 131))	('affected', 'Reg', (62, 70))	('indel frameshift changes', 'Var', (159, 183))
33039	27996046	The top ranked gene exome-wide was DNAAF1/LRRC50 (Dynein, Axonemal, Assembly Factor 1/Leucine-rich repeat containing 50), with the rare disruptive mutations p.Arg636Ter and p.Gly434ProfsTer4 (Fig.	('p.Gly434Pro', 'Var', (173, 184))	('p.Arg636Ter', 'Var', (157, 168))	('LRRC50', 'Gene', '123872', (42, 48))	('p.Arg636Ter', 'Mutation', 'rs748869874', (157, 168))	('Dynein, Axonemal, Assembly Factor 1', 'Gene', '123872', (50, 85))	('LRRC50', 'Gene', (42, 48))	('p.Gly434Pro', 'SUBSTITUTION', 'None', (173, 184))
33040	27996046	A deleterious phenotype in humans for disruptive DNAAF1 mutations has previously been established, with biallelic mutations causing recessive primary ciliary dyskinesia (PCD), which is characterized by impaired primary cilia function, chronic lung disease, male infertility and hearing impairment.	('DNAAF1', 'Gene', (49, 55))	('impaired primary cilia function', 'Disease', (202, 233))	('ciliary dyskinesia', 'Phenotype', 'HP:0012265', (150, 168))	('male infertility', 'Disease', 'MESH:D007248', (257, 273))	('chronic lung disease', 'Disease', (235, 255))	('recessive', 'Disease', (132, 141))	('mutations', 'Var', (56, 65))	('causing', 'Reg', (124, 131))	('hearing impairment', 'Disease', 'MESH:D034381', (278, 296))	('PCD', 'Disease', (170, 173))	('hearing impairment', 'Disease', (278, 296))	('PCD', 'Disease', 'MESH:D007619', (170, 173))	('male infertility', 'Phenotype', 'HP:0003251', (257, 273))	('male infertility', 'Disease', (257, 273))	('humans', 'Species', '9606', (27, 33))	('biallelic mutations', 'Var', (104, 123))	('dyskinesia', 'Disease', 'MESH:D004409', (158, 168))	('chronic lung disease', 'Phenotype', 'HP:0006528', (235, 255))	('impaired primary cilia function', 'Disease', 'MESH:D003072', (202, 233))	('infertility', 'Phenotype', 'HP:0000789', (262, 273))	('chronic lung disease', 'Disease', 'MESH:D029424', (235, 255))	('dyskinesia', 'Disease', (158, 168))	('hearing impairment', 'Phenotype', 'HP:0000365', (278, 296))	('lung disease', 'Phenotype', 'HP:0002088', (243, 255))	('dyskinesia', 'Phenotype', 'HP:0100660', (158, 168))
33041	27996046	In addition to DNAAF1, mutations in the paralogue genes LRRC6 (ref.)	('mutations', 'Var', (23, 32))	('LRRC6', 'Gene', '23639', (56, 61))	('LRRC6', 'Gene', (56, 61))
33044	27996046	20); Joubert syndrome:CEP290 (refs); and Senior-Loken syndrome:MAP4 via TRAF3IP1 mutation).	('CEP290', 'Gene', '80184', (22, 28))	('Senior-Loken syndrome', 'Disease', (41, 62))	('CEP290', 'Gene', (22, 28))	('TRAF3IP1', 'Gene', '26146', (72, 80))	('TRAF3IP1', 'Gene', (72, 80))	('MAP4', 'Gene', (63, 67))	('mutation', 'Var', (81, 89))	('Joubert syndrome', 'Disease', (5, 21))	('Joubert syndrome', 'Disease', 'MESH:C536293', (5, 21))	('MAP4', 'Gene', '4134', (63, 67))	('Senior-Loken syndrome', 'Disease', 'MESH:C537580', (41, 62))
33047	27996046	In gene-set enrichment analysis (GSEA), association was replicated in this data set for the cilia-microtubule gene set (P=0.024, Fisher's Exact Test), with additional rare disruptive case variants identified in DNAAF1, MAP4, DRC1, DYNC2H1 and CEP290.	('variants', 'Var', (188, 196))	('DYNC2H1', 'Gene', (231, 238))	('DRC1', 'Gene', (225, 229))	('CEP290', 'Gene', '80184', (243, 249))	('DRC1', 'Gene', '92749', (225, 229))	('men', 'Species', '9606', (18, 21))	('MAP4', 'Gene', (219, 223))	('MAP4', 'Gene', '4134', (219, 223))	('CEP290', 'Gene', (243, 249))	('GSEA', 'Chemical', '-', (33, 37))	('DNAAF1', 'Gene', (211, 217))	('DYNC2H1', 'Gene', '79659', (231, 238))
33048	27996046	Remarkably as well as an additional DNAAF1 mutation, an additional MAP4 mutation was observed, taking the total number of MAP4 rare disruptive case mutations to three; whereas no rare disruptive mutations in MAP4 were observed in 27,173 ExAC controls (P=1.9 x 10-5, Fisher's Exact Test), the 1,644 UK controls or 4,300 European controls from the exome variant server project.	('MAP4', 'Gene', '4134', (67, 71))	('mutations', 'Var', (148, 157))	('MAP4', 'Gene', (122, 126))	('MAP4', 'Gene', '4134', (122, 126))	('mutation', 'Var', (43, 51))	('MAP4', 'Gene', (208, 212))	('MAP4', 'Gene', '4134', (208, 212))	('MAP4', 'Gene', (67, 71))
33049	27996046	Immunohistochemistry (IHC) staining for DNAAF1 showed complete absence in 3/3 tumours available from DNAAF1 mutation carriers, with presence of the protein demonstrable in normal surrounding tissue (Fig.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('DNAAF1', 'Gene', (101, 107))	('tumours', 'Disease', (78, 85))	('absence', 'NegReg', (63, 70))	('mutation', 'Var', (108, 116))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
33052	27996046	We have previously implicated mutation of DNAAF1 as a cause of TGCT in zebrafish (n=30) with loss of heterozygosity of DNAAF1 demonstrated in the tumours.	('cause', 'Reg', (54, 59))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('mutation', 'Var', (30, 38))	('TGCT', 'Disease', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('DNAAF1', 'Gene', (42, 48))	('zebrafish', 'Species', '7955', (71, 80))
33053	27996046	To further explore the link between disruptive mutations in DNAAF1, ciliary function and TGCT, we conducted additional studies in dnaaf1hu255h mutant and wild-type zebrafish.	('zebrafish', 'Species', '7955', (164, 173))	('dnaaf1hu255h mutant', 'Var', (130, 149))	('mutations', 'Var', (47, 56))	('dnaaf1hu255h', 'Gene', (130, 142))	('DNAAF1', 'Gene', (60, 66))
33062	27996046	Analysis of 150 human TGCTs publically available through the cancer genome atlas project (http://cancergenome.nih.gov/) showed significant focal somatic deletion at 16q23-16q24.3 (Q=1.6 x 10-4, from GISTIC2 with significance assessed by permutation, corrected for multiple testing using the Benjamini-Hochberg method), encompassing DNAAF1, is a feature in 24.7% of tumours, which predominantly have seminoma histology.	('seminoma', 'Disease', (399, 407))	('cancer genome atlas', 'Disease', 'MESH:D009369', (61, 80))	('deletion', 'Var', (153, 161))	('cancer', 'Disease', (97, 103))	('cancer genome atlas', 'Disease', (61, 80))	('tumours', 'Disease', 'MESH:D009369', (365, 372))	('tumours', 'Disease', (365, 372))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('seminoma', 'Disease', 'MESH:D018239', (399, 407))	('tumour', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('human', 'Species', '9606', (16, 21))	('tumours', 'Phenotype', 'HP:0002664', (365, 372))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
33064	27996046	Intriguingly all of the five cases we identified with rare germline DNAAF1 mutation had either seminoma (n=4) or mixed histology (n=1).	('seminoma', 'Disease', (95, 103))	('mutation', 'Var', (75, 83))	('DNAAF1', 'Gene', (68, 74))	('seminoma', 'Disease', 'MESH:D018239', (95, 103))
33065	27996046	Collectively these data are consistent with loss of DNAAF1 having a more general impact on seminoma oncogenesis.	('impact', 'Reg', (81, 87))	('loss', 'Var', (44, 48))	('seminoma oncogenesis', 'Disease', (91, 111))	('DNAAF1', 'Gene', (52, 58))	('seminoma oncogenesis', 'Disease', 'MESH:D063646', (91, 111))
33066	27996046	A pertinent question relates to the overlapping phenotypic impact of CMG mutation, with the genetic and functional data presented here linking heterozygote mutation to TGCT risk, while homozygote mutations have been previously associated with a range of rare autosomal recessive ciliopathies.	('mutation', 'Var', (73, 81))	('autosomal recessive ciliopathies', 'Disease', (259, 291))	('autosomal recessive ciliopathies', 'Disease', 'MESH:D000072661', (259, 291))	('TGCT', 'Disease', (168, 172))
33071	27996046	), in which candidate missense variants in human TGCT cases were proposed as pathogenic; case-control analysis of these variants confirms that they are of equivalent frequency between cases and control series (Supplementary Table 2).	('missense variants', 'Var', (22, 39))	('men', 'Species', '9606', (216, 219))	('variants', 'Var', (120, 128))	('human', 'Species', '9606', (43, 48))
33072	27996046	In conclusion, we have provided evidence for the role of inherited mutations in CMGs as determinants of TGCT, identifying germline disruptive mutations in 9% of familial pedigrees, with additional evidence implicating disruptive mutations in DNAAF1 in TGC tumorigenesis from IHC and sequencing studies of human tumours and a dnaaf1hu255h (+/-) zebrafish model displaying a 94% frequency of TGCT.	('tumours', 'Phenotype', 'HP:0002664', (311, 318))	('mutations', 'Var', (229, 238))	('DNAAF1', 'Gene', (242, 248))	('tumours', 'Disease', 'MESH:D009369', (311, 318))	('tumorigenesis', 'CPA', (256, 269))	('tumours', 'Disease', (311, 318))	('mutations', 'Var', (67, 76))	('TGC', 'Gene', (252, 255))	('zebrafish', 'Species', '7955', (344, 353))	('tumour', 'Phenotype', 'HP:0002664', (311, 317))	('human', 'Species', '9606', (305, 310))
33088	27996046	Rare disruptive variants in CMG found by WES were confirmed by Sanger sequencing, and examined for loss of heterozygosity in tumour samples relative to germline samples.	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('CMG', 'Gene', (28, 31))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('variants', 'Var', (16, 24))
33097	27996046	Before tissue isolation, zebrafish were euthanized by overdose of MS222 or ice bath.	('MS222', 'Var', (66, 71))	('zebrafish', 'Species', '7955', (25, 34))	('overdose', 'Disease', 'MESH:D062787', (54, 62))	('overdose', 'Disease', (54, 62))
33288	33243205	Nonetheless, a growing body of work has demonstrated that aberrant expression of lncRNAs is correlated with biological processes, including tumour progression, angiogenesis, metastasis, and invasion, indicating that lncRNAs can serve as tumour suppressors or oncogenes for cancer control.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('invasion', 'CPA', (190, 198))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('angiogenesis', 'CPA', (160, 172))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('correlated', 'Reg', (92, 102))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('aberrant', 'Var', (58, 66))	('tumour', 'Disease', (140, 146))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('lncRNAs', 'Gene', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumour', 'Disease', (237, 243))	('expression', 'MPA', (67, 77))	('metastasis', 'CPA', (174, 184))
33291	33243205	As a tumour oncogene, lncRNA SNHG15 functions as a competing endogenous RNA (ceRNA) to sponge miR-153, miR-38, miR-141, and miR-141-3p, which consequently promotes cell proliferation, migration, invasion, autophagy, and cisplatin resistance in glioma, breast cancer, osteosarcoma, and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (285, 309))	('glioma', 'Disease', (244, 250))	('invasion', 'CPA', (195, 203))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('promotes', 'PosReg', (155, 163))	('osteosarcoma', 'Disease', (267, 279))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('osteosarcoma', 'Disease', 'MESH:D012516', (267, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('hepatocellular carcinoma', 'Disease', (285, 309))	('tumour', 'Disease', (5, 11))	('autophagy', 'CPA', (205, 214))	('miR-38', 'Var', (103, 109))	('SNHG15', 'Gene', (29, 35))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('SNHG15', 'Gene', '285958', (29, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('breast cancer', 'Disease', (252, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('miR-141', 'Gene', '406933', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (285, 309))	('osteosarcoma', 'Phenotype', 'HP:0002669', (267, 279))	('miR-141', 'Gene', (111, 118))	('migration', 'CPA', (184, 193))	('miR-141', 'Gene', '406933', (124, 131))	('cell proliferation', 'CPA', (164, 182))	('cisplatin', 'MPA', (220, 229))	('miR-141', 'Gene', (124, 131))
33328	33243205	However, as next-generation genome-wide sequencing and microarrays have been widely applied in clinical settings in recent years, new research has suggested that aberrant expression of lncRNAs may promote or suppress tumour growth, leading to carcinogenesis and cancer progression.	('cancer', 'Disease', (262, 268))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour growth', 'Disease', (217, 230))	('carcinogenesis', 'Disease', 'MESH:D063646', (243, 257))	('leading to', 'Reg', (232, 242))	('suppress', 'NegReg', (208, 216))	('tumour growth', 'Disease', 'MESH:D006130', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('carcinogenesis', 'Disease', (243, 257))	('lncRNAs', 'Gene', (185, 192))	('aberrant expression', 'Var', (162, 181))	('promote', 'PosReg', (197, 204))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
33329	33243205	For example, some lncRNAs, such as NOC2L-4.1, TUG1, and MALAT1, are well established to promote tumour growth, while other lncRNAs, such as ASMTL-AS1, LINC02381, and LINC02499 have been found to inhibit tumour progression.	('MALAT1', 'Gene', '378938', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('LINC02499', 'Var', (166, 175))	('ASMTL-AS1', 'Gene', '80161', (140, 149))	('promote', 'PosReg', (88, 95))	('TUG1', 'Gene', '55000', (46, 50))	('MALAT1', 'Gene', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour growth', 'Disease', (96, 109))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (203, 209))	('TUG1', 'Gene', (46, 50))	('inhibit', 'NegReg', (195, 202))	('tumour growth', 'Disease', 'MESH:D006130', (96, 109))	('ASMTL-AS1', 'Gene', (140, 149))	('tumour', 'Disease', (96, 102))
33345	33243205	Similarly, in non-small cell lung cancer, two studies have demonstrated that SNHG15 knockdown suppresses tumorigenesis by inhibiting the expression of EMT, MMP2, and MMP9 and regulating the miR-486/CDK14 axis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('knockdown', 'Var', (84, 93))	('MMP9', 'Gene', (166, 170))	('MMP9', 'Gene', '4318', (166, 170))	('CDK14', 'Gene', '5218', (198, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))	('miR-486', 'Gene', (190, 197))	('MMP2', 'Gene', '4313', (156, 160))	('inhibiting', 'NegReg', (122, 132))	('expression', 'MPA', (137, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('SNHG15', 'Gene', (77, 83))	('tumor', 'Disease', (105, 110))	('EMT', 'Gene', (151, 154))	('EMT', 'Gene', '3702', (151, 154))	('CDK14', 'Gene', (198, 203))	('miR-486', 'Gene', '619554', (190, 197))	('SNHG15', 'Gene', '285958', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('non-small cell lung cancer', 'Disease', (14, 40))	('suppresses', 'NegReg', (94, 104))	('regulating', 'Reg', (175, 185))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MMP2', 'Gene', (156, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
33356	32038496	Association Between BAK1 Gene rs210138 Polymorphisms and Testicular Germ Cell Tumors: A Systematic Review and Meta-Analysis Background: Several studies including some genome-wide association studies (GWAS) had shown that BAK1 gene rs210138 polymorphisms might be associated with testicular germ cell tumors (TGCT).	('germ cell tumor', 'Phenotype', 'HP:0100728', (290, 305))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('associated', 'Reg', (263, 273))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (279, 306))	('rs210138', 'Mutation', 'rs210138', (30, 38))	('Tumors', 'Phenotype', 'HP:0002664', (78, 84))	('polymorphisms', 'Var', (240, 253))	('testicular germ cell tumors', 'Disease', (279, 306))	('TGCT', 'Disease', 'MESH:C563236', (308, 312))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('rs210138 polymorphisms', 'Var', (231, 253))	('rs210138', 'Mutation', 'rs210138', (231, 239))	('BAK1', 'Gene', (20, 24))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (68, 84))	('Association', 'Interaction', (0, 11))	('germ cell tumors', 'Phenotype', 'HP:0100728', (290, 306))	('TGCT', 'Disease', (308, 312))	('BAK1', 'Gene', (221, 225))
33357	32038496	Methods: Studies associated with BAK1 rs210138 and TGCT was systematically searched in databases.	('BAK1', 'Gene', (33, 37))	('rs210138', 'Mutation', 'rs210138', (38, 46))	('rs210138', 'Var', (38, 46))	('TGCT', 'Disease', (51, 55))	('TGCT', 'Disease', 'MESH:C563236', (51, 55))
33359	32038496	Conclusions: Compared with adenine (A), BAK1 rs210138 guanine (G) is associated with increased risk of TGCT.	('adenine', 'Chemical', 'MESH:D000225', (27, 34))	('rs210138', 'Mutation', 'rs210138', (45, 53))	('TGCT', 'Disease', (103, 107))	('guanine', 'Chemical', 'MESH:D006147', (54, 61))	('BAK1 rs210138 guanine', 'Var', (40, 61))	('TGCT', 'Disease', 'MESH:C563236', (103, 107))
33363	32038496	Several studies including some genome-wide association studies (GWAS) had shown that BAK1 gene rs210138 polymorphisms might be associated with TGCT.	('TGCT', 'Disease', (143, 147))	('associated', 'Reg', (127, 137))	('rs210138 polymorphisms', 'Var', (95, 117))	('TGCT', 'Disease', 'MESH:C563236', (143, 147))	('BAK1 gene', 'Gene', (85, 94))	('polymorphisms', 'Var', (104, 117))	('rs210138', 'Mutation', 'rs210138', (95, 103))
33365	32038496	And in other databases, these terms were used without limitation: "BAK1" AND "cancer of testis OR carcinoma of testis OR testicular cancer OR testis cancer OR ball cancer OR testicular germ cell tumors OR TGCT" AND "polymorphisms OR polymorphism."	('testicular germ cell tumors', 'Disease', (174, 201))	('germ cell tumors', 'Phenotype', 'HP:0100728', (185, 201))	('polymorphisms', 'Var', (216, 229))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('carcinoma of testis', 'Phenotype', 'HP:0010788', (98, 117))	('germ cell tumor', 'Phenotype', 'HP:0100728', (185, 200))	('testis cancer', 'Phenotype', 'HP:0010788', (142, 155))	('testicular cancer', 'Phenotype', 'HP:0010788', (121, 138))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('TGCT', 'Disease', 'MESH:C563236', (205, 209))	('polymorphism', 'Var', (233, 245))	('" AND "cancer', 'Disease', 'MESH:D009369', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TGCT', 'Disease', (205, 209))	('cancer of testis', 'Phenotype', 'HP:0010788', (78, 94))	('testis OR carcinoma of testis OR testicular cancer OR testis cancer OR ball cancer', 'Disease', 'MESH:D013736', (88, 170))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (174, 201))	('" AND "cancer', 'Disease', (71, 84))
33366	32038496	Independently, two researchers made the selection according to the following inclusion criteria: (1) evaluation of the association between BAK1 rs210138 and TGCT susceptibility; (2) case-control study; (3) studies focusing on tissues of human beings; (4) elaborate genotype data in non-GWAS study or enough data in GWAS study could be acquired.	('BAK1', 'Gene', (139, 143))	('rs210138', 'Var', (144, 152))	('association', 'Interaction', (119, 130))	('TGCT', 'Disease', (157, 161))	('rs210138', 'Mutation', 'rs210138', (144, 152))	('TGCT', 'Disease', 'MESH:C563236', (157, 161))
33367	32038496	Pooled ORs and 95% CIs were calculated to evaluate the strength of the association between BAK1 gene rs210138 polymorphisms and TGCT susceptibility.	('rs210138 polymorphisms', 'Var', (101, 123))	('TGCT', 'Disease', (128, 132))	('BAK1 gene', 'Gene', (91, 100))	('rs210138', 'Mutation', 'rs210138', (101, 109))	('polymorphisms', 'Var', (110, 123))	('TGCT', 'Disease', 'MESH:C563236', (128, 132))
33369	32038496	In overall group and its Caucasian subgroup, significantly increased risk of TGCT was found in all genetic models of BAK1 rs210138 (Table 3 and Figure 2).	('TGCT', 'Disease', (77, 81))	('rs210138', 'Var', (122, 130))	('rs210138', 'Mutation', 'rs210138', (122, 130))	('TGCT', 'Disease', 'MESH:C563236', (77, 81))	('increased', 'PosReg', (59, 68))	('BAK1', 'Gene', (117, 121))
33371	32038496	Above all, we found BAK1 rs210138 guanine (G) was associated with increased risk of TGCT in most genetic models in the meta-analysis of single case-control studies.	('guanine', 'Chemical', 'MESH:D006147', (34, 41))	('rs210138', 'Mutation', 'rs210138', (25, 33))	('TGCT', 'Disease', 'MESH:C563236', (84, 88))	('rs210138 guanine', 'Var', (25, 41))	('BAK1', 'Gene', (20, 24))	('TGCT', 'Disease', (84, 88))
33372	32038496	In GWAS studies, follow-up studies and their meta-analysis based on OR and 95% CIs, BAK1 rs210138 guanine (G) also showed association with increased risk of TGCT in allelic comparison, which was consistent with the results in the meta-analysis of single case-control studies.	('rs210138', 'Mutation', 'rs210138', (89, 97))	('TGCT', 'Disease', (157, 161))	('BAK1', 'Gene', (84, 88))	('rs210138 guanine', 'Var', (89, 105))	('TGCT', 'Disease', 'MESH:C563236', (157, 161))	('guanine', 'Chemical', 'MESH:D006147', (98, 105))
33373	32038496	With those limitations, the study provided some insights on the potential association between BAK1 rs210138 and TGCT susceptibility.	('BAK1', 'Gene', (94, 98))	('rs210138', 'Var', (99, 107))	('rs210138', 'Mutation', 'rs210138', (99, 107))	('TGCT', 'Disease', 'MESH:C563236', (112, 116))	('TGCT', 'Disease', (112, 116))
33374	32038496	Our results suggested that: Compared with adenine (A), BAK1 rs210138 guanine (G) is associated with increased risk of TGCT.	('rs210138 guanine', 'Var', (60, 76))	('TGCT', 'Disease', 'MESH:C563236', (118, 122))	('adenine', 'Chemical', 'MESH:D000225', (42, 49))	('guanine', 'Chemical', 'MESH:D006147', (69, 76))	('TGCT', 'Disease', (118, 122))	('BAK1', 'Gene', (55, 59))	('rs210138', 'Mutation', 'rs210138', (60, 68))
33419	27957372	Although WT-1 mutation was well documented in renal nephroblastoma, the histological origin and molecular mechanisms of testicular nephroblastoma are poorly understood.	('WT-1', 'Gene', '7490', (9, 13))	('renal nephroblastoma', 'Disease', (46, 66))	('testicular nephroblastoma', 'Disease', 'MESH:D009396', (120, 145))	('renal nephroblastoma', 'Disease', 'MESH:D009396', (46, 66))	('men', 'Species', '9606', (36, 39))	('mutation', 'Var', (14, 22))	('nephroblastoma', 'Phenotype', 'HP:0002667', (52, 66))	('testicular nephroblastoma', 'Disease', (120, 145))	('nephroblastoma', 'Phenotype', 'HP:0002667', (131, 145))	('WT-1', 'Gene', (9, 13))
33500	18171485	Combined, the 203 patients treated with SD-CT had an estimated 10-year risk of cancer mortality of 43%, which was substantially higher than that for the 182 patients treated with HD-CT chemotherapy (10-year risk of cancer mortality 28%).	('CT', 'Chemical', 'MESH:D002251', (43, 45))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SD-CT', 'Var', (40, 45))	('CT', 'Chemical', 'MESH:D002251', (182, 184))	('patients', 'Species', '9606', (157, 165))	('SD-CT', 'Chemical', '-', (40, 45))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (79, 85))	('HD', 'Disease', 'MESH:D006816', (179, 181))	('higher', 'PosReg', (128, 134))
33557	31292129	Single Nucleotide Polymorphisms at a Distance from Aryl Hydrocarbon Receptor (AHR) Binding Sites Influence AHR Ligand-Dependent Gene Expression Greater than 90% of significant genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) are in noncoding regions of the genome, but only 25.6% are known expression quantitative trait loci (eQTLs).	('single-nucleotide', 'Chemical', '-', (213, 230))	('AHR', 'Gene', (107, 110))	('Single Nucleotide Polymorphisms', 'Var', (0, 31))	('Aryl Hydrocarbon Receptor', 'Gene', '196', (51, 76))	('AHR', 'Gene', '196', (78, 81))	('AHR', 'Gene', (78, 81))	('single-nucleotide polymorphisms', 'Var', (213, 244))	('Aryl Hydrocarbon Receptor', 'Gene', (51, 76))	('AHR', 'Gene', '196', (107, 110))	('Influence', 'Reg', (97, 106))
33563	31292129	Expression quantitative trait loci (eQTLs) have identified important functions for noncoding single-nucleotide polymorphisms (SNPs) across the genome:some of which have been associated with drug response phenotypes identified during genome-wide association studies (GWAS).	('single-nucleotide polymorphisms', 'Var', (93, 124))	('associated', 'Reg', (174, 184))	('single-nucleotide', 'Chemical', '-', (93, 110))
33564	31292129	Furthermore, some of those SNPs are associated with variation in gene expression only in response to an environmental stimulus such as drug exposure, but are not associated with variation in gene expression under basal conditions.	('men', 'Species', '9606', (111, 114))	('gene expression', 'MPA', (65, 80))	('variation', 'Var', (52, 61))
33566	31292129	In that study, we identified a SNP (rs2470893) in the promoter of the cytochrome P450 1A1 (CYP1A1) gene that was associated with variation in differential expression of CYP1A1 after exposure to the AHR ligand 3-methylcholanthrene (3-MC) as compared with vehicle treatment, even though rs2470893 was not an eQTL for CYP1A1 prior to exposure to 3-MC.	('cytochrome P450 1A1', 'Gene', '1543', (70, 89))	('CYP1A1', 'Gene', '1543', (169, 175))	('3-MC', 'Chemical', 'MESH:D008748', (343, 347))	('AHR', 'Gene', '196', (198, 201))	('CYP1A1', 'Gene', (315, 321))	('3-MC', 'Chemical', 'MESH:D008748', (231, 235))	('variation', 'Var', (129, 138))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (209, 229))	('rs2470893', 'Mutation', 'rs2470893', (285, 294))	('CYP1A1', 'Gene', (91, 97))	('CYP1A1', 'Gene', '1543', (315, 321))	('CYP1A1', 'Gene', '1543', (91, 97))	('cytochrome P450 1A1', 'Gene', (70, 89))	('CYP1A1', 'Gene', (169, 175))	('expression', 'MPA', (155, 165))	('rs2470893', 'Mutation', 'rs2470893', (36, 45))	('AHR', 'Gene', (198, 201))	('men', 'Species', '9606', (267, 270))	('associated', 'Reg', (113, 123))
33568	31292129	CYP1A1 plays an important role in the metabolism of xenobiotics and drugs, so the rs2470893 SNP genotype could alter individual response to drugs that are metabolized by CYP1A1.	('rs2470893 SNP', 'Var', (82, 95))	('CYP1A1', 'Gene', '1543', (0, 6))	('CYP1A1', 'Gene', (170, 176))	('rs2470893', 'Mutation', 'rs2470893', (82, 91))	('individual response to drugs', 'MPA', (117, 145))	('CYP1A1', 'Gene', '1543', (170, 176))	('alter', 'Reg', (111, 116))	('CYP1A1', 'Gene', (0, 6))
33569	31292129	That observation raised the possibility that SNPs at a distance from AHREs might influence AHR ligand-dependent target gene expression and could have important implications for health, disease, and variation in drug response.	('influence', 'Reg', (81, 90))	('implications', 'Reg', (160, 172))	('AHR', 'Gene', '196', (91, 94))	('AHR', 'Gene', (91, 94))	('SNPs', 'Var', (45, 49))	('AHR', 'Gene', '196', (69, 72))	('AHR', 'Gene', (69, 72))
33573	31292129	In summary, we systematically identified and tested SNPs across the genome that did not create/destroy AHREs and were associated with variation in AHR ligand-dependent expression but were not associated with variation in the absence of AHR ligand exposure.	('AHR', 'Gene', '196', (103, 106))	('AHR', 'Gene', (103, 106))	('variation', 'Var', (134, 143))	('AHR', 'Gene', '196', (236, 239))	('AHR', 'Gene', (236, 239))	('AHR', 'Gene', '196', (147, 150))	('AHR', 'Gene', (147, 150))	('associated', 'Reg', (118, 128))
33581	31292129	GM17212, GM17223, GM17229, GM17240, GM17264, GM17276, GM17281, and GM17295 LCLs from the human variation panel were used to perform the RNA-seq studies.	('GM17295', 'Var', (67, 74))	('human', 'Species', '9606', (89, 94))	('GM17281', 'Var', (54, 61))	('GM17264', 'Var', (36, 43))	('GM17240', 'Var', (27, 34))	('LCL', 'Chemical', '-', (75, 78))	('GM17229', 'Var', (18, 25))	('GM17223', 'Var', (9, 16))	('GM17276', 'Var', (45, 52))
33582	31292129	Metadata, including sex of the LCL donors, AHR expression levels in each LCL, and rs2470893 (CYP1A1 cis PGx-eQTL) SNP genotype status of each LCL studied, are provided in Supplemental Table 1.	('LCL', 'Chemical', '-', (31, 34))	('LCL', 'Chemical', '-', (142, 145))	('CYP1A1', 'Gene', (93, 99))	('LCL', 'Chemical', '-', (73, 76))	('AHR', 'Gene', '196', (43, 46))	('rs2470893', 'Mutation', 'rs2470893', (82, 91))	('CYP1A1', 'Gene', '1543', (93, 99))	('rs2470893', 'Var', (82, 91))	('men', 'Species', '9606', (177, 180))	('AHR', 'Gene', (43, 46))
33613	31292129	We reported previously that a SNP (rs2470893) at a distance from an AHRE in the promoter of the CYP1A1 gene was a cis PGx-eQTL for CYP1A1 after treatment with an exogenous AHR agonist, 3-MC, even though it was not an eQTL in the absence of 3-MC exposure.	('CYP1A1', 'Gene', (96, 102))	('rs2470893', 'Mutation', 'rs2470893', (35, 44))	('CYP1A1', 'Gene', (131, 137))	('3-MC', 'Chemical', 'MESH:D008748', (185, 189))	('men', 'Species', '9606', (149, 152))	('3-MC', 'Chemical', 'MESH:D008748', (240, 244))	('CYP1A1', 'Gene', '1543', (96, 102))	('CYP1A1', 'Gene', '1543', (131, 137))	('AHR', 'Gene', '196', (68, 71))	('AHR', 'Gene', (68, 71))	('AHR', 'Gene', '196', (172, 175))	('AHR', 'Gene', (172, 175))	('rs2470893', 'Var', (35, 44))
33614	31292129	In the present series of studies, to test the hypothesis that many other SNPs across the genome that are near AHR-regulated genes but that do not create/destroy AHREs:the DNA sequence recognized and bound by ligand-activated AHR:might influence variation in AHR ligand-dependent gene expression, we performed RNA-seq using eight LCLs:four homozygous wild-type and four homozygous variants for the rs2470893 SNP.	('AHR', 'Gene', (110, 113))	('AHR', 'Gene', (258, 261))	('AHR', 'Gene', '196', (225, 228))	('AHR', 'Gene', (225, 228))	('rs2470893', 'Var', (397, 406))	('AHR', 'Gene', '196', (258, 261))	('rs2470893', 'Mutation', 'rs2470893', (397, 406))	('variation', 'MPA', (245, 254))	('LCL', 'Chemical', '-', (329, 332))	('AHR', 'Gene', '196', (161, 164))	('AHR', 'Gene', (161, 164))	('AHR', 'Gene', '196', (110, 113))	('influence', 'Reg', (235, 244))
33623	31292129	1, Step 3) were tested for association (Spearman's rank-order correlation) with variation in differential gene expression after treatment with 3-MC or GNF-351 (Fig.	('differential gene expression', 'MPA', (93, 121))	('GNF-351', 'Gene', (151, 158))	('men', 'Species', '9606', (133, 136))	('variation', 'Var', (80, 89))	('GNF-351', 'Chemical', 'MESH:C560625', (151, 158))	('3-MC', 'Chemical', 'MESH:D008748', (143, 147))
33624	31292129	We selected a distance of 500 bp from a given AHR peak because all previously identified PGx-eQTLs have been within this distance and we were underpowered to investigate the association of all SNPs with variation in ligand-dependent gene expression.	('PGx-eQTLs', 'Gene', (89, 98))	('variation', 'Var', (203, 212))	('AHR', 'Gene', '196', (46, 49))	('AHR', 'Gene', (46, 49))
33634	31292129	As a quality control measure, we next asked whether the previously identified rs2470893 SNP in the promoter of the CYP1A1 gene was a significant cis PGx-eQTL across the eight cell lines studied (four homozygous variant and four homozygous wild-type) based on our RNA-seq data.	('rs2470893', 'Mutation', 'rs2470893', (78, 87))	('rs2470893 SNP', 'Var', (78, 91))	('CYP1A1', 'Gene', (115, 121))	('CYP1A1', 'Gene', '1543', (115, 121))
33647	31292129	Furthermore, we observed a striking decrease in the expression of AHR-regulated genes from our panel of differentially expressed genes after AHR knockdown indicated that AHR regulated the expression of these genes at baseline (Supplemental Fig.	('AHR', 'Gene', (141, 144))	('knockdown', 'Var', (145, 154))	('AHR', 'Gene', '196', (141, 144))	('expression', 'MPA', (188, 198))	('AHR', 'Gene', '196', (170, 173))	('AHR', 'Gene', (170, 173))	('expression', 'MPA', (52, 62))	('AHR', 'Gene', '196', (66, 69))	('AHR', 'Gene', (66, 69))	('men', 'Species', '9606', (233, 236))	('decrease', 'NegReg', (36, 44))
33652	31292129	We next attempted to identify cis PGx-eQTLs from across the genome that did not create/destroy AHREs in ChIP-seq-identified AHR-binding peaks by testing SNPs for their association with variation in the 69 highly differentially expressed genes (FDR <=0.05,  fold change  >=2) that we had identified after exposure to either 3-MC or GNF-351 as compared with vehicle (Fig.	('AHR', 'Gene', (124, 127))	('GNF-351', 'Chemical', 'MESH:C560625', (331, 338))	('variation', 'Var', (185, 194))	('association', 'Interaction', (168, 179))	('AHR', 'Gene', '196', (95, 98))	('AHR', 'Gene', (95, 98))	('3-MC', 'Chemical', 'MESH:D008748', (323, 327))	('AHR', 'Gene', '196', (124, 127))
33655	31292129	Of the 212 SNPs within 500 bp of the AHR-binding peaks, 36 SNPs at 19 loci were associated with variation in RNA-seq-based differential gene expression after exposure to 3-MC or GNF-351 relative to vehicle, thus raising the possibility that they might be cis PGx-eQTLs.	('AHR', 'Gene', '196', (37, 40))	('GNF-351', 'Gene', (178, 185))	('variation', 'Var', (96, 105))	('AHR', 'Gene', (37, 40))	('associated', 'Reg', (80, 90))	('GNF-351', 'Chemical', 'MESH:C560625', (178, 185))	('3-MC', 'Chemical', 'MESH:D008748', (170, 174))	('RNA-seq-based differential gene', 'Gene', (109, 140))
33656	31292129	Most loci included just one AHR-binding peak, but one locus (in intron 4 of the AHRR gene) included three AHR-binding peaks because the tightly linked SNPs that were associated with variation in AHRR differential expression after exposure to 3-MC mapped across multiple peaks (Supplemental Table 4).	('AHR', 'Gene', '196', (80, 83))	('AHR', 'Gene', (80, 83))	('AHRR', 'Gene', '57491', (80, 84))	('3-MC', 'Chemical', 'MESH:D008748', (242, 246))	('variation', 'Var', (182, 191))	('AHRR', 'Gene', (80, 84))	('AHR', 'Gene', '196', (195, 198))	('AHRR', 'Gene', '57491', (195, 199))	('AHR', 'Gene', '196', (106, 109))	('men', 'Species', '9606', (283, 286))	('AHR', 'Gene', (106, 109))	('associated', 'Reg', (166, 176))	('AHR', 'Gene', (28, 31))	('AHR', 'Gene', '196', (28, 31))	('AHRR', 'Gene', (195, 199))	('AHR', 'Gene', (195, 198))
33660	31292129	Those 10 validated loci included 25 SNPs across 11 AHR-binding peaks that were associated with variation in differential gene expression after either 3-MC or GNF-351 exposure.	('3-MC', 'Chemical', 'MESH:D008748', (150, 154))	('differential gene expression', 'MPA', (108, 136))	('variation', 'Var', (95, 104))	('GNF-351', 'Chemical', 'MESH:C560625', (158, 165))	('AHR', 'Gene', '196', (51, 54))	('AHR', 'Gene', (51, 54))
33663	31292129	None of the cis PGx-eQTLs that we identified were both 3-MC dependent and GNF-351 dependent, which means that the SNPs that were associated with variation in gene expression after 3-MC exposure relative to vehicle were different from the SNPs that were associated with variation in gene expression after GNF-351 exposure.	('gene expression', 'MPA', (158, 173))	('3-MC', 'Chemical', 'MESH:D008748', (55, 59))	('GNF-351', 'Chemical', 'MESH:C560625', (304, 311))	('GNF-351', 'Chemical', 'MESH:C560625', (74, 81))	('3-MC', 'Chemical', 'MESH:D008748', (180, 184))	('variation', 'Var', (145, 154))
33664	31292129	The variation in expression of three genes following ligand exposure were associated with two independent cis PGx-eQTLs for each of the genes:AHRR, TMEM119, and STK32C.	('variation', 'Var', (4, 13))	('AHRR', 'Gene', (142, 146))	('expression', 'MPA', (17, 27))	('TMEM119', 'Gene', '338773', (148, 155))	('STK32C', 'Gene', '282974', (161, 167))	('STK32C', 'Gene', (161, 167))	('TMEM119', 'Gene', (148, 155))	('AHRR', 'Gene', '57491', (142, 146))	('associated', 'Reg', (74, 84))
33676	31292129	These 12 regions included one peak that was surrounded by two independent SNP LD blocks (R2 = 0.324) that were associated with variation in GNF-351-dependent STK32C gene expression and one SNP LD block that was associated with variation in 3-MC dependent AHRR gene expression that spanned three AHR-binding peaks over a 8944-bp genomic region (Supplemental Table 4).	('AHRR', 'Gene', (255, 259))	('GNF-351-dependent', 'Gene', (140, 157))	('variation', 'Var', (127, 136))	('3-MC', 'Chemical', 'MESH:D008748', (240, 244))	('STK32C', 'Gene', '282974', (158, 164))	('STK32C', 'Gene', (158, 164))	('variation', 'Var', (227, 236))	('AHRR', 'Gene', '57491', (255, 259))	('AHR', 'Gene', '196', (295, 298))	('GNF-351', 'Chemical', 'MESH:C560625', (140, 147))	('AHR', 'Gene', (295, 298))	('AHR', 'Gene', '196', (255, 258))	('AHR', 'Gene', (255, 258))	('men', 'Species', '9606', (350, 353))
33679	31292129	For purposes of brevity, we only provide detailed results from the luciferase experiments in the main text for three of the cis PGx-eQTLs:one associated with 3-MC-dependent CYP1A1 expression and two associated with variation in ligand-dependent AHRR expression:because CYP1A1 and AHRR are prototypic targets of AHR.	('CYP1A1', 'Gene', (269, 275))	('AHRR', 'Gene', '57491', (280, 284))	('AHRR', 'Gene', '57491', (245, 249))	('3-MC', 'Chemical', 'MESH:D008748', (158, 162))	('AHR', 'Gene', '196', (245, 248))	('AHR', 'Gene', (245, 248))	('CYP1A1', 'Gene', '1543', (269, 275))	('CYP1A1', 'Gene', (173, 179))	('AHRR', 'Gene', (280, 284))	('AHR', 'Gene', (280, 283))	('AHR', 'Gene', (311, 314))	('AHRR', 'Gene', (245, 249))	('AHR', 'Gene', '196', (280, 283))	('AHR', 'Gene', '196', (311, 314))	('men', 'Species', '9606', (84, 87))	('associated', 'Reg', (142, 152))	('CYP1A1', 'Gene', '1543', (173, 179))	('variation', 'Var', (215, 224))
33680	31292129	During the present studies, we identified a new cis PGx-eQTL SNP (rs3826041) in the promoter of the CYP1A1 gene.	('rs3826041', 'Mutation', 'rs3826041', (66, 75))	('CYP1A1', 'Gene', (100, 106))	('rs3826041', 'Var', (66, 75))	('CYP1A1', 'Gene', '1543', (100, 106))
33683	31292129	The rs3826041 SNP in the promoter region of the CYP1A1 gene (Fig.	('CYP1A1', 'Gene', '1543', (48, 54))	('rs3826041 SNP', 'Var', (4, 17))	('rs3826041', 'Mutation', 'rs3826041', (4, 13))	('CYP1A1', 'Gene', (48, 54))
33684	31292129	3A) was not in LD with the rs2470893 SNP (R2 = 0.079), which we had previously described as a cis PGx-eQTL, and the rs3826041 SNP had a smaller effect on CYP1A1 3-MC-dependent differential expression (Cohen's d = 1.0) than did the SNP that we had reported previously (rs2470893; Cohen's d = 2.0).	('3-MC', 'Chemical', 'MESH:D008748', (161, 165))	('rs2470893', 'Mutation', 'rs2470893', (27, 36))	('rs3826041', 'Var', (116, 125))	('rs3826041', 'Mutation', 'rs3826041', (116, 125))	('CYP1A1', 'Gene', (154, 160))	('CYP1A1', 'Gene', '1543', (154, 160))	('rs2470893', 'Mutation', 'rs2470893', (268, 277))
33685	31292129	Furthermore, we previously reported that the rs2470893 SNP was 196 bp from a putative canonical AHRE motif (not shown in Fig.	('rs2470893', 'Var', (45, 54))	('AHR', 'Gene', '196', (96, 99))	('rs2470893', 'Mutation', 'rs2470893', (45, 54))	('AHR', 'Gene', (96, 99))
33687	31292129	Our AHR ChIP-seq data showed that the rs2470893 SNP was 466 bp from the nearest AHR-binding peak and 471 bp from the nearest AHRE located within that binding peak (Fig.	('rs2470893', 'Var', (38, 47))	('AHR', 'Gene', '196', (80, 83))	('AHR', 'Gene', '196', (125, 128))	('AHR', 'Gene', (80, 83))	('AHR', 'Gene', (125, 128))	('AHR', 'Gene', '196', (4, 7))	('AHR', 'Gene', (4, 7))	('rs2470893', 'Mutation', 'rs2470893', (38, 47))
33688	31292129	The new rs3826041 CYP1A1 cis PGx-eQTL SNP was located in an AHR-binding peak, but was 34 bp distant from an AHR core-binding motif (5'-CACGC-3'), indicating that it did not disrupt the AHRE DNA motif recognized by AHR (Fig.	('AHR', 'Gene', '196', (108, 111))	('rs3826041', 'Var', (8, 17))	('AHR', 'Gene', (108, 111))	('CYP1A1', 'Gene', (18, 24))	('AHR', 'Gene', '196', (60, 63))	('AHR', 'Gene', (60, 63))	('AHR', 'Gene', '196', (214, 217))	('AHR', 'Gene', (214, 217))	('CYP1A1', 'Gene', '1543', (18, 24))	('AHR', 'Gene', '196', (185, 188))	('AHR', 'Gene', (185, 188))	('rs3826041', 'Mutation', 'rs3826041', (8, 17))
33689	31292129	The rs3826041 variant SNP genotype was associated with a smaller increase in CYP1A1 expression after 3-MC treatment (Fig.	('men', 'Species', '9606', (111, 114))	('rs3826041', 'Var', (4, 13))	('rs3826041', 'Mutation', 'rs3826041', (4, 13))	('3-MC', 'Chemical', 'MESH:D008748', (101, 105))	('CYP1A1', 'Gene', (77, 83))	('CYP1A1', 'Gene', '1543', (77, 83))	('expression', 'MPA', (84, 94))
33692	31292129	The luciferase reporter gene constructs that were used to investigate the rs3825041 SNP effect did not contain the previously identified rs2470893 SNP.	('rs3825041', 'Var', (74, 83))	('rs2470893', 'Mutation', 'rs2470893', (137, 146))	('rs3825041', 'Mutation', 'rs3825041', (74, 83))	('rs2470893', 'Var', (137, 146))
33698	31292129	The first AHRR cis PGx-eQTL:in intron 3 of the AHRR gene:included one SNP (rs1877843) that was 241 bp away from AHR-binding peak 13160 and was associated with variation in AHRR expression after GNF-351 exposure relative to vehicle (Fig.	('AHRR', 'Gene', (10, 14))	('AHR', 'Gene', '196', (112, 115))	('AHRR', 'Gene', '57491', (172, 176))	('expression', 'MPA', (177, 187))	('rs1877843', 'Mutation', 'rs1877843', (75, 84))	('AHR', 'Gene', '196', (47, 50))	('AHRR', 'Gene', (47, 51))	('AHRR', 'Gene', '57491', (10, 14))	('AHR', 'Gene', '196', (172, 175))	('AHR', 'Gene', (10, 13))	('rs1877843', 'Var', (75, 84))	('associated with', 'Reg', (143, 158))	('AHR', 'Gene', (112, 115))	('variation', 'Var', (159, 168))	('AHRR', 'Gene', (172, 176))	('GNF-351', 'Chemical', 'MESH:C560625', (194, 201))	('AHRR', 'Gene', '57491', (47, 51))	('AHR', 'Gene', (47, 50))	('AHR', 'Gene', '196', (10, 13))	('AHR', 'Gene', (172, 175))
33699	31292129	Variant genotypes for the SNPs near AHR-binding peak 13160 (rs1877843 and rs1877840) in intron 3 of the AHRR gene (Fig.	('rs1877843', 'Mutation', 'rs1877843', (60, 69))	('AHRR', 'Gene', (104, 108))	('rs1877840', 'Var', (74, 83))	('AHR', 'Gene', '196', (36, 39))	('AHR', 'Gene', (36, 39))	('AHR', 'Gene', (104, 107))	('rs1877840', 'Mutation', 'rs1877840', (74, 83))	('AHRR', 'Gene', '57491', (104, 108))	('AHR', 'Gene', '196', (104, 107))	('rs1877843', 'Var', (60, 69))
33704	31292129	Variant genotypes for these 10 SNPs were associated with higher AHRR expression relative to the wild-type genotypes after 3-MC exposure (Fig.	('3-MC', 'Chemical', 'MESH:D008748', (122, 126))	('AHRR', 'Gene', '57491', (64, 68))	('higher', 'PosReg', (57, 63))	('AHRR', 'Gene', (64, 68))	('Variant', 'Var', (0, 7))
33710	31292129	Indeed, the luciferase plasmids that contained AHR-binding peak 13163 with the surrounding SNPs (Fig.	('13163', 'Var', (64, 69))	('AHR', 'Gene', '196', (47, 50))	('AHR', 'Gene', (47, 50))
33712	31292129	The variant SNP genotypes demonstrated a larger increase in luciferase activity than the wild-type SNP genotypes after 3-MC treatment (Fig.	('3-MC', 'Chemical', 'MESH:D008748', (119, 123))	('luciferase', 'Enzyme', (60, 70))	('men', 'Species', '9606', (129, 132))	('activity', 'MPA', (71, 79))	('variant', 'Var', (4, 11))	('increase', 'PosReg', (48, 56))
33713	31292129	These results indicate that AHR-binding peak 13163 together with the surrounding SNPs is functional and may contribute to the SNP-by-treatment-dependent variation in AHRR expression observed by qRT-PCR (Fig.	('expression', 'MPA', (171, 181))	('AHR', 'Gene', '196', (166, 169))	('AHR', 'Gene', (166, 169))	('men', 'Species', '9606', (138, 141))	('AHRR', 'Gene', (166, 170))	('13163', 'Var', (45, 50))	('AHR', 'Gene', '196', (28, 31))	('AHRR', 'Gene', '57491', (166, 170))	('AHR', 'Gene', (28, 31))
33714	31292129	In addition, luciferase plasmids that contained peak 13164 and SNP rs872848 demonstrated a SNP-by-treatment-dependent variation in luciferase activity in HepG2 cells and HMC3 cells, but not in LCLs (Fig.	('activity', 'MPA', (142, 150))	('LCL', 'Chemical', '-', (193, 196))	('men', 'Species', '9606', (103, 106))	('SNP rs872848', 'Var', (63, 75))	('HepG2', 'CellLine', 'CVCL:0027', (154, 159))	('HMC3', 'CellLine', 'CVCL:0003', (170, 174))	('rs872848', 'Mutation', 'rs872848', (67, 75))	('luciferase', 'Enzyme', (131, 141))
33716	31292129	Even though the luciferase activity increased in HMC3 cells and decreased in HepG2 cells, the SNP-dependent effect was maintained, because the variant genotype demonstrated a larger increase after 3-MC treatment in HMC3 cells and a smaller decrease after 3-MC treatment in HepG2 cells (Fig.	('increase', 'PosReg', (182, 190))	('luciferase', 'Enzyme', (16, 26))	('3-MC', 'Chemical', 'MESH:D008748', (255, 259))	('men', 'Species', '9606', (265, 268))	('HepG2', 'CellLine', 'CVCL:0027', (77, 82))	('HMC3', 'CellLine', 'CVCL:0003', (49, 53))	('men', 'Species', '9606', (207, 210))	('HepG2', 'CellLine', 'CVCL:0027', (273, 278))	('variant', 'Var', (143, 150))	('HMC3', 'CellLine', 'CVCL:0003', (215, 219))	('3-MC', 'Chemical', 'MESH:D008748', (197, 201))	('activity', 'MPA', (27, 35))
33719	31292129	Specifically, the regions of this locus that included peak 13163 with the surrounding SNPs and peak 13164 with rs872848 both demonstrated SNP-by-treatment-dependent variation in luciferase activity, which suggests that they may both contribute to the overall SNP-by-treatment-dependent variation observed by qRT-PCR (Fig.	('men', 'Species', '9606', (271, 274))	('rs872848', 'Mutation', 'rs872848', (111, 119))	('rs872848', 'Var', (111, 119))	('luciferase', 'Enzyme', (178, 188))	('men', 'Species', '9606', (150, 153))	('activity', 'MPA', (189, 197))
33726	31292129	The cis PGx-eQTL that contained peak 3966 and SNP rs2287555 demonstrated a significant SNP-by-treatment-dependent variation in luciferase activity in HMC3 cells, where the variant SNP genotype was associated with decreased luciferase activity compared with the wild-type SNP genotype following 3-MC exposure:opposite to the LCL qRT-PCR results (Supplemental Fig.	('LCL', 'Chemical', '-', (324, 327))	('activity', 'MPA', (138, 146))	('HMC3', 'CellLine', 'CVCL:0003', (150, 154))	('decreased', 'NegReg', (213, 222))	('rs2287555', 'Var', (50, 59))	('men', 'Species', '9606', (351, 354))	('SNP', 'Gene', (46, 49))	('men', 'Species', '9606', (99, 102))	('luciferase', 'Enzyme', (127, 137))	('3-MC', 'Chemical', 'MESH:D008748', (294, 298))	('luciferase', 'Enzyme', (223, 233))	('rs2287555', 'Mutation', 'rs2287555', (50, 59))	('activity', 'MPA', (234, 242))
33728	31292129	The cis PGx-eQTL that included peak 3967 and SNP rs880844 demonstrated SNP-by-treatment-dependent variation in luciferase activity in all three cell lines (Supplemental Fig.	('luciferase', 'Enzyme', (111, 121))	('SNP', 'Var', (45, 48))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (162, 165))	('rs880844', 'Mutation', 'rs880844', (49, 57))	('activity', 'MPA', (122, 130))
33732	31292129	The luciferase assays demonstrated SNP-by-treatment-dependent variation in luciferase activity for which variant SNP genotypes were associated with higher expression than were wild-type SNP genotypes following 3-MC exposure in HepG2 cells and LCLs (suggestive P = 0.06; Supplemental Fig.	('3-MC', 'Chemical', 'MESH:D008748', (210, 214))	('luciferase', 'Enzyme', (75, 85))	('activity', 'MPA', (86, 94))	('variant', 'Var', (105, 112))	('expression', 'MPA', (155, 165))	('men', 'Species', '9606', (276, 279))	('LCL', 'Chemical', '-', (243, 246))	('SNP', 'Gene', (113, 116))	('men', 'Species', '9606', (47, 50))	('HepG2', 'CellLine', 'CVCL:0027', (227, 232))	('higher', 'PosReg', (148, 154))
33738	31292129	11B), the variant rs941490 SNP genotype was associated with higher luciferase activity compared with the wild-type SNP genoptype following 3-MC exposure in LCLs and HepG2 cells, but the variant SNP genotype was associated with lower luciferase activity compared with the wild-type SNP genotypes in HMC3 cells (Supplemental Fig.	('men', 'Species', '9606', (316, 319))	('activity', 'MPA', (244, 252))	('HMC3', 'CellLine', 'CVCL:0003', (298, 302))	('luciferase', 'Enzyme', (67, 77))	('higher', 'PosReg', (60, 66))	('lower', 'NegReg', (227, 232))	('rs941490 SNP', 'Var', (18, 30))	('LCL', 'Chemical', '-', (156, 159))	('3-MC', 'Chemical', 'MESH:D008748', (139, 143))	('luciferase', 'Enzyme', (233, 243))	('rs941490', 'Mutation', 'rs941490', (18, 26))	('HepG2', 'CellLine', 'CVCL:0027', (165, 170))	('activity', 'MPA', (78, 86))
33741	31292129	The cis PGx-eQTL that included peak 2391 and rs11146335 SNP, which was in the AHR-binding peak but was not in an AHRE, demonstrated SNP-by-treatment-dependent variation in luciferase activity following GNF-351 exposure in all three cell lines studied.	('men', 'Species', '9606', (144, 147))	('activity', 'MPA', (183, 191))	('AHR', 'Gene', '196', (113, 116))	('AHR', 'Gene', (113, 116))	('AHR', 'Gene', '196', (78, 81))	('AHR', 'Gene', (78, 81))	('rs11146335', 'Var', (45, 55))	('rs11146335', 'Mutation', 'rs11146335', (45, 55))	('GNF-351', 'Chemical', 'MESH:C560625', (202, 209))	('luciferase', 'Enzyme', (172, 182))
33742	31292129	12B), the variant rs11146335 SNP genotype was associated with lower luciferase activity compared with the wild-type SNP genotype in HepG2 cells, but the variant SNP genotype was associated with higher expression compared with the wild-type SNP genotype in LCLs and HMC3 cells (Supplemental Fig.	('activity', 'MPA', (79, 87))	('higher', 'PosReg', (194, 200))	('HepG2', 'CellLine', 'CVCL:0027', (132, 137))	('variant rs11146335 SNP', 'Var', (10, 32))	('luciferase', 'Enzyme', (68, 78))	('lower', 'NegReg', (62, 67))	('LCL', 'Chemical', '-', (256, 259))	('men', 'Species', '9606', (283, 286))	('HMC3', 'CellLine', 'CVCL:0003', (265, 269))	('expression', 'MPA', (201, 211))	('rs11146335', 'Mutation', 'rs11146335', (18, 28))
33743	31292129	The STK32C cis PGx-eQTL that included the four linked SNPs around peak 2391 demonstrated SNP-by-treatment-dependent variation in luciferase activity in LCLs in which variant SNP genotypes were associated with higher luciferase activity compared with wild-type SNP genotypes, which was consistent with the LCL qRT-PCR expression results (Supplemental Fig.	('activity', 'MPA', (227, 235))	('LCL', 'Chemical', '-', (152, 155))	('luciferase', 'Enzyme', (129, 139))	('men', 'Species', '9606', (101, 104))	('LCL', 'Chemical', '-', (305, 308))	('STK32C', 'Gene', (4, 10))	('higher', 'PosReg', (209, 215))	('STK32C', 'Gene', '282974', (4, 10))	('luciferase', 'Enzyme', (216, 226))	('men', 'Species', '9606', (343, 346))	('activity', 'MPA', (140, 148))	('SNP', 'Gene', (174, 177))	('variant', 'Var', (166, 173))
33751	31292129	We have described a novel type of eQTL in which SNPs at a distance from AHR binding sites are associated with interindividual variation in target gene expression in a ligand-by-genotype-dependent fashion.	('SNPs', 'Var', (48, 52))	('AHR', 'Gene', (72, 75))	('associated', 'Reg', (94, 104))	('AHR', 'Gene', '196', (72, 75))
33763	31292129	The rs3826041 cis PGx-eQTL SNP in the promoter of the CYP1A1 gene (Fig.	('rs3826041', 'Mutation', 'rs3826041', (4, 13))	('rs3826041', 'Var', (4, 13))	('CYP1A1', 'Gene', '1543', (54, 60))	('CYP1A1', 'Gene', (54, 60))
33764	31292129	6A) or SNPs in tight LD with that SNP (rs4886605, r2 = 0.87; rs1456432, r2 = 0.87) were previously associated with variability in coronary artery disease risk in Uygur men, variation in warfarin response, and in hepatocellular carcinoma risk.	('coronary artery disease', 'Disease', 'MESH:D003324', (130, 153))	('hepatocellular carcinoma', 'Disease', (212, 236))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (212, 236))	('associated with', 'Reg', (99, 114))	('rs4886605', 'Mutation', 'rs4886605', (39, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('coronary artery disease', 'Disease', (130, 153))	('rs1456432', 'Mutation', 'rs1456432', (61, 70))	('rs4886605', 'Var', (39, 48))	('warfarin', 'Chemical', 'MESH:D014859', (186, 194))	('men', 'Species', '9606', (168, 171))	('rs1456432', 'Var', (61, 70))	('warfarin response', 'MPA', (186, 203))
33765	31292129	In another study, the same SNPs were associated with risk for testicular germ cell tumors and variation in oxychlorodane concentration, a chemical that has been associated with AHR activation.	('AHR', 'Gene', '196', (177, 180))	('AHR', 'Gene', (177, 180))	('oxychlorodane concentration', 'MPA', (107, 134))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('associated', 'Reg', (37, 47))	('variation', 'Var', (94, 103))	('oxychlorodane', 'Chemical', '-', (107, 120))
33767	31292129	In addition, the rs2671903 cis PGx-eQTL SNP in intron 4 of the AHRR gene near peak 13161 (Fig.	('rs2671903 cis', 'Var', (17, 30))	('rs2671903', 'Mutation', 'rs2671903', (17, 26))	('AHRR', 'Gene', '57491', (63, 67))	('AHRR', 'Gene', (63, 67))
33768	31292129	5A) has previously been associated with variation in CpG methylation in cigarette smokers versus nonsmokers, which indicated a gene-by-environment interaction that resulted in significant variation in AHRR expression.	('variation', 'Var', (40, 49))	('methylation', 'Var', (57, 68))	('men', 'Species', '9606', (142, 145))	('associated', 'Reg', (24, 34))	('variation', 'Reg', (188, 197))	('expression', 'MPA', (206, 216))	('AHRR', 'Gene', (201, 205))	('CpG', 'Gene', (53, 56))	('AHRR', 'Gene', '57491', (201, 205))
33770	31292129	The rs880844 cis PGx-eQTL SNP 3' of the TMEM119 (Supplemental Fig.	('rs880844', 'Var', (4, 12))	('men', 'Species', '9606', (55, 58))	('TMEM119', 'Gene', '338773', (40, 47))	('rs880844', 'Mutation', 'rs880844', (4, 12))	('TMEM119', 'Gene', (40, 47))
33773	31292129	Finally, the SNPs that were in tight LD (r2 > 0.8) with the RARRES2 cis PGx-eQTL SNPs have previously been associated with variation in body mass index, metabolic, and inflammatory diseases and levels of chemerin (the protein encoded by the RARRES2 gene).	('PGx-eQTL SNPs', 'Disease', 'None', (72, 85))	('RARRES2', 'Gene', (60, 67))	('chemerin', 'Gene', (204, 212))	('metabolic', 'Disease', (153, 162))	('chemerin', 'Gene', '5919', (204, 212))	('variation', 'Var', (123, 132))	('body mass', 'Disease', (136, 145))	('PGx-eQTL SNPs', 'Disease', (72, 85))	('RARRES2', 'Gene', (241, 248))	('RARRES2', 'Gene', '5919', (60, 67))	('inflammatory diseases', 'Disease', 'MESH:D007249', (168, 189))	('associated with', 'Reg', (107, 122))	('inflammatory diseases', 'Disease', (168, 189))	('RARRES2', 'Gene', '5919', (241, 248))
33779	31292129	Obviously, this study has not resulted in an exhaustive list of AHR ligand-dependent PGx-eQTLs, but this series of experiments has provided evidence that SNPs across the genome that are at a distance from AHREs can influence AHR ligand-dependent expression.	('AHR', 'Gene', '196', (205, 208))	('AHR', 'Gene', '196', (225, 228))	('AHR', 'Gene', (205, 208))	('AHR', 'Gene', (225, 228))	('men', 'Species', '9606', (121, 124))	('influence', 'Reg', (215, 224))	('AHR', 'Gene', '196', (64, 67))	('AHR', 'Gene', (64, 67))	('SNPs', 'Var', (154, 158))
33888	31006710	In fact, disruption of hsf2 in mice affected testicular size and induced spermatogenic defects.	('testicular size', 'CPA', (45, 60))	('hsf2', 'Gene', '15500', (23, 27))	('hsf2', 'Gene', (23, 27))	('mice', 'Species', '10090', (31, 35))	('spermatogenic defects', 'Phenotype', 'HP:0008669', (73, 94))	('induced', 'Reg', (65, 72))	('spermatogenic defects', 'Disease', (73, 94))	('disruption', 'Var', (9, 19))	('spermatogenic defects', 'Disease', 'OMIM:108420', (73, 94))	('affected', 'Reg', (36, 44))
33963	30271379	Studies investigating the magnitude of this damage could have a considerable translational importance in the management of cancer patients, as they could identify the time needed for the germ cell line to repair nuclear damage and thus produce gametes with a reduced risk for the offspring.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('men', 'Species', '9606', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('nuclear', 'Var', (212, 219))	('patients', 'Species', '9606', (130, 138))	('cancer', 'Disease', (123, 129))	('reduced', 'NegReg', (259, 266))
33994	30271379	- SCSA: The sperm chromatin structure assay (SCSA) is a cytofluorometric technique which indirectly assesses DNA strand breaks and protamine-histone replacement defects by measuring the resistance of sperm chromatin to the action of denaturing agents using the dye acridine orange.	('resistance', 'MPA', (186, 196))	('defects', 'Var', (161, 168))	('men', 'Species', '9606', (156, 159))	('acridine orange', 'Chemical', 'MESH:D000165', (265, 280))
34026	30271379	In fact, this study found a negative correlation with sperm motility and a positive correlation with abnormal forms, predominantly affecting the head, in TC patients.	('sperm motility', 'CPA', (54, 68))	('patients', 'Species', '9606', (157, 165))	('negative', 'NegReg', (28, 36))	('abnormal', 'Var', (101, 109))	('TC', 'Phenotype', 'HP:0010788', (154, 156))
34037	30271379	The authors identified a mean of 12.6% sperm cells with apoptotic DNA fragmentation in the control group, 12.2% in the non-seminoma group and 12.5% in the seminoma group.	('seminoma', 'Disease', (123, 131))	('apoptotic', 'Var', (56, 65))	('non-seminoma', 'Disease', 'MESH:D018239', (119, 131))	('seminoma', 'Disease', 'MESH:D018239', (155, 163))	('seminoma', 'Disease', 'MESH:D018239', (123, 131))	('men', 'Species', '9606', (74, 77))	('seminoma', 'Disease', (155, 163))	('non-seminoma', 'Disease', (119, 131))
34049	30271379	detected increased sperm DNA damage in 19 testicular cancers patients vs. 20 semen donors with both alkaline and neutral COMET, with higher levels of sperm DNA fragmentation in TC patients with abnormal semen parameters.	('men', 'Species', '9606', (79, 82))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('testicular cancers', 'Phenotype', 'HP:0010788', (42, 60))	('19 testicular cancers', 'Disease', (39, 60))	('19 testicular cancers', 'Disease', 'MESH:D013736', (39, 60))	('patients', 'Species', '9606', (61, 69))	('increased', 'PosReg', (9, 18))	('higher', 'PosReg', (133, 139))	('COMET', 'Species', '302767', (121, 126))	('men', 'Species', '9606', (205, 208))	('testicular cancer', 'Phenotype', 'HP:0010788', (42, 59))	('TC', 'Phenotype', 'HP:0010788', (177, 179))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('sperm', 'CPA', (19, 24))	('alkaline', 'Var', (100, 108))	('patients', 'Species', '9606', (180, 188))	('men', 'Species', '9606', (164, 167))
34064	30271379	The negative effects include impaired spermatogenesis, resulting in oligozoospermia or azoospermia, and an increase in aneuploidies for up to 18-24 months after the end of the therapy.	('spermatogenesis', 'CPA', (38, 53))	('aneuploidies', 'Var', (119, 131))	('increase', 'PosReg', (107, 115))	('impaired', 'NegReg', (29, 37))	('oligozoospermia or azoospermia', 'Disease', 'MESH:D009845', (68, 98))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (29, 53))	('oligozoospermia or azoospermia', 'Disease', (68, 98))	('azoospermia', 'Phenotype', 'HP:0000027', (87, 98))
34073	30271379	RT has a higher impact on DFI than CT alone; after a follow-up of 0.5-3.3 years (median 1.1) this study found a significant increase in DFI in patients who had undergone RT or RT+CH compared to those who underwent chemotherapy alone.	('RT+CH', 'Var', (176, 181))	('increase', 'PosReg', (124, 132))	('patients', 'Species', '9606', (143, 151))	('DFI', 'MPA', (136, 139))
34088	30271379	compared patients treated with BEP, carboplatin or under surveillance alone, finding that BEP caused significantly more DNA damage than one cycle carboplatin.	('patients', 'Species', '9606', (9, 17))	('BEP', 'Chemical', 'MESH:C038328', (31, 34))	('DNA damage', 'MPA', (120, 130))	('BEP', 'Chemical', 'MESH:C038328', (90, 93))	('carboplatin', 'Chemical', 'MESH:D016190', (146, 157))	('carboplatin', 'Chemical', 'MESH:D016190', (36, 47))	('BEP', 'Var', (90, 93))
34110	30271379	Studies in mouse models have shown that cisplatin induces chromatid breaks and fragments in spermatocytes and spermatogonia immediately after treatment, whereas conflicting results have been reported in relation to diploidy and disomy in treated patients.	('mouse', 'Species', '10090', (11, 16))	('cisplatin', 'Var', (40, 49))	('chromatid breaks', 'CPA', (58, 74))	('patients', 'Species', '9606', (246, 254))	('men', 'Species', '9606', (83, 86))	('chromatid breaks', 'Phenotype', 'HP:0040012', (58, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('men', 'Species', '9606', (147, 150))	('induces', 'Reg', (50, 57))	('diploidy and disomy', 'Disease', 'MESH:D024182', (215, 234))
34171	30271379	Studies investigating the extent of this damage could have a considerable translational importance in the management of cancer patients, as they could identify the time needed for the germ cell line to repair nuclear damage and thus produce gametes with a reduced risk for the offspring.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('nuclear', 'Var', (209, 216))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('patients', 'Species', '9606', (127, 135))	('reduced', 'NegReg', (256, 263))	('men', 'Species', '9606', (112, 115))
34304	33945571	Some reports have suggested a link between SPATS1 underexpression/mutation and human pathologies such as male infertility and testicular cancer.	('male infertility', 'Disease', 'MESH:D007248', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('human', 'Species', '9606', (79, 84))	('male infertility', 'Disease', (105, 121))	('infertility', 'Phenotype', 'HP:0000789', (110, 121))	('testicular cancer', 'Phenotype', 'HP:0010788', (126, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('underexpression/mutation', 'Var', (50, 74))	('SPATS1', 'Gene', (43, 49))	('male infertility', 'Phenotype', 'HP:0003251', (105, 121))
34309	33945571	Besides, although an involvement of SPATS1 in the Wnt signaling pathway has been suggested, we did not detect changes in the expression levels of typical Wnt pathway-target genes in mutant individuals.	('men', 'Species', '9606', (28, 31))	('SPATS1', 'Gene', (36, 42))	('involvement', 'Reg', (21, 32))	('Wnt signaling pathway', 'Pathway', (50, 71))	('mutant', 'Var', (182, 188))
34310	33945571	Thus, albeit Spats1 alteration might be a risk factor for male testicular health, we hereby show that this gene is not individually essential for male fertility and spermatogenesis in mouse.	('alteration', 'Var', (20, 30))	('mouse', 'Species', '10090', (184, 189))	('rat', 'Species', '10116', (24, 27))	('Spats1', 'Gene', (13, 19))
34317	33945571	Furthermore, an exome-wide sequencing study has proposed a possible association between Spats1 mutation and the development of human seminomas, which are the most common type of testicular cancers.	('testicular cancers', 'Phenotype', 'HP:0010788', (178, 196))	('human', 'Species', '9606', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mutation', 'Var', (95, 103))	('testicular cancer', 'Phenotype', 'HP:0010788', (178, 195))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('seminomas', 'Disease', 'MESH:D018239', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('men', 'Species', '9606', (119, 122))	('Spats1', 'Gene', (88, 94))	('seminomas', 'Disease', (133, 142))	('cancers', 'Disease', (189, 196))
34384	33945571	The deletion resulted in a frameshift at residue 90, to generate a putative aberrant protein of 111 amino acids instead of the WT, 269-residue protein.	('generate', 'Reg', (56, 64))	('frameshift at', 'Var', (27, 40))	('resulted in', 'Reg', (13, 24))	('rat', 'Species', '10116', (60, 63))
34401	33945571	Likewise, we did not detect expression of Dvl2 in the testes of either WT or mutant animals.	('mutant', 'Var', (77, 83))	('Dvl2', 'Gene', (42, 46))	('Dvl2', 'Gene', '13543', (42, 46))
34404	33945571	Wnt4, one of the initiators of Wnt signaling, is a key gene for the development of female genitalia, with its absence leading to partial female-to-male sex reversal in mouse (e.g.).	('Wnt4', 'Gene', (0, 4))	('leading to', 'Reg', (118, 128))	('mouse', 'Species', '10090', (168, 173))	('sex reversal', 'Phenotype', 'HP:0012245', (152, 164))	('men', 'Species', '9606', (75, 78))	('absence', 'Var', (110, 117))	('partial female-to-male sex reversal', 'CPA', (129, 164))	('Wnt4', 'Gene', '22417', (0, 4))
34405	33945571	A fine tuning of Wnt4 expression is also implicated in testis development and spermatogenesis.	('spermatogenesis', 'CPA', (78, 93))	('men', 'Species', '9606', (69, 72))	('implicated', 'Reg', (41, 51))	('testis development', 'CPA', (55, 73))	('fine tuning', 'Var', (2, 13))	('Wnt4', 'Gene', '22417', (17, 21))	('Wnt4', 'Gene', (17, 21))
34409	33945571	Progressive spermatogenic defects have been reported for mutant mice with germ cell-specific constitutive activation of beta-catenin as age increases.	('beta-catenin', 'Gene', '12387', (120, 132))	('mice', 'Species', '10090', (64, 68))	('activation', 'PosReg', (106, 116))	('mutant', 'Var', (57, 63))	('Progressive spermatogenic defects', 'Phenotype', 'HP:0008669', (0, 33))	('spermatogenic defects', 'CPA', (12, 33))	('beta-catenin', 'Gene', (120, 132))
34422	33945571	Moreover, disruption of a single gene may not cause an evident effect on fertility, but it may have dramatic consequences in combination with environmental factors, or with other mutations or polymorphisms.	('disruption', 'Var', (10, 20))	('consequences', 'Reg', (109, 121))	('men', 'Species', '9606', (149, 152))
34423	33945571	If this were the case for Spats1, it could possibly reconcile the discrepancies between the lack of phenotype of Spats1 KO mice, and the reports that associate alterations or polymorphisms of Spats1 with human male pathologies such as infertility and testicular cancer.	('cancer', 'Disease', (262, 268))	('infertility', 'Phenotype', 'HP:0000789', (235, 246))	('Spats1', 'Gene', (192, 198))	('polymorphisms', 'Var', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('alterations', 'Var', (160, 171))	('infertility', 'Disease', 'MESH:D007247', (235, 246))	('human', 'Species', '9606', (204, 209))	('rat', 'Species', '10116', (164, 167))	('testicular cancer', 'Phenotype', 'HP:0010788', (251, 268))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('infertility', 'Disease', (235, 246))	('mice', 'Species', '10090', (123, 127))
34424	33945571	Furthermore, we cannot exclude the possibility that the absence of SPATS1 be better tolerated in mice than in humans.	('humans', 'Species', '9606', (110, 116))	('rat', 'Species', '10116', (88, 91))	('mice', 'Species', '10090', (97, 101))	('SPATS1', 'Gene', (67, 73))	('absence', 'Var', (56, 63))
34427	33945571	In this regard, we remark the relative validity of heterologous somatic cell cultures and transpolation of results to the complex testicular tissue, and the obvious importance of performing in vivo studies, such as the generation of loss-of-function mutants.	('rat', 'Species', '10116', (223, 226))	('loss-of-function', 'NegReg', (233, 249))	('mutants', 'Var', (250, 257))
34429	33945571	While according to other reports a defect in Spats1 may be a risk factor for male testicular health in human and bull, we here show that the lack of SPATS1 protein alone does not cause an evident phenotype in mouse.	('male testicular health', 'Disease', (77, 99))	('defect', 'Var', (35, 41))	('human', 'Species', '9606', (103, 108))	('Spats1', 'Gene', (45, 51))	('protein', 'Protein', (156, 163))	('SPATS1', 'Gene', (149, 155))	('lack', 'Var', (141, 145))	('mouse', 'Species', '10090', (209, 214))
34499	33945571	in mutants with altered beta-catenin expression).	('beta-catenin', 'Gene', (24, 36))	('beta-catenin', 'Gene', '12387', (24, 36))	('altered', 'Reg', (16, 23))	('expression', 'MPA', (37, 47))	('mutants', 'Var', (3, 10))
34500	33945571	On one hand, aberrant activation of Wnt signaling targets in testis disrupts Sertoli cells differentiation and their ability to support spermatogenesis, resulting in seminiferous tubule degeneration and infertility.	('disrupts', 'NegReg', (68, 76))	('Sertoli cells', 'Phenotype', 'HP:0100619', (77, 90))	('infertility', 'Phenotype', 'HP:0000789', (203, 214))	('tubule degeneration', 'Phenotype', 'HP:0000092', (179, 198))	('activation', 'PosReg', (22, 32))	('Sertoli cells differentiation', 'CPA', (77, 106))	('tubule degeneration and infertility', 'Disease', 'MESH:D007247', (179, 214))	('ability', 'CPA', (117, 124))	('aberrant', 'Var', (13, 21))
34510	33945571	Furthermore, since - as mentioned in the ms - a report suggested a possible link between Spats1 mutation and human testicular cancer, we found it interesting to analyze if the expression levels of c-Myc (a proto-oncogene) were altered in the testes of Spats1-deficient mice.	('testicular cancer', 'Phenotype', 'HP:0010788', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (109, 114))	('Spats1', 'Gene', (89, 95))	('men', 'Species', '9606', (24, 27))	('altered', 'Reg', (227, 234))	('expression levels', 'MPA', (176, 193))	('mutation', 'Var', (96, 104))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mice', 'Species', '10090', (269, 273))
34560	30949131	The pooled OR indicated that the presence of TM is associated with a ~18-fold higher odd for testicular cancer (pooled OR:18.11, 95%CI: 8.09, 40.55; P < 0.0001).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('testicular cancer', 'Disease', (93, 110))	('presence', 'Var', (33, 41))	('testicular cancer', 'Phenotype', 'HP:0010788', (93, 110))	('testicular cancer', 'Disease', 'MESH:D013736', (93, 110))	('TM', 'Phenotype', 'HP:0012215', (45, 47))
34562	30949131	Conclusions: In infertile men the presence of TM is associated to an ~18-fold higher prevalence of testicular cancer.	('TM', 'Phenotype', 'HP:0012215', (46, 48))	('testicular cancer', 'Phenotype', 'HP:0010788', (99, 116))	('testicular cancer', 'Disease', 'MESH:D013736', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('men', 'Species', '9606', (26, 29))	('presence', 'Var', (34, 42))	('testicular cancer', 'Disease', (99, 116))
34570	30949131	However, whether and to what extent the presence of TM in infertile men actually confers a significantly higher risk of testicular cancer remains unclear, as, in this population, an association of TM with a higher prevalence of testicular cancer has been reported by some studies but not by others.	('testicular cancer', 'Phenotype', 'HP:0010788', (228, 245))	('TM', 'Phenotype', 'HP:0012215', (197, 199))	('testicular cancer', 'Disease', 'MESH:D013736', (228, 245))	('presence', 'Var', (40, 48))	('testicular cancer', 'Phenotype', 'HP:0010788', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('testicular cancer', 'Disease', 'MESH:D013736', (120, 137))	('testicular cancer', 'Disease', (228, 245))	('TM', 'Phenotype', 'HP:0012215', (52, 54))	('men', 'Species', '9606', (68, 71))	('testicular cancer', 'Disease', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
34586	30949131	As shown in Figure 2, pooled estimate indicated that the presence of TM is associated with a ~18-fold higher odd for testicular cancer (OR: 18.11, 95% CI: 8.09, 40.55; P < 0.0001).	('TM', 'Phenotype', 'HP:0012215', (69, 71))	('testicular cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('presence', 'Var', (57, 65))	('testicular cancer', 'Phenotype', 'HP:0010788', (117, 134))	('testicular cancer', 'Disease', 'MESH:D013736', (117, 134))
34606	30949131	Similarly, any disturbance in early fetal life of the development/differentiation of Leydig and Sertoli cells may lead to an impairment of both production of testosterone and insulin-like factor 3 (INSL3) and germ cell development, resulting in genital malformations (such as hypospadias and cryptorchidism) and, later in life, impaired spermatogenesis.	('cryptorchidism', 'Disease', 'MESH:D003456', (292, 306))	('men', 'Species', '9606', (131, 134))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (328, 352))	('hypospadias', 'Disease', (276, 287))	('cryptorchidism', 'Disease', (292, 306))	('hypospadias', 'Disease', 'MESH:D007021', (276, 287))	('INSL3', 'Gene', '3640', (198, 203))	('impaired', 'NegReg', (328, 336))	('insulin-like factor 3', 'Gene', (175, 196))	('disturbance', 'Var', (15, 26))	('cryptorchidism', 'Phenotype', 'HP:0000028', (292, 306))	('men', 'Species', '9606', (226, 229))	('genital malformations', 'Disease', (245, 266))	('germ cell development', 'CPA', (209, 230))	('insulin-like factor 3', 'Gene', '3640', (175, 196))	('genital malformations', 'Phenotype', 'HP:0000078', (245, 266))	('production of testosterone', 'MPA', (144, 170))	('impairment', 'NegReg', (125, 135))	('testosterone', 'Chemical', 'MESH:D013739', (158, 170))	('spermatogenesis', 'CPA', (337, 352))	('Sertoli cells', 'Phenotype', 'HP:0100619', (96, 109))	('men', 'Species', '9606', (61, 64))	('genital malformations', 'Disease', 'MESH:D000014', (245, 266))	('hypospadias', 'Phenotype', 'HP:0000047', (276, 287))	('INSL3', 'Gene', (198, 203))
34607	30949131	The model of the testicular dysgenesis syndrome not only could explain why infertility represents a risk factor for testicular cancer but also why the presence of TM is associated with an even higher risk: TM might be the expression of an already existent CIS.	('testicular cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('testicular dysgenesis syndrome', 'Disease', (17, 47))	('CIS', 'Phenotype', 'HP:0030075', (256, 259))	('testicular dysgenesis syndrome', 'Disease', 'MESH:D013733', (17, 47))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))	('infertility', 'Phenotype', 'HP:0000789', (75, 86))	('infertility', 'Disease', 'MESH:D007247', (75, 86))	('TM', 'Phenotype', 'HP:0012215', (206, 208))	('presence', 'Var', (151, 159))	('infertility', 'Disease', (75, 86))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (17, 38))	('TM', 'Phenotype', 'HP:0012215', (163, 165))
34627	28266817	Although unilateral orchiectomy does not result directly in infertility, because the remaining testicle may present normal spermatogenesis, potential side effects are disruption of retroperitoneal sympathetic nerves, which may result in retrograde ejaculation, and a high risk of hypogonadotropic hypogonadismdue to the reduction in testosterone production.	('result in', 'Reg', (227, 236))	('spermatogenesis', 'CPA', (123, 138))	('reduction', 'NegReg', (320, 329))	('hypogonadotropic hypogonadismdue', 'Phenotype', 'HP:0000044', (280, 312))	('testosterone', 'Chemical', 'MESH:D013739', (333, 345))	('disruption', 'Var', (167, 177))	('testosterone production', 'MPA', (333, 356))	('retrograde ejaculation', 'Phenotype', 'HP:0012877', (237, 259))	('hypogonadotropic hypogonadismdue', 'Disease', (280, 312))	('reduction in testosterone production', 'Phenotype', 'HP:0040171', (320, 356))	('infertility', 'Disease', 'MESH:D007247', (60, 71))	('unilateral orchiectomy', 'Phenotype', 'HP:0012741', (9, 31))	('infertility', 'Phenotype', 'HP:0000789', (60, 71))	('infertility', 'Disease', (60, 71))	('retrograde ejaculation', 'CPA', (237, 259))
34628	28266817	The seminal plasma, however, represents the main protection system, which includes a chain of enzymatic antioxidants, composed by superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), which are capable of neutralizing ROS, thus preventing damage caused by oxidative stress.	('oxidative stress', 'MPA', (279, 295))	('ROS', 'Chemical', 'MESH:D017382', (241, 244))	('ROS', 'Protein', (241, 244))	('neutralizing', 'Var', (228, 240))	('superoxide dismutase', 'Gene', '6647', (130, 150))	('CAT', 'Gene', '847', (168, 171))	('oxidative stress', 'Phenotype', 'HP:0025464', (279, 295))	('CAT', 'Gene', (168, 171))	('damage', 'MPA', (262, 268))	('preventing', 'NegReg', (251, 261))	('superoxide dismutase', 'Gene', (130, 150))
34672	28740458	Echocardiographic evaluation showed abnormal diastolic function of the left ventricle in 33% of the patients treated with cisplatin based chemotherapy, probably as an early sign of microvasculopathy.	('microvasculopathy', 'Disease', (181, 198))	('cisplatin', 'Var', (122, 131))	('microvasculopathy', 'Disease', 'None', (181, 198))	('abnormal diastolic function', 'Phenotype', 'HP:0025168', (36, 63))	('diastolic function', 'MPA', (45, 63))	('patients', 'Species', '9606', (100, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('abnormal', 'Reg', (36, 44))
34679	28740458	Moreover, in this study, risk for cardiac events was increased in patients treated with radiotherapy (RR = 2.4, 95% CI, 1.04 to 5.45), although a minority of them - only 8.3%, received mediastinal radiotherapy.	('radiotherapy', 'Var', (88, 100))	('cardiac', 'CPA', (34, 41))	('patients', 'Species', '9606', (66, 74))
34709	28740458	In comparision with the general population, mortality from circulatory disease was significantly increased in patients treated with radiotherapy at the age under 35 years (SMR = 1.7, 95% CI, 1.21 to 2.31), as well as in patients treated with chemotherapy (with or without radiotherapy) at the age under 35 years after 1975 (SMR = 1.58, 95% CI, 1.25 to 2.01).	('radiotherapy', 'Var', (132, 144))	('increased', 'PosReg', (97, 106))	('circulatory disease', 'Disease', (59, 78))	('patients', 'Species', '9606', (220, 228))	('patients', 'Species', '9606', (110, 118))
34722	28740458	The same author in another study also reported on small, but statistically significant increase in carotid intima media thickness in patients treated with cisplatin based chemotherapy, which was shown to be associated with higher myocardial infarction incidence.	('myocardial infarction', 'Disease', (230, 251))	('myocardial infarction', 'Disease', 'MESH:D009203', (230, 251))	('increase', 'PosReg', (87, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('patients', 'Species', '9606', (133, 141))	('myocardial infarction', 'Phenotype', 'HP:0001658', (230, 251))	('carotid intima media thickness', 'MPA', (99, 129))	('higher', 'PosReg', (223, 229))	('cisplatin based', 'Var', (155, 170))
34755	28740458	Data from the literature indicate that irradiation of the heart leads to the tissue damage through microvasculopathy and eventually macrovasculopathy.	('irradiation', 'Var', (39, 50))	('macrovasculopathy', 'Disease', (132, 149))	('microvasculopathy', 'Disease', 'None', (99, 116))	('tissue damage', 'CPA', (77, 90))	('macrovasculopathy', 'Disease', 'None', (132, 149))	('microvasculopathy', 'Disease', (99, 116))
34776	24970206	Perturbations of imprinted loci can result in pathological manifestations including Prader-Willi Syndrome, Angelman Syndrome, Beckwith-Wiedemann Syndrome, and Silver-Russell Syndrome, as well as some cancers.	('Beckwith-Wiedemann Syndrome', 'Disease', (126, 153))	('Angelman Syndrome', 'Disease', 'MESH:D017204', (107, 124))	('Angelman Syndrome', 'Disease', (107, 124))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (200, 207))	('result in', 'Reg', (36, 45))	('Prader-Willi Syndrome', 'Disease', (84, 105))	('Beckwith-Wiedemann Syndrome', 'Disease', 'MESH:D001506', (126, 153))	('Perturbations', 'Var', (0, 13))	('Silver-Russell Syndrome', 'Disease', (159, 182))	('Prader-Willi Syndrome', 'Disease', 'MESH:D011218', (84, 105))
34798	24970206	Once settled along the Xi with the spreading Xist transcripts, PRC2 is responsible for marking the chromatin with H3K27 trimethylation (a repressive histone modification), which occurs in conjunction with the loss of active histone marks such as H4 acetylation, as well as H3K4 and H3K36 methylation.	('PRC2', 'Gene', (63, 67))	('H3K4', 'Protein', (273, 277))	('Xist', 'Gene', '7503', (45, 49))	('Xist', 'Gene', (45, 49))	('H3K36', 'Protein', (282, 287))	('H3K27', 'Var', (114, 119))
34799	24970206	In hnRNP U deficient cells, this H3K27 repressive mark is not established, leading to defects in XI formation.	('deficient', 'Var', (11, 20))	('hnRNP U', 'Gene', (3, 10))	('hnRNP U', 'Gene', '3192', (3, 10))	('XI formation', 'CPA', (97, 109))	('defects', 'NegReg', (86, 93))
34817	24970206	Paternal transmission of an ICR deletion results in no expression of Kcnq1ot1 and biallelic expression of the maternal genes in mice, while a maternally-inherited deletion has no effect on imprinting.	('deletion', 'Var', (32, 40))	('Kcnq1ot1', 'Gene', (69, 77))	('biallelic expression', 'MPA', (82, 102))	('ICR', 'Gene', (28, 31))	('expression', 'MPA', (55, 65))	('mice', 'Species', '10090', (128, 132))
34820	24970206	Indeed, the silencing of the locus is linked to the presence of the repressive histone marks H3K9me3 and H3K27me3, mediated in part by the histone methyltransferase G9A/EHMT2.	('G9A', 'Gene', (165, 168))	('H3K27me3', 'Var', (105, 113))	('EHMT2', 'Gene', '10919', (169, 174))	('silencing', 'NegReg', (12, 21))	('H3K9me3', 'Protein', (93, 100))	('G9A', 'Gene', '10919', (165, 168))	('EHMT2', 'Gene', (169, 174))
34833	24970206	In addition, truncations that prematurely terminate Airn before it reaches the Igf2r promoter result in de-repression of the paternal Igf2r allele.	('de-repression', 'MPA', (104, 117))	('Airn', 'Gene', (52, 56))	('truncations', 'Var', (13, 24))	('Igf2r', 'Gene', (134, 139))	('Airn', 'Gene', '100271873', (52, 56))
34858	24970206	Interestingly, the H19 area produces two different types of antisense transcripts with seemingly opposing functions:a nuclear 120 kb noncoding isoform called 91H that is associated with tumorigenesis, and a 6 kb coding form called HOTS, whose protein product has been identified mostly in the nuclei of fetal tissues and is believed to function as a tumor-suppressor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('tumor', 'Disease', (186, 191))	('91H', 'Chemical', '-', (158, 161))	('antisense', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('H19', 'Gene', '283120', (19, 22))	('H19', 'Gene', (19, 22))	('associated', 'Reg', (170, 180))
34861	24970206	Disruptions of this locus by mutation or aberrant imprinting are linked to Beckwith-Wiedemann Syndrome and/or Silver-Russell Syndrome, as well as several cancers.	('aberrant imprinting', 'Var', (41, 60))	('mutation', 'Var', (29, 37))	('Disruptions', 'Var', (0, 11))	('linked', 'Reg', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('Beckwith-Wiedemann Syndrome', 'Disease', 'MESH:D001506', (75, 102))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('and/or', 'Disease', (103, 109))	('Beckwith-Wiedemann Syndrome', 'Disease', (75, 102))	('Silver-Russell Syndrome', 'Disease', (110, 133))
34863	24970206	This anti-RTL1 RNA may also be polycistronic/contiguous with the transcripts that host multiple snoRNA clusters (the SNORD112s, SNORD113s, and SNORD114s), as well as several miRNAs, and the lncRNA MEG8 (also known as Rian in mouse), starting with MEG3 and ending with MIRG.	('snoRNA', 'Gene', '85390', (96, 102))	('anti-RTL1', 'Gene', (5, 14))	('MIRG', 'Gene', (268, 272))	('Rian', 'Gene', (217, 221))	('SNORD113s', 'Var', (128, 137))	('MEG8', 'Gene', (197, 201))	('mouse', 'Species', '10090', (225, 230))	('MEG8', 'Gene', '75745', (197, 201))	('snoRNA', 'Gene', (96, 102))	('SNORD114s', 'Var', (143, 152))	('Rian', 'Gene', '75745', (217, 221))	('MIRG', 'Gene', '100040724', (268, 272))	('multiple snoRNA', 'Phenotype', 'HP:0025267', (87, 102))
34868	24970206	This indicates that the IG-DMR is not involved in silencing the paternal Meg3 transcript, but is necessary (in the unmethylated state, perhaps acting as an activator) for expression of the maternal Meg3 and silencing the maternal Dlk1 gene.	('DMR', 'Chemical', '-', (27, 30))	('Dlk1', 'Gene', '8788', (230, 234))	('Meg3', 'Gene', '55384', (73, 77))	('silencing', 'Var', (207, 216))	('Meg3', 'Gene', (73, 77))	('Dlk1', 'Gene', (230, 234))	('Meg3', 'Gene', '55384', (198, 202))	('Meg3', 'Gene', (198, 202))
34870	24970206	Meg3 knockdown also revealed a two-fold increase in Dlk1 expression, suggesting reactivation of the maternally imprinted (silenced) allele.	('expression', 'MPA', (57, 67))	('knockdown', 'Var', (5, 14))	('Meg3', 'Gene', '55384', (0, 4))	('Meg3', 'Gene', (0, 4))	('Dlk1', 'Gene', '8788', (52, 56))	('increase', 'PosReg', (40, 48))	('Dlk1', 'Gene', (52, 56))
34873	24970206	Indeed, Meg3 knockdown resulted in a decrease in EZH2 (a subunit of the PRC2 complex) recruitment to the Dlk1 promoter, and a corresponding decrease in the PRC2-mediated chromatin mark H3K27me3, consistent with Dlk1 upregulation, which was similarly seen upon EZH2 knockdown.	('EZH2', 'Gene', '2146', (260, 264))	('recruitment', 'MPA', (86, 97))	('decrease', 'NegReg', (37, 45))	('EZH2', 'Gene', (260, 264))	('EZH2', 'Gene', '2146', (49, 53))	('Dlk1', 'Gene', (105, 109))	('Dlk1', 'Gene', (211, 215))	('decrease', 'NegReg', (140, 148))	('EZH2', 'Gene', (49, 53))	('Dlk1', 'Gene', '8788', (105, 109))	('PRC2-mediated chromatin mark H3K27me3', 'MPA', (156, 193))	('Dlk1', 'Gene', '8788', (211, 215))	('knockdown', 'Var', (13, 22))	('Meg3', 'Gene', '55384', (8, 12))	('Meg3', 'Gene', (8, 12))
34875	24970206	In addition, deletion or aberrant imprinting of this region has been linked to tumorigenesis in mammals.	('tumor', 'Disease', (79, 84))	('aberrant', 'Var', (25, 33))	('linked', 'Reg', (69, 75))	('deletion', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
34882	24970206	Interestingly, a relatively small deletion in the mouse Snurf-Snrpn promoter prevents expression of Snrpn transcript, if inherited paternally, but leaves imprinting of other genes in the region (Ndn, Magel2, and Mkrn3) intact.	('Ndn', 'Gene', (195, 198))	('mouse', 'Species', '10090', (50, 55))	('Snurf', 'Gene', '8926', (56, 61))	('Mkrn3', 'Gene', '22652', (212, 217))	('prevents', 'NegReg', (77, 85))	('expression', 'MPA', (86, 96))	('deletion', 'Var', (34, 42))	('Magel2', 'Gene', (200, 206))	('Ndn', 'Gene', '17984', (195, 198))	('Snrpn', 'Gene', (100, 105))	('Magel2', 'Gene', '27385', (200, 206))	('Mkrn3', 'Gene', (212, 217))	('Snurf', 'Gene', (56, 61))
34886	24970206	Conversely, the AS-IC is inactive in the male germline, which allows the PWS-IC DMR to stay unmethylated (although it is still bears the active marks H3K4 di- and tri-methylation), leaving it primed for transcription.	('H3K4', 'Var', (150, 154))	('transcription', 'MPA', (203, 216))	('AS-IC', 'Gene', (16, 21))	('PWS-IC', 'Disease', 'MESH:D011218', (73, 79))	('DMR', 'Chemical', '-', (80, 83))	('PWS-IC', 'Disease', (73, 79))	('primed', 'MPA', (192, 198))	('AS-IC', 'Gene', '41', (16, 21))
34889	24970206	Furthermore, double deletions of both the AS-IC and the PWS-IC, passed through either the maternal or paternal lineage, reveal a phenotype consistent with paternal genes not being properly expressed, suggesting a bi-maternal chromosomal configuration, which means that the PWS-IC is epistatic to the AS-IC.	('AS-IC', 'Gene', '41', (42, 47))	('PWS-IC', 'Disease', 'MESH:D011218', (56, 62))	('AS-IC', 'Gene', '41', (300, 305))	('PWS-IC', 'Disease', (56, 62))	('PWS-IC', 'Disease', 'MESH:D011218', (273, 279))	('PWS-IC', 'Disease', (273, 279))	('double deletions', 'Var', (13, 29))	('AS-IC', 'Gene', (42, 47))	('AS-IC', 'Gene', (300, 305))
34892	24970206	This antisense transcription silences the paternal alleles of UBE3A and, in perhaps is some cases, ATP10A:causing maternal-only expression in neurons.	('maternal-only expression in', 'MPA', (114, 141))	('ATP10A', 'Gene', (99, 105))	('antisense transcription', 'Var', (5, 28))	('UBE3A', 'Gene', '7337', (62, 67))	('silences', 'NegReg', (29, 37))	('UBE3A', 'Gene', (62, 67))	('causing', 'Reg', (106, 113))	('ATP10A', 'Gene', '57194', (99, 105))
34894	24970206	Increased attention has been paid to the region containing the SNORD116 cluster, as a deletion encompassing these snoRNAs has been found to be the minimal deletion sufficient to cause PWS.	('SNORD116', 'Gene', (63, 71))	('snoRNA', 'Gene', '85390', (114, 120))	('PWS', 'Disease', (184, 187))	('cause', 'Reg', (178, 183))	('PWS', 'Disease', 'MESH:D011218', (184, 187))	('SNORD116', 'Gene', '692236', (63, 71))	('snoRNA', 'Gene', (114, 120))	('deletion', 'Var', (86, 94))
34895	24970206	These initial findings were extended to a Snord116 deletion mouse model of PWS, and overlap between significantly altered transcripts and 116HG interacting genes in the cortex indicates that 116HG has a role in the dysregulated metabolic phenotype observed in the mouse.	('mouse', 'Species', '10090', (264, 269))	('Snord116', 'Gene', (42, 50))	('PWS', 'Disease', (75, 78))	('PWS', 'Disease', 'MESH:D011218', (75, 78))	('mouse', 'Species', '10090', (60, 65))	('deletion', 'Var', (51, 59))	('dysregulated metabolic phenotype', 'MPA', (215, 247))
34897	24970206	In cells without Snord116 deletions, these R-loops create a balance between RNA PolII stalling and transcriptional elongation, which results in Ube3a-ATS and silencing of Ube3A.	('Ube3A', 'Gene', '7337', (171, 176))	('Snord116', 'Gene', (17, 25))	('deletions', 'Var', (26, 35))	('Ube3A', 'Gene', (171, 176))	('Ube3a', 'Gene', (144, 149))	('results in', 'Reg', (133, 143))	('silencing', 'NegReg', (158, 167))	('Ube3a', 'Gene', '7337', (144, 149))
34898	24970206	This balance can be upset, however, either by deletion of the repetitive Snord116 region leading to increased transcriptional activity of Ube3a-ATS, or addition of the topoisomerase inhibitor topotecan leading to increased R-loop formation and decreased Ube3a-ATS .	('Ube3a', 'Gene', '7337', (254, 259))	('deletion', 'Var', (46, 54))	('decreased', 'NegReg', (244, 253))	('Ube3a', 'Gene', '7337', (138, 143))	('increased', 'PosReg', (100, 109))	('topotecan', 'Chemical', 'MESH:D019772', (192, 201))	('Snord116', 'Gene', (73, 81))	('transcriptional activity', 'MPA', (110, 134))	('Ube3a', 'Gene', (254, 259))	('R-loop formation', 'MPA', (223, 239))	('Ube3a', 'Gene', (138, 143))	('increased', 'PosReg', (213, 222))
34902	24970206	Additional characterizations of the five sno-lncRNAs arising from the SNORD116 cluster (in the 15q11-13 locus) revealed that they were rich in binding sites for members of the FOX family of splicing factors, and knockdown of these sno-lncRNAs produced specific splicing changes, so they may function as protein sinks to regulate gene expression.	('sno', 'Gene', '55206', (231, 234))	('binding', 'Interaction', (143, 150))	('sno', 'Gene', (231, 234))	('SNORD116', 'Gene', (70, 78))	('sno', 'Gene', '55206', (41, 44))	('splicing changes', 'MPA', (261, 277))	('knockdown', 'Var', (212, 221))	('sno', 'Gene', (41, 44))	('SNORD116', 'Gene', '692236', (70, 78))
34905	24970206	In addition, STELLA (DPPA3) has been shown to have a more global protective role on methylated ICRs in the early embryo.	('STELLA', 'Gene', (13, 19))	('STELLA', 'Gene', '359787', (13, 19))	('methylated', 'Var', (84, 94))	('DPPA3', 'Gene', '359787', (21, 26))	('DPPA3', 'Gene', (21, 26))
34975	22699423	Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice A significant decline in human male reproductive function has been reported for the past 20 years but the molecular mechanisms remain poorly understood.	('human male reproductive function', 'CPA', (151, 183))	('connexin 43', 'Gene', '14609', (34, 45))	('human', 'Species', '9606', (151, 156))	('testicular gene', 'Gene', (79, 94))	('knockout', 'Var', (22, 30))	('alterations', 'Reg', (64, 75))	('connexin 43', 'Gene', (34, 45))	('decline', 'NegReg', (140, 147))
34978	22699423	Alterations of its expression are associated with different forms of spermatogenic disorders and infertility.	('associated', 'Reg', (34, 44))	('expression', 'MPA', (19, 29))	('spermatogenic disorders', 'Disease', (69, 92))	('infertility', 'Disease', 'MESH:D007247', (97, 108))	('Alterations', 'Var', (0, 11))	('spermatogenic disorders', 'Disease', 'OMIM:108420', (69, 92))	('infertility', 'Phenotype', 'HP:0000789', (97, 108))	('infertility', 'Disease', (97, 108))	('spermatogenic disorders', 'Phenotype', 'HP:0008669', (69, 92))
34984	22699423	Our data show that deletion of Cx43 in SCs leads to multiple alterations of gene expression in prepubertal mice and primarily affects GCs.	('SCs', 'Gene', (39, 42))	('GCs', 'Disease', (134, 137))	('deletion', 'Var', (19, 27))	('alterations of gene expression', 'MPA', (61, 91))	('affects', 'Reg', (126, 133))	('mice', 'Species', '10090', (107, 111))	('Cx43', 'Gene', '14609', (31, 35))	('Cx43', 'Gene', (31, 35))
35002	22699423	Finally, alterations of CX43 expression have been correlated to the development of human carcinoma in situ (CIS) of the testis and testicular tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('testicular tumors', 'Phenotype', 'HP:0010788', (131, 148))	('carcinoma in situ', 'Disease', 'MESH:D002278', (89, 106))	('human', 'Species', '9606', (83, 88))	('alterations', 'Var', (9, 20))	('testicular tumors', 'Disease', (131, 148))	('correlated', 'Reg', (50, 60))	('men', 'Species', '9606', (75, 78))	('CX43', 'Protein', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('expression', 'MPA', (29, 39))	('carcinoma in situ', 'Disease', (89, 106))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (89, 106))	('testicular tumors', 'Disease', 'MESH:D013736', (131, 148))
35003	22699423	that support functional roles of CX43 in the regulation of human spermatogenesis: (1) CX43 forms intercellular channels between SCs and proliferating GCs, indicating that this CX is involved in the physiological maturation and proliferation processes of these cell types; (2) alterations of CX43 expression are correlated with testicular disorders in men; for example, individuals with CIS and seminoma, the most frequent type of human GC tumors, show a reduction of CX43 expression in SCs and tumor cells.	('tumors', 'Disease', 'MESH:D009369', (439, 445))	('CX', 'Gene', '100128922', (176, 178))	('CX', 'Gene', '100128922', (33, 35))	('tumor', 'Disease', (439, 444))	('human', 'Species', '9606', (430, 435))	('men', 'Species', '9606', (351, 354))	('correlated', 'Reg', (311, 321))	('seminoma', 'Disease', (394, 402))	('tumor', 'Disease', 'MESH:D009369', (439, 444))	('reduction', 'NegReg', (454, 463))	('tumor', 'Disease', (494, 499))	('CX', 'Gene', '100128922', (467, 469))	('tumors', 'Phenotype', 'HP:0002664', (439, 445))	('CIS', 'Disease', (386, 389))	('seminoma', 'Disease', 'MESH:D018239', (394, 402))	('testicular disorders', 'Disease', 'MESH:D013733', (327, 347))	('CX', 'Gene', '100128922', (86, 88))	('tumor', 'Disease', 'MESH:D009369', (494, 499))	('CX', 'Gene', '100128922', (291, 293))	('tumor', 'Phenotype', 'HP:0002664', (439, 444))	('human', 'Species', '9606', (59, 64))	('testicular disorders', 'Disease', (327, 347))	('tumors', 'Disease', (439, 445))	('alterations', 'Var', (276, 287))	('testicular disorders', 'Phenotype', 'HP:0000035', (327, 347))	('tumor', 'Phenotype', 'HP:0002664', (494, 499))
35004	22699423	In CIS tubules, the reduction of CX43 expression was shown to be regulated at the transcriptional level and accompanied with a dedifferentiation of SCs; (3) moreover, possible mutations in the human CX43 gene have been discussed because a recent study working with a mutant mouse model of oculodentodigital dysplasia (ODDD) showed impaired spermatogenesis, supporting the possibility of subfertility in ODDD human males.	('impaired', 'NegReg', (331, 339))	('human', 'Species', '9606', (408, 413))	('spermatogenesis', 'CPA', (340, 355))	('ODDD', 'Disease', 'MESH:C563160', (318, 322))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (331, 355))	('oculodentodigital dysplasia', 'Disease', (289, 316))	('ODDD', 'Disease', 'MESH:C563160', (403, 407))	('oculodentodigital dysplasia', 'Disease', 'MESH:C563160', (289, 316))	('mutant', 'Var', (267, 273))	('ODDD', 'Disease', (318, 322))	('mouse', 'Species', '10090', (274, 279))	('ODDD', 'Disease', (403, 407))	('human', 'Species', '9606', (193, 198))
35021	22699423	GC number was three times higher in testes of WT mice, whereas the number of SCs (and LCs) was not affected by the deletion of Cx43 (Figs 1, 2).	('deletion', 'Var', (115, 123))	('higher', 'PosReg', (26, 32))	('Cx43', 'Gene', '14609', (127, 131))	('mice', 'Species', '10090', (49, 53))	('Cx43', 'Gene', (127, 131))
35056	22699423	Deletion of Cx43 in SCs results in no obvious changes in OCLN protein synthesis and localization when comparing 8-day-old WT (Fig.	('changes', 'Reg', (46, 53))	('Cx43', 'Gene', (12, 16))	('OCLN', 'Gene', '18260', (57, 61))	('localization', 'MPA', (84, 96))	('OCLN', 'Gene', (57, 61))	('Cx43', 'Gene', '14609', (12, 16))	('Deletion', 'Var', (0, 8))
35077	22699423	However, our results can be explained by the juxtaposition and dependency of the two cell types, which is interrupted by the deletion of the Cx43 gene.	('Cx43', 'Gene', '14609', (141, 145))	('deletion', 'Var', (125, 133))	('Cx43', 'Gene', (141, 145))
35078	22699423	Together with the observation that the gene expression of mainly GCs is influenced, our results might lead to the assumption that the interruption of poorly characterized mediators of signals from SCs to GCs affect primarily the normal development of early GC populations, preventing the initiation of spermatogenesis.	('interruption', 'Var', (134, 146))	('spermatogenesis', 'CPA', (302, 317))	('affect', 'Reg', (208, 214))	('preventing', 'NegReg', (273, 283))	('men', 'Species', '9606', (243, 246))
35085	22699423	further demonstrated that a deletion of RARalpha leads to an alteration of gap-junction-based cell coupling.	('RARalpha', 'Gene', '19401', (40, 48))	('alteration', 'Reg', (61, 71))	('deletion', 'Var', (28, 36))	('RARalpha', 'Gene', (40, 48))	('gap-junction-based cell coupling', 'MPA', (75, 107))
35086	22699423	KO studies of the Stra8 gene revealed its importance for functional spermatogenesis: its deletion leads to infertility of male and female mice.	('Stra8', 'Gene', (18, 23))	('infertility', 'Phenotype', 'HP:0000789', (107, 118))	('infertility', 'Disease', 'MESH:D007247', (107, 118))	('mice', 'Species', '10090', (138, 142))	('infertility', 'Disease', (107, 118))	('deletion', 'Var', (89, 97))	('Stra8', 'Gene', '20899', (18, 23))	('functional spermatogenesis', 'Phenotype', 'HP:0008669', (57, 83))	('leads to', 'Reg', (98, 106))
35108	22699423	Sohlh1 and Sox3 single KO mice show an arrest of spermatogenesis at the level of spermatogonia and, comparable to the present mouse model, their deletion leads to a disruption of GC differentiation beyond early developmental stages and to infertility.	('mouse', 'Species', '10090', (126, 131))	('leads to', 'Reg', (154, 162))	('deletion', 'Var', (145, 153))	('arrest of spermatogenesis', 'Phenotype', 'HP:0031038', (39, 64))	('spermatogenesis', 'CPA', (49, 64))	('mice', 'Species', '10090', (26, 30))	('infertility', 'Disease', 'MESH:D007247', (239, 250))	('infertility', 'Phenotype', 'HP:0000789', (239, 250))	('men', 'Species', '9606', (218, 221))	('disruption', 'Reg', (165, 175))	('infertility', 'Disease', (239, 250))
35109	22699423	By contrast, the deletion of Sycp2 and Piwil2 leads to a spermatogenic arrest from zygotene to early pachytene stages.	('spermatogenic arrest', 'CPA', (57, 77))	('leads to', 'Reg', (46, 54))	('Sycp2', 'Gene', (29, 34))	('deletion', 'Var', (17, 25))	('spermatogenic arrest', 'Phenotype', 'HP:0031038', (57, 77))	('Piwil2', 'Gene', (39, 45))	('zygotene', 'Chemical', '-', (83, 91))	('pachytene', 'Chemical', '-', (101, 110))
35122	22699423	Because no significant alterations in Tjp1 and Ocln gene expression profiles have been detected in the present study at day 8 p.p., the observed alterations in TJP1 and OCLN levels in adult KO mice seem to occur after postnatal day 8, together with a functional BTB formation but possibly associated with (1) an impairment in the dynamic process of opening and closing of this barrier and/or (2) permanent BTB closure as suggested by the authors.	('opening', 'Disease', 'MESH:D005597', (349, 356))	('Ocln', 'Gene', '18260', (47, 51))	('alterations', 'Var', (145, 156))	('opening', 'Disease', (349, 356))	('TJP1', 'Gene', (160, 164))	('BTB', 'CPA', (262, 265))	('Ocln', 'Gene', (47, 51))	('OCLN', 'Gene', '18260', (169, 173))	('mice', 'Species', '10090', (193, 197))	('associated', 'Reg', (289, 299))	('OCLN', 'Gene', (169, 173))	('men', 'Species', '9606', (318, 321))	('Tjp1', 'Gene', (38, 42))	('Tjp1', 'Gene', '21872', (38, 42))
35135	22699423	A recent in vitro study confirms the involvement of CX43 gap junctions in the regulation of GC number by controlling spermatogonia survival rather than proliferation.	('spermatogonia survival', 'CPA', (117, 139))	('CX43 gap junctions', 'Var', (52, 70))	('men', 'Species', '9606', (44, 47))
35141	22699423	Whether CX43 from SCs is involved in GC growth by controlling primordial GC and/or spermatogonia survival rather than their proliferation, as shown by Gilleron et al., remains to be elucidated for SCCx43KO mutants in future studies.	('Cx43', 'Gene', (199, 203))	('mutants', 'Var', (206, 213))	('Cx43', 'Gene', '14609', (199, 203))
35144	22699423	(and these differences have a negative impact on protein synthesis in young and adult KO mice), (2) SC-specific deletion of Cx43 seems to effect primarily GCs and (3) expression of important GC-specific genes seems to be Cx43 associated and/or regulated.	('Cx43', 'Gene', (221, 225))	('effect', 'Reg', (138, 144))	('mice', 'Species', '10090', (89, 93))	('deletion', 'Var', (112, 120))	('Cx43', 'Gene', '14609', (124, 128))	('Cx43', 'Gene', '14609', (221, 225))	('protein synthesis', 'MPA', (49, 66))	('GCs', 'CPA', (155, 158))	('Cx43', 'Gene', (124, 128))
35145	22699423	Because several of the altered genes have been shown to be essential for normal (mitotic and meiotic) progression of GC development and initiation of spermatogenesis, it was additionally demonstrated that corresponding proteins are altered in adult mutants.	('mutants', 'Var', (249, 256))	('proteins', 'Protein', (219, 227))	('men', 'Species', '9606', (127, 130))	('altered', 'Reg', (232, 239))
35147	22699423	In conclusion, observed changes in gene expression in the mutant mice suggest a role for SC-GC crosstalk via CX43 gap junctions.	('mutant', 'Var', (58, 64))	('CX43 gap junctions', 'MPA', (109, 127))	('mice', 'Species', '10090', (65, 69))	('gene expression', 'MPA', (35, 50))	('changes', 'Reg', (24, 31))
35148	22699423	Changes in candidate gene expression patterns could have also been caused by (4) a loss of direct Cx43 effects on gene transcription, because it was demonstrated in a study working with fetal Cx43-null mutants that the loss of the Cx43 gene is able to exert profound effects on the expression pattern of other testicular CX genes.	('loss', 'Var', (219, 223))	('Cx43', 'Gene', '14609', (98, 102))	('Cx43', 'Gene', (231, 235))	('Cx43', 'Gene', '14609', (192, 196))	('expression pattern', 'MPA', (282, 300))	('Cx43', 'Gene', (98, 102))	('Cx43', 'Gene', (192, 196))	('effects', 'Reg', (267, 274))	('Cx43', 'Gene', '14609', (231, 235))	('CX', 'Gene', '100128922', (321, 323))
35203	22699423	These data show that deletion of Cx43 in SCs leads to changes in the expression of multiple genes in prepubertal mice, and affects primarily germ cells.	('Cx43', 'Gene', '14609', (33, 37))	('SCs', 'Gene', (41, 44))	('changes', 'Reg', (54, 61))	('Cx43', 'Gene', (33, 37))	('affects', 'Reg', (123, 130))	('deletion', 'Var', (21, 29))	('expression of multiple genes', 'MPA', (69, 97))	('mice', 'Species', '10090', (113, 117))
35218	16333245	Increased dysadherin expression was correlated with aberrant E-cadherin expression in most tumours.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('E-cadherin', 'Gene', (61, 71))	('tumours', 'Disease', (91, 98))	('expression', 'MPA', (21, 31))	('E-cadherin', 'Gene', '999', (61, 71))	('expression', 'MPA', (72, 82))	('Increased', 'PosReg', (0, 9))	('aberrant', 'Var', (52, 60))	('dysadherin', 'Gene', (10, 20))	('dysadherin', 'Gene', '53827', (10, 20))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
35250	16333245	After washing with PBS for 5 min, the primary antibodies NCC-M53 (dilution 1 : 1000) and CM170B (dilution 1 : 50) were applied for incubation (30 min at room temperature and overnight at 4 C, respectively).	('CM170B', 'Var', (89, 95))	('NCC-M53', 'Gene', (57, 64))	('170B', 'Species', '696258', (91, 95))
35271	16333245	Specifically, aberrant cytoplasmic expression of E-cadherin was detected in most of them (67%), while membranous expression in >50% of neoplastic cells was noted in only eight cases (17%) (Figure 2B and C, Table 1).	('E-cadherin', 'Gene', (49, 59))	('detected', 'Reg', (64, 72))	('E-cadherin', 'Gene', '999', (49, 59))	('aberrant', 'Var', (14, 22))
35311	16333245	Interestingly, spermatocytic seminoma, which is regarded as a low-grade malignancy, showed increased expression of dysadherin and absent E-cadherin, while anaplastic tumours, that have more aggressive behaviour exhibited concomitant high expression of dysadherin and aberrant E-cadherin, similar to that observed in embryonal carcinomas.	('anaplastic tumours', 'Disease', 'MESH:D065646', (155, 173))	('anaplastic tumours', 'Disease', (155, 173))	('absent E-cadherin', 'Phenotype', 'HP:0030117', (130, 147))	('E-cadherin', 'Gene', (276, 286))	('E-cadherin', 'Gene', '999', (276, 286))	('embryonal carcinomas', 'Disease', 'MESH:D018236', (316, 336))	('malignancy', 'Disease', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('dysadherin', 'Gene', '53827', (115, 125))	('increased', 'PosReg', (91, 100))	('absent', 'NegReg', (130, 136))	('expression', 'MPA', (238, 248))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (190, 210))	('dysadherin', 'Gene', '53827', (252, 262))	('embryonal carcinomas', 'Phenotype', 'HP:0002898', (316, 336))	('E-cadherin', 'Gene', (137, 147))	('E-cadherin', 'Gene', '999', (137, 147))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('aberrant', 'Var', (267, 275))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (316, 335))	('dysadherin', 'Gene', (252, 262))	('embryonal carcinomas', 'Disease', (316, 336))	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('spermatocytic seminoma', 'Disease', (15, 37))	('dysadherin', 'Gene', (115, 125))	('spermatocytic seminoma', 'Phenotype', 'HP:0100617', (15, 37))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('expression', 'MPA', (101, 111))	('spermatocytic seminoma', 'Disease', 'MESH:C563236', (15, 37))
35314	16333245	Increased dysadherin expression was correlated with aberrant E-cadherin expression.	('E-cadherin', 'Gene', (61, 71))	('expression', 'MPA', (21, 31))	('E-cadherin', 'Gene', '999', (61, 71))	('expression', 'MPA', (72, 82))	('Increased', 'PosReg', (0, 9))	('aberrant', 'Var', (52, 60))	('dysadherin', 'Gene', (10, 20))	('dysadherin', 'Gene', '53827', (10, 20))
35320	16333245	Many other factors may also be involved, such as methylation of the promoter region, gene mutation, involvement of snail, sip-1, and slug transcription factors, ubiquination of E-cadherin, tyrosine phosphorylation of a-catenin, as well as catenin abnormalities, such as absence of alpha-catenin.	('E-cadherin', 'Gene', (177, 187))	('snail', 'Gene', (115, 120))	('methylation', 'MPA', (49, 60))	('mutation', 'Var', (90, 98))	('a-catenin', 'Chemical', '-', (285, 294))	('men', 'Species', '9606', (107, 110))	('tyrosine phosphorylation', 'MPA', (189, 213))	('a-catenin', 'Chemical', '-', (217, 226))	('E-cadherin', 'Gene', '999', (177, 187))	('alpha-catenin', 'Protein', (281, 294))	('sip-1', 'Gene', '9839', (122, 127))	('ubiquination', 'MPA', (161, 173))	('snail', 'Gene', '6615', (115, 120))	('a-catenin', 'Protein', (217, 226))	('sip-1', 'Gene', (122, 127))	('tyrosine', 'Chemical', 'MESH:D014443', (189, 197))
35361	33510591	Imaging for suspected T1a-T1b renal tumors and complex cysts were delayed for 6-9 months.	('renal tumors', 'Disease', 'MESH:D007674', (30, 42))	('renal tumors', 'Disease', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('T1a-T1b', 'Var', (22, 29))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('renal tumors', 'Phenotype', 'HP:0009726', (30, 42))
35432	33455540	Analysis of the association between LNR/LNC and clinical pathological characteristics showed that high LNR patients tended to have significantly larger tumor sizes (chi2 = 7.877, P = 0.005), as well as advanced T (chi2 = 13.195, P = 0.004), N ( chi2 = 86.775, P < 0.001), M (chi2 = 19.948, P < 0.001) and 7th AJCC (chi2 = 103.074, P < 0.001) stages.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('larger', 'PosReg', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('high', 'Var', (98, 102))	('tumor', 'Disease', (152, 157))	('7th AJCC', 'Disease', (305, 313))	('LNR', 'Gene', (103, 106))	('patients', 'Species', '9606', (107, 115))
35433	33455540	In addition, high LNC patients were significantly associated with T (chi2 = 8.799, P = 0.032), N (chi2 = 74.390, P < 0.001) and 7th AJCC (chi2 = 111.759, P < 0.001) stages.	('7th AJCC', 'Disease', (128, 136))	('patients', 'Species', '9606', (22, 30))	('high LNC', 'Var', (13, 21))
35434	33455540	LNR was a better predictor for long-term prognosis and was closely associated with clinical pathological characteristics than LNC in patients with testicular germ cell tumors.	('germ cell tumor', 'Phenotype', 'HP:0100728', (158, 173))	('germ cell tumors', 'Phenotype', 'HP:0100728', (158, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (133, 141))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('associated', 'Reg', (67, 77))	('LNR', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
35442	33455540	Although numerous studies have demonstrated the potential prognostic value for LNC and LNR in various cancers, their clinical prognostic roles in testicular germ cell tumor remain unknown.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('germ cell tumor', 'Phenotype', 'HP:0100728', (157, 172))	('LNC', 'Var', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancers', 'Disease', (102, 109))	('LNR', 'Gene', (87, 90))	('tumor', 'Disease', (167, 172))
35457	33455540	We found that high LNR patients tended to have significantly larger tumor sizes (chi2 = 7.877, P = 0.005), advanced T (chi2 = 13.195, P = 0.004), N stage ( chi2 = 86.775, P < 0.001), M stage (chi2 = 19.948, P < 0.001) and 7th AJCC (chi2 = 103.074, P < 0.001) stages.	('tumor', 'Disease', (68, 73))	('7th AJCC', 'CPA', (222, 230))	('M stage', 'CPA', (183, 190))	('patients', 'Species', '9606', (23, 31))	('high LNR', 'Var', (14, 22))	('N stage', 'CPA', (146, 153))	('larger', 'PosReg', (61, 67))	('advanced T', 'CPA', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
35481	33455540	Our results showed that LNR, rather than LNC, could predict both overall and cancer specific survival time for patients.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('LNR', 'Var', (24, 27))	('patients', 'Species', '9606', (111, 119))
35497	32158433	Both ALA and cis-9, trans-11 CLA reduced the CCND2 expression and cis-9, trans-11 CLA induced apoptosis.	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (66, 85))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (13, 32))	('expression', 'MPA', (51, 61))	('reduced', 'NegReg', (33, 40))	('CCND2', 'Gene', (45, 50))	('cis-9', 'Var', (66, 71))	('ALA', 'Chemical', 'MESH:D017962', (5, 8))	('apoptosis', 'CPA', (94, 103))
35510	32158433	Among other dietary fats, conjugated linoleic acid (CLA) isomers (cis-9, trans-11 and trans-10, cis-12) comprise a group of PUFA derived from LA during incomplete biohydrogenation by the ruminal flora in cattle and sheep.	('trans-10, cis-12', 'Chemical', '-', (86, 102))	('CLA', 'Chemical', 'MESH:D044243', (52, 55))	('trans-10', 'Var', (86, 94))	('cattle', 'Species', '9913', (204, 210))	('cis-9, trans-11', 'Chemical', 'MESH:C046938', (66, 81))	('sheep', 'Species', '9940', (215, 220))	('linoleic acid', 'Chemical', 'MESH:D019787', (37, 50))	('fats', 'Chemical', 'MESH:D005223', (20, 24))	('cis-12', 'Var', (96, 102))
35535	32158433	The IVP protocol was executed using the IVF Bioscience media suite formulated for bovine embryo production according to the manufacturer's instructions (IVF Bioscience, Falmouth, United Kingdom, catalog # 61002, 61004, 61003, 61010, 61001, and 62000).	('IVF Bioscience', 'Disease', 'None', (153, 167))	('bovine', 'Species', '9913', (82, 88))	('61003', 'Var', (219, 224))	('IVF Bioscience', 'Disease', 'None', (40, 54))	('61010', 'Var', (226, 231))	('IVF Bioscience', 'Disease', (153, 167))	('IVF Bioscience', 'Disease', (40, 54))
35552	32158433	While cis-9, trans-11 CLA isomer was significantly higher (P < 0.05) in the CLA and EFA+CLA diet groups with 0.4 +- 0.12% and 0.29 +- 0.03%, as compared to the CTRL and EFA diet groups (0.15 +- 0.15% and 0.07 +- 0.03%).	('EFA', 'Chemical', '-', (169, 172))	('CLA', 'Chemical', 'MESH:D044243', (76, 79))	('cis-9', 'Var', (6, 11))	('CLA', 'Chemical', 'MESH:D044243', (22, 25))	('EFA', 'Chemical', '-', (84, 87))	('CLA', 'Chemical', 'MESH:D044243', (88, 91))	('higher', 'PosReg', (51, 57))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (6, 25))
35553	32158433	Further, due to higher proportions of ALA and cis-9, trans-11 CLA in FF, we speculate that GC are exposed to relatively high levels of ALA and cis-9, trans-11 CLA which might affect the functionality of GC residing within.	('ALA', 'Chemical', 'MESH:D017962', (38, 41))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (46, 65))	('ALA', 'Chemical', 'MESH:D017962', (135, 138))	('affect', 'Reg', (175, 181))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (143, 162))	('cis-9', 'Var', (46, 51))
35564	32158433	Cis-9, trans-11 CLA also reduced E2 significantly (P < 0.05) at 30 and 60 muM as compared to the control (Figure 2B).	('reduced', 'NegReg', (25, 32))	('Cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (0, 19))	('Cis-9', 'Var', (0, 5))
35576	32158433	Whereas, GC treated with cis-9, trans-11 CLA at 60 muM resulted in higher percentage of apoptotic cells (16.3 +- 3.1%) compared to control (10.5 +- 3%).	('trans-11 CLA', 'Var', (32, 44))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (25, 44))	('apoptotic cells', 'CPA', (88, 103))
35578	32158433	The percentage of dead cells in GC treated with cis-9, trans-11 CLA at 30 and 60 muM (12.2 +- 2.2% and 12.4 +- 1.5%, respectively) were significantly higher as compared to the control (8 +- 1.6%).	('higher', 'PosReg', (150, 156))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (48, 67))	('trans-11 CLA', 'Var', (55, 67))	('cis-9', 'Var', (48, 53))
35579	32158433	These results were well reflected by the percentage of viable cells going significantly down to 67.5 +- 2.8% in GC treated with 60 muM cis-9, trans-11 CLA as compare to 78.3 +- 1.8% in the control (Table 3).	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (135, 154))	('down', 'NegReg', (88, 92))	('cis-9', 'Var', (135, 140))
35580	32158433	Dietary lipid supplementation is supposed to improve fertility in dairy cows by increasing the size of the ovulatory follicle, plasma concentration of P4 and lifespan of CL though, the influence on reproductive performance is by far not fully understood.	('fertility', 'CPA', (53, 62))	('cows', 'Species', '9913', (72, 76))	('size of the ovulatory follicle', 'CPA', (95, 125))	('plasma concentration of P4', 'MPA', (127, 153))	('improve', 'PosReg', (45, 52))	('improve fertility', 'Phenotype', 'HP:0000144', (45, 62))	('lipid', 'Chemical', 'MESH:D008055', (8, 13))	('lifespan', 'CPA', (158, 166))	('rat', 'Species', '10116', (141, 144))	('supplementation', 'Var', (14, 29))	('ovulatory follicle', 'Phenotype', 'HP:0031067', (107, 125))	('increasing', 'PosReg', (80, 90))
35582	32158433	Following dietary supplementations, as expected we observed a higher percentage of ALA in the FF of EFA and EFA + CLA diet fed cows, while the percentage of the cis-9, trans-11 CLA was higher in the FF of CLA and EFA+CLA diet fed cows as compared to the CTRL diet fed cows.	('cows', 'Species', '9913', (268, 272))	('EFA', 'Chemical', '-', (108, 111))	('CLA', 'Chemical', 'MESH:D044243', (114, 117))	('CLA', 'Chemical', 'MESH:D044243', (217, 220))	('CLA', 'Chemical', 'MESH:D044243', (177, 180))	('cis-9', 'Var', (161, 166))	('ALA', 'Chemical', 'MESH:D017962', (83, 86))	('CLA', 'Chemical', 'MESH:D044243', (205, 208))	('higher', 'PosReg', (62, 68))	('cows', 'Species', '9913', (127, 131))	('EFA', 'Chemical', '-', (213, 216))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (161, 180))	('cows', 'Species', '9913', (230, 234))	('higher', 'PosReg', (185, 191))	('ALA', 'MPA', (83, 86))	('EFA', 'Chemical', '-', (100, 103))
35588	32158433	In previous studies, Holstein cows when fed with diets enriched in PUFA especially 18:2 and 18:3 FA despite improving dominant follicle size and CL volume failed to improve both cleavage and blastocyst rates of in vitro produced embryos.	('cleavage', 'CPA', (178, 186))	('18:3', 'Var', (92, 96))	('CL volume', 'CPA', (145, 154))	('cows', 'Species', '9913', (30, 34))	('rat', 'Species', '10116', (202, 205))	('dominant follicle size', 'CPA', (118, 140))	('blastocyst rates', 'CPA', (191, 207))	('improving', 'PosReg', (108, 117))
35594	32158433	In the present study we speculate that adverse effects of EFA and CLA diets on oocyte competence could be associated with higher proportions of ALA and cis-9, trans-11 CLA as observed in the FF.	('cis-9', 'Var', (152, 157))	('CLA', 'Chemical', 'MESH:D044243', (66, 69))	('ALA', 'Chemical', 'MESH:D017962', (144, 147))	('higher', 'PosReg', (122, 128))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (152, 171))	('oocyte competence', 'CPA', (79, 96))	('CLA', 'Chemical', 'MESH:D044243', (168, 171))	('EFA', 'Chemical', '-', (58, 61))
35598	32158433	Furthermore, the selective dietary uptake of EFA and CLA supplementation leading to increased proportions of ALA and cis-9, trans-11 CLA in the follicular fluid might adversely affect developmental competence of oocytes residing within the follicles.	('EFA', 'Chemical', '-', (45, 48))	('developmental competence', 'CPA', (184, 208))	('affect', 'Reg', (177, 183))	('trans-11', 'Var', (124, 132))	('CLA', 'Chemical', 'MESH:D044243', (53, 56))	('increased', 'PosReg', (84, 93))	('CLA', 'Chemical', 'MESH:D044243', (133, 136))	('ALA', 'Chemical', 'MESH:D017962', (109, 112))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (117, 136))
35599	32158433	In vitro supplementation of ALA and cis-9, trans-11 CLA induced significant alterations of the morphology of cultured GC.	('alterations', 'Reg', (76, 87))	('morphology of cultured GC', 'CPA', (95, 120))	('rat', 'Species', '10116', (80, 83))	('ALA', 'Chemical', 'MESH:D017962', (28, 31))	('cis-9', 'Var', (36, 41))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (36, 55))
35603	32158433	Cis-9, trans-11 CLA induced lipid accumulation in human macrophages and in mice 15P-1 cell lines (testicular cells) along with an elevated expression of CD36.	('mice', 'Species', '10090', (75, 79))	('CD36', 'Protein', (153, 157))	('lipid accumulation', 'MPA', (28, 46))	('Cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (0, 19))	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('elevated', 'PosReg', (130, 138))	('CD36', 'Species', '42374', (153, 157))	('Cis-9', 'Var', (0, 5))	('expression', 'MPA', (139, 149))	('human', 'Species', '9606', (50, 55))
35607	32158433	Inducible deletion of FOXL2 in adult ovarian follicles can upregulate the testis-specific marker gene SOX9.	('FOXL2', 'Gene', (22, 27))	('FOXL2', 'Gene', '281770', (22, 27))	('deletion', 'Var', (10, 18))	('SOX9', 'Gene', '100336535', (102, 106))	('upregulate', 'PosReg', (59, 69))	('SOX9', 'Gene', (102, 106))
35619	32158433	The transcript level of STAR as well as the E2 production was significantly downregulated by both ALA and cis-9, trans-11 CLA.	('E2 production', 'MPA', (44, 57))	('STAR', 'Gene', '281507', (24, 28))	('STAR', 'Gene', (24, 28))	('cis-9', 'Var', (106, 111))	('downregulated', 'NegReg', (76, 89))	('ALA', 'Chemical', 'MESH:D017962', (98, 101))	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (106, 125))	('transcript level', 'MPA', (4, 20))
35630	32158433	Surprisingly, cis-9, trans-11 CLA significantly upregulated HSD3B1 gene expression while reducing the P4 concentration in conditioned media.	('cis-9, trans-11 CLA', 'Chemical', 'MESH:C503589', (14, 33))	('reducing', 'NegReg', (89, 97))	('HSD3B1 gene', 'Gene', (60, 71))	('expression', 'MPA', (72, 82))	('rat', 'Species', '10116', (112, 115))	('cis-9', 'Var', (14, 19))	('upregulated', 'PosReg', (48, 59))	('P4 concentration in conditioned', 'MPA', (102, 133))
35635	32158433	However, only cis-9, trans-11CLA could elicit significant apoptotic effects in GC.	('cis-9, trans-11CLA', 'Chemical', 'MESH:C046938', (14, 32))	('apoptotic effects', 'CPA', (58, 75))	('elicit', 'Reg', (39, 45))	('cis-9', 'Var', (14, 19))
35637	32158433	CCND2 mRNA expression is FSH dependent as reported in FSHR null mutant mice exhibiting decreased CCND2 mRNA levels.	('mice', 'Species', '10090', (71, 75))	('mRNA levels', 'MPA', (103, 114))	('decreased', 'NegReg', (87, 96))	('CCND2', 'MPA', (97, 102))	('mutant', 'Var', (64, 70))
35641	32158433	According to previous immunocytochemistry studies different cis-9,trans-11 CLA concentrations at different time periods could significantly decrease the PCNA expression and inhibit cell growth and proliferation in mammary cancer cells (MCF-7 cells) and in gastric adenocarcinoma cell lines (SGC-7901).	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (256, 278))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('gastric adenocarcinoma', 'Disease', (256, 278))	('cis-9,trans-11 CLA', 'Chemical', 'MESH:C503589', (60, 78))	('cancer', 'Disease', (222, 228))	('cis-9', 'Var', (60, 65))	('rat', 'Species', '10116', (204, 207))	('decrease', 'NegReg', (140, 148))	('MCF-7', 'CellLine', 'CVCL:0031', (236, 241))	('PCNA', 'Protein', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('SGC-7901', 'CellLine', 'CVCL:0520', (291, 299))	('rat', 'Species', '10116', (86, 89))	('inhibit', 'NegReg', (173, 180))
35644	32158433	Further, the study clearly suggests that GC morphology and functionality could be considerably affected with increased follicular proportions of ALA and cis9, trans-11CLA particularly constraining steroidogenesis in GC.	('cis9,', 'Chemical', '-', (153, 158))	('follicular proportions of ALA', 'CPA', (119, 148))	('increased follicular proportions', 'Phenotype', 'HP:0100874', (109, 141))	('trans-11CLA', 'Chemical', '-', (159, 170))	('GC morphology', 'CPA', (41, 54))	('constraining', 'NegReg', (184, 196))	('ALA', 'Chemical', 'MESH:D017962', (145, 148))	('trans-11CLA', 'Var', (159, 170))	('steroidogenesis', 'MPA', (197, 212))	('steroid', 'Chemical', 'MESH:D013256', (197, 204))	('increased', 'PosReg', (109, 118))	('affected', 'Reg', (95, 103))
35745	31145458	Non-Hispanic male and female patients had higher overall cancer death rates than those of Hispanic ethnicity.	('patients', 'Species', '9606', (29, 37))	('cancer death', 'Disease', (57, 69))	('higher', 'PosReg', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer death', 'Disease', 'MESH:D009369', (57, 69))	('Non-Hispanic', 'Var', (0, 12))
35899	26005633	DNA Methylation and Flavonoids in Genitourinary Cancers Malignancies of the genitourinary system have some of the highest cancer incidence and mortality rates.	('Flavonoids', 'Chemical', 'MESH:D005419', (20, 30))	('Malignancies', 'Disease', (56, 68))	('Genitourinary Cancers', 'Disease', 'MESH:D014565', (34, 55))	('Cancers Malignancies of the genitourinary system', 'Phenotype', 'HP:0007379', (48, 96))	('Genitourinary Cancers', 'Disease', (34, 55))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('genitourinary system', 'Phenotype', 'HP:0000119', (76, 96))	('Flavonoids', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Cancers', 'Phenotype', 'HP:0002664', (48, 55))	('Malignancies', 'Disease', 'MESH:D009369', (56, 68))
35903	26005633	Hypomethylation leads to activation of cancer-causing genes with global DNA hypomethylation being commonly associated with metastatic disease.	('global', 'Var', (65, 71))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('Hypomethylation', 'Var', (0, 15))	('metastatic disease', 'Disease', (123, 141))	('associated', 'Reg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('activation', 'PosReg', (25, 35))
35904	26005633	Hypermethylation-mediated silencing of tumor suppressive genes is commonly associated with cancer development.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('men', 'Species', '9606', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Hypermethylation-mediated', 'Var', (0, 25))	('silencing', 'NegReg', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (39, 44))	('associated', 'Reg', (75, 85))
35908	26005633	Epigenetic changes that modify the contact between transcription machinery and gene promoters can lead to aberrant activation or inhibition of numerous signaling cascades resulting in different diseases including cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('activation', 'PosReg', (115, 125))	('lead to', 'Reg', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('contact', 'Interaction', (35, 42))	('inhibition', 'NegReg', (129, 139))	('cancer', 'Disease', (213, 219))	('Epigenetic changes', 'Var', (0, 18))
35924	26005633	In this chapter we discuss DNA methylation changes in different genitourinary cancers (summarized in table 1), their ability to modulate expression of genes involved in cancer development and progression and the role of flavonoids in regulating epigenetic modifications in these malignancies.	('modulate', 'Reg', (128, 136))	('cancer', 'Disease', (169, 175))	('expression', 'MPA', (137, 147))	('genitourinary cancers', 'Disease', 'MESH:D014565', (64, 85))	('flavonoids', 'Chemical', 'MESH:D005419', (220, 230))	('malignancies', 'Disease', 'MESH:D009369', (279, 291))	('men', 'Species', '9606', (183, 186))	('cancer', 'Disease', (78, 84))	('changes', 'Var', (43, 50))	('genitourinary cancers', 'Disease', (64, 85))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('methylation changes', 'Var', (31, 50))	('malignancies', 'Disease', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
35925	26005633	DNA methylation at palindromic CpG sites by DNA methyltransferases (DNMTs) generates a pattern of methylated CpG dinucleotides at the 5' end of the promoter of human genes.	('human', 'Species', '9606', (160, 165))	('methylated', 'MPA', (98, 108))	('methylation', 'Var', (4, 15))
35926	26005633	Methylation is a mechanism to control embryonic development, silence the X-chromosome, and prevent unwanted transcription etc.	('prevent', 'NegReg', (91, 98))	('X-chromosome', 'Protein', (73, 85))	('men', 'Species', '9606', (55, 58))	('silence', 'NegReg', (61, 68))	('Methylation', 'Var', (0, 11))	('transcription', 'MPA', (108, 121))	('embryonic development', 'CPA', (38, 59))
35928	26005633	DNMT1 shows a preference for hemimethylated DNA and is considered to be a maintenance enzyme that keeps the methylation pattern intact after DNA replication.	('hemimethylated', 'Var', (29, 43))	('methylation pattern', 'MPA', (108, 127))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))
35934	26005633	However, the theory of demethylation of oncogenes leading to their activation has been replaced by the growing popularity of hypermethylation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('demethylation', 'Var', (23, 36))	('activation', 'PosReg', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('oncogenes', 'Protein', (40, 49))
35936	26005633	As discussed below DNA methylation plays an important role in genitourinary cancers through the modulation of numerous genes that play critical roles in cancer cell biology.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('genitourinary cancers', 'Disease', (62, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancer', 'Disease', (153, 159))	('methylation', 'Var', (23, 34))	('genes', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('genitourinary cancers', 'Disease', 'MESH:D014565', (62, 83))	('modulation', 'Reg', (96, 106))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
35937	26005633	Genes involved in regulation of cellular processes such as hormone response, cell cycle progression, DNA damage and repair, signal transduction, tumor invasion and architecture have deregulated hypermethylation providing the needed advantage to the sustenance of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('advantage', 'PosReg', (232, 241))	('cancer', 'Disease', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('hypermethylation', 'MPA', (194, 210))	('deregulated', 'Var', (182, 193))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))
35938	26005633	The tumor suppressor, PTEN is commonly silenced by promoter methylation in many of the genitourinary cancers.	('tumor', 'Disease', (4, 9))	('genitourinary cancers', 'Disease', (87, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('PTEN', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('genitourinary cancers', 'Disease', 'MESH:D014565', (87, 108))	('PTEN', 'Gene', '5728', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('promoter methylation', 'Var', (51, 71))
35939	26005633	PTEN hypermethylation is an early event seen in patients with recurrent or fatal cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancer', 'Disease', (81, 96))	('hypermethylation', 'Var', (5, 21))	('PTEN', 'Gene', (0, 4))	('patients', 'Species', '9606', (48, 56))	('PTEN', 'Gene', '5728', (0, 4))
35942	26005633	In cervical cancer cells hypermethylation of RASSF1A is a mechanism through which cervical cancer cells extinguish death receptor mediated cell death.	('hypermethylation', 'Var', (25, 41))	('RASSF1A', 'Gene', (45, 52))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('death', 'Disease', 'MESH:D003643', (144, 149))	('cervical cancer', 'Disease', (82, 97))	('death', 'Disease', (144, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (82, 97))	('cervical cancer', 'Disease', (3, 18))	('RASSF1A', 'Gene', '11186', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('death', 'Disease', 'MESH:D003643', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('death', 'Disease', (115, 120))	('extinguish', 'NegReg', (104, 114))
35943	26005633	Aberrant DNA methylation of POU2F3 promoter, which is a transcription factor with putative tumor suppressive function involved in cell type-specific differentiation, is common in cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('POU2F3', 'Gene', '25833', (28, 34))	('Aberrant DNA methylation', 'Var', (0, 24))	('common', 'Reg', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cervical cancer', 'Disease', 'MESH:D002583', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('POU2F3', 'Gene', (28, 34))	('cervical cancer', 'Disease', (179, 194))	('tumor', 'Disease', (91, 96))
35944	26005633	Testisin, a putative tumor suppressor and testicular protease involved in sperm cell maturation and the CDK inhibitor, p16INK4a are hypermethylated in testicular cancer.	('testicular cancer', 'Disease', (151, 168))	('hypermethylated', 'Var', (132, 147))	('tumor', 'Disease', (21, 26))	('p16INK4a', 'Gene', (119, 127))	('Testisin', 'Gene', '10942', (0, 8))	('p16INK4a', 'Gene', '1029', (119, 127))	('testicular cancer', 'Disease', 'MESH:D013736', (151, 168))	('testicular cancer', 'Phenotype', 'HP:0010788', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Testisin', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
35945	26005633	Methylation of p16INK4a promoter and subsequent inactivation is involved in the initiation of bladder cancer.	('p16INK4a', 'Gene', (15, 23))	('involved', 'Reg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('initiation of bladder cancer', 'Disease', 'MESH:D001749', (80, 108))	('Methylation', 'Var', (0, 11))	('p16INK4a', 'Gene', '1029', (15, 23))	('inactivation', 'NegReg', (48, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('initiation of bladder cancer', 'Disease', (80, 108))
35946	26005633	Hypermethylation of the other gene product of CDKN2A, p14 in normal bladder samples after resection has been found to be a predictor of bladder cancer recurrence.	('p14', 'Gene', '1029', (54, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('CDKN2A', 'Gene', (46, 52))	('Hypermethylation', 'Var', (0, 16))	('CDKN2A', 'Gene', '1029', (46, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (136, 161))	('p14', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
35947	26005633	The most important genetic event in ccRCC is the hypermethylation-mediated inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which stabilizes hypoxia-inducible transcription factors HIF-1 and HIF-2 and the induction of a multitude of hypoxia inducible genes.	('hypermethylation-mediated inactivation', 'Var', (49, 87))	('RCC', 'Disease', (38, 41))	('stabilizes', 'PosReg', (148, 158))	('inactivation', 'Var', (75, 87))	('hypoxia', 'Disease', (251, 258))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (199, 214))	('hypoxia', 'Disease', 'MESH:D000860', (251, 258))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (95, 124))	('hypoxia', 'Disease', 'MESH:D000860', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hypoxia', 'Disease', (159, 166))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
35948	26005633	RASSF1 is frequently methylated in sporadic RCC (either biallelically or as a second hit following 3p deletion).	('methylated', 'Var', (21, 31))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RASSF1', 'Gene', '11186', (0, 6))	('RCC', 'Disease', (44, 47))	('RASSF1', 'Gene', (0, 6))
35949	26005633	RASSF1A methylation was detected in normal kidney tissues adjacent to the tumor but not in distant normal tissues indicating that the TSG methylation is part of a 'field effect' and an early event in cancer development causing epigenetic alterations in a large number of cells which is then accompanied by additional genetic and epigenetic changes.	('causing', 'Reg', (219, 226))	('RASSF1A', 'Gene', (0, 7))	('TSG', 'Gene', '57045', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epigenetic alterations', 'MPA', (227, 249))	('RASSF1A', 'Gene', '11186', (0, 7))	('tumor', 'Disease', (74, 79))	('methylation', 'Var', (138, 149))	('men', 'Species', '9606', (214, 217))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('TSG', 'Gene', (134, 137))	('cancer', 'Disease', (200, 206))
35950	26005633	Another tumor suppressor gene TU3A (located at 3p21.1) is also found to be methylated in 42% of ccRCC and 25% of pRCC.	('methylated', 'Var', (75, 85))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('TU3A', 'Gene', '11170', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TU3A', 'Gene', (30, 34))	('RCC', 'Disease', (98, 101))	('pRCC', 'Gene', '5546', (113, 117))	('tumor', 'Disease', (8, 13))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('pRCC', 'Gene', (113, 117))
35952	26005633	Methylation of RARbeta, which regulates cell proliferation and differentiation, is also reported in less than 20% of RCC cases.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RARbeta', 'Gene', (15, 22))	('Methylation', 'Var', (0, 11))	('reported', 'Reg', (88, 96))	('RARbeta', 'Gene', '5915', (15, 22))
35954	26005633	Interestingly late-stage prostate cancer tissues have methylated AR promoters implicating methylation of AR promoter as a late event in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (136, 151))	('AR', 'Gene', '367', (105, 107))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('prostate cancer', 'Disease', (25, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('AR', 'Gene', '367', (65, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('methylated', 'Var', (54, 64))
35957	26005633	Methylation of progesterone receptor (PR) is found in some prostate cancer cell lines and is believed to also be a late stage event in prostate cancer.	('prostate cancer', 'Disease', (135, 150))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('Methylation', 'Var', (0, 11))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('progesterone receptor', 'Gene', (15, 36))	('progesterone receptor', 'Gene', '5241', (15, 36))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('PR', 'Gene', '5241', (38, 40))	('prostate cancer', 'Disease', (59, 74))	('found', 'Reg', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
35958	26005633	Estrogen and progesterone receptor genes are also methylated in cervical cancer.	('methylated', 'Var', (50, 60))	('cervical cancer', 'Disease', (64, 79))	('cervical cancer', 'Disease', 'MESH:D002583', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('progesterone receptor', 'Gene', (13, 34))	('progesterone receptor', 'Gene', '5241', (13, 34))
35963	26005633	Transcriptional silencing of apoptosis-related genes such as Death-associated Kinase (DAPK) due to aberrant promoter methylation leads to the impairment of the apoptotic machinery and disrupts cell growth and death homeostasis in prostate and cervical cancer cells.	('aberrant', 'Var', (99, 107))	('apoptotic machinery', 'CPA', (160, 179))	('death homeostasis in prostate', 'Disease', (209, 238))	('promoter', 'MPA', (108, 116))	('cervical cancer', 'Disease', (243, 258))	('cervical cancer', 'Disease', 'MESH:D002583', (243, 258))	('silencing', 'NegReg', (16, 25))	('impairment', 'NegReg', (142, 152))	('men', 'Species', '9606', (148, 151))	('DAPK', 'Gene', (86, 90))	('DAPK', 'Gene', '1612', (86, 90))	('death homeostasis in prostate', 'Disease', 'MESH:D003643', (209, 238))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('apoptosis-related genes', 'Gene', (29, 52))	('disrupts', 'NegReg', (184, 192))
35969	26005633	Methylation of the MGMT promoter leads to its inactivation and the development of non-seminomatous testicular cancer and is also seen in cervical cancer.	('inactivation', 'MPA', (46, 58))	('Methylation', 'Var', (0, 11))	('cervical cancer', 'Disease', 'MESH:D002583', (137, 152))	('testicular cancer', 'Phenotype', 'HP:0010788', (99, 116))	('MGMT', 'Gene', '4255', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('non-seminomatous testicular cancer', 'Disease', (82, 116))	('MGMT', 'Gene', (19, 23))	('cervical cancer', 'Disease', (137, 152))	('men', 'Species', '9606', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-seminomatous testicular cancer', 'Disease', 'MESH:C537844', (82, 116))
35971	26005633	Promoter hypermethylation of BRCA1 observed in ovarian cancer may be an alternative mechanism in silencing the tumor suppressive function of this gene in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('silencing', 'NegReg', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ovarian cancer', 'Disease', (47, 61))	('BRCA1', 'Gene', '672', (29, 34))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ovarian cancer', 'Disease', (154, 168))	('BRCA1', 'Gene', (29, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))	('Promoter hypermethylation', 'Var', (0, 25))
35973	26005633	Methylation of LAMA3 and LAMB3 has been found to be associated with poor grade and stage in bladder cancer while the methylation of LAMC2 has been linked to a drop in survival time in patients.	('patients', 'Species', '9606', (184, 192))	('LAMA3', 'Gene', (15, 20))	('Methylation', 'Var', (0, 11))	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('LAMB3', 'Gene', (25, 30))	('LAMC2', 'Gene', (132, 137))	('LAMA3', 'Gene', '3909', (15, 20))	('drop', 'NegReg', (159, 163))	('survival', 'MPA', (167, 175))	('methylation', 'Var', (117, 128))	('LAMC2', 'Gene', '3918', (132, 137))	('LAMB3', 'Gene', '3914', (25, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))
35974	26005633	Aberrant methylation LN5 gene and E-cadherin has been found to correlate with clinicopathological features and invasion in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('prostate cancer', 'Disease', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('E-cadherin', 'Gene', (34, 44))	('LN5 gene', 'Gene', (21, 29))	('E-cadherin', 'Gene', '999', (34, 44))	('Aberrant methylation', 'Var', (0, 20))	('correlate', 'Reg', (63, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))
35975	26005633	Other genes implicated in tumor invasion such as Familial adenomatous polyposis (APC), (Caveolin 1CAV 1), Cadherin 1CD44 Cluster differentiation antigen (CDH1), alpha-3 Laminin (LAMA 3), gamma2 Laminin (LAM C2), TIMP3 have also been found to undergo hypermethylation in prostate cancer.	('LAM C2', 'Gene', (203, 209))	('Familial adenomatous polyposis', 'Disease', 'MESH:D011125', (49, 79))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (58, 79))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('prostate cancer', 'Disease', 'MESH:D011471', (270, 285))	('tumor', 'Disease', (26, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (270, 285))	('CDH1', 'Gene', '999', (154, 158))	('prostate cancer', 'Disease', (270, 285))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('hypermethylation', 'Var', (250, 266))	('TIMP3', 'Gene', (212, 217))	('TIMP3', 'Gene', '7078', (212, 217))	('APC', 'Disease', 'MESH:D011125', (81, 84))	('CDH1', 'Gene', (154, 158))	('LAMA 3', 'Gene', '3909', (178, 184))	('LAMA 3', 'Gene', (178, 184))	('APC', 'Disease', (81, 84))	('LAM C2', 'Gene', '3918', (203, 209))	('Familial adenomatous polyposis', 'Disease', (49, 79))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
35976	26005633	In bladder cancer, down regulation of the CDH1 gene through promoter hypermethylation is frequently correlated with staging and grading of bladder cancer but the relation with methylation patterns is somewhat inconsistent with other studies showing high to low level of methylation at the promoter of CDH1 in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (139, 153))	('bladder cancer', 'Disease', (139, 153))	('CDH1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('CDH1', 'Gene', '999', (42, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (309, 323))	('CDH1', 'Gene', (301, 305))	('promoter hypermethylation', 'Var', (60, 85))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('bladder cancer', 'Disease', 'MESH:D001749', (309, 323))	('bladder cancer', 'Disease', (309, 323))	('bladder cancer', 'Disease', (3, 17))	('down regulation', 'NegReg', (19, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (139, 153))	('CDH1', 'Gene', '999', (301, 305))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))
35977	26005633	Promoter methylation of E-cadherin is also seen in cervical cancer.	('E-cadherin', 'Gene', '999', (24, 34))	('E-cadherin', 'Gene', (24, 34))	('Promoter methylation', 'Var', (0, 20))	('seen', 'Reg', (43, 47))	('cervical cancer', 'Disease', (51, 66))	('cervical cancer', 'Disease', 'MESH:D002583', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
35978	26005633	Other cell adhesion genes including OPCML, ICAM-1and CDH1 are hypermethylated in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('OPCML', 'Gene', (36, 41))	('ovarian cancer', 'Disease', (81, 95))	('ICAM-1', 'Gene', '3383', (43, 49))	('hypermethylated', 'Var', (62, 77))	('CDH1', 'Gene', (53, 57))	('ICAM-1', 'Gene', (43, 49))	('OPCML', 'Gene', '4978', (36, 41))	('CDH1', 'Gene', '999', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
35980	26005633	Global methylation at long interspersed nuclear elements-1 (LINE-1) is inherited in familial testicular cancer kindred.	('familial testicular cancer', 'Disease', 'MESH:D013736', (84, 110))	('Global methylation', 'Var', (0, 18))	('men', 'Species', '9606', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('familial testicular cancer', 'Disease', (84, 110))	('testicular cancer', 'Phenotype', 'HP:0010788', (93, 110))	('inherited', 'Reg', (71, 80))
35981	26005633	Interestingly, hypermethylation mediated silencing of the small regulatory PIWI-interacting RNAs (piRNAs) including PIWIL1, PIWIL2, PIWIL4, and TDRD1, which regulate male germ line development has been observed in primary seminoma and non-seminoma testicular cancer.	('seminoma', 'Disease', (222, 230))	('PIWIL4', 'Gene', (132, 138))	('PIWIL1', 'Gene', (116, 122))	('PIWIL2', 'Gene', (124, 130))	('seminoma', 'Disease', 'MESH:D018239', (222, 230))	('PIWI', 'Gene', '9271', (132, 136))	('PIWI', 'Gene', '9271', (124, 128))	('TDRD1', 'Gene', '56165', (144, 149))	('non-seminoma testicular cancer', 'Disease', 'MESH:D018239', (235, 265))	('hypermethylation', 'Var', (15, 31))	('PIWI', 'Gene', '9271', (116, 120))	('testicular cancer', 'Phenotype', 'HP:0010788', (248, 265))	('PIWIL4', 'Gene', '143689', (132, 138))	('PIWIL2', 'Gene', '55124', (124, 130))	('PIWI', 'Gene', (132, 136))	('PIWI', 'Gene', (124, 128))	('PIWI', 'Gene', '9271', (75, 79))	('observed', 'Reg', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('men', 'Species', '9606', (188, 191))	('TDRD1', 'Gene', (144, 149))	('PIWI', 'Gene', (116, 120))	('silencing', 'NegReg', (41, 50))	('seminoma', 'Disease', (239, 247))	('non-seminoma testicular cancer', 'Disease', (235, 265))	('PIWIL1', 'Gene', '9271', (116, 122))	('seminoma', 'Disease', 'MESH:D018239', (239, 247))	('PIWI', 'Gene', (75, 79))
35982	26005633	Several genes involved in signal transduction including Dickkopf (DKK3), Endothelin receptor type B (EDNRB), RASSF1A, Runt-related transcription factor 3 (RUNX3) and Secreted frizzled-related protein 1 (SFRP1) have been found to be hypermethylated in prostate cancer.	('SFRP1', 'Gene', '6422', (203, 208))	('Dickkopf', 'Gene', (56, 64))	('RUNX3', 'Gene', '864', (155, 160))	('hypermethylated', 'Var', (232, 247))	('EDNRB', 'Gene', '1910', (101, 106))	('Secreted frizzled-related protein 1', 'Gene', (166, 201))	('EDNRB', 'Gene', (101, 106))	('Endothelin receptor type B', 'Gene', '1910', (73, 99))	('Endothelin receptor type B', 'Gene', (73, 99))	('Secreted frizzled-related protein 1', 'Gene', '6422', (166, 201))	('SFRP1', 'Gene', (203, 208))	('RUNX3', 'Gene', (155, 160))	('DKK3', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('prostate cancer', 'Disease', 'MESH:D011471', (251, 266))	('prostate cancer', 'Phenotype', 'HP:0012125', (251, 266))	('RASSF1A', 'Gene', '11186', (109, 116))	('Runt-related transcription factor 3', 'Gene', '864', (118, 153))	('DKK3', 'Gene', '27122', (66, 70))	('Runt-related transcription factor 3', 'Gene', (118, 153))	('prostate cancer', 'Disease', (251, 266))	('Dickkopf', 'Gene', '22943', (56, 64))	('RASSF1A', 'Gene', (109, 116))
35983	26005633	Loss of DNA methylation was the first reported epigenetic change in human cancer.	('human', 'Species', '9606', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('DNA', 'Protein', (8, 11))	('cancer', 'Disease', (74, 80))	('Loss', 'NegReg', (0, 4))	('methylation', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
35988	26005633	Hypomethylation of gene promoters in cancer are associated with decreased overall genomic methylation or satellite DNA that correlates with increased transcription.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('transcription', 'MPA', (150, 163))	('cancer', 'Disease', (37, 43))	('Hypomethylation', 'Var', (0, 15))	('genomic methylation', 'MPA', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('satellite DNA', 'CPA', (105, 118))	('increased', 'PosReg', (140, 149))	('decreased', 'NegReg', (64, 73))
35989	26005633	Evidence for the contribution of gene-region hypomethylation to oncogenesis suggests a greater involvement in activating genes involved with tumor invasion and metastasis as well as drug-resistance.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('drug-resistance', 'Phenotype', 'HP:0020174', (182, 197))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('activating genes', 'MPA', (110, 126))	('hypomethylation', 'Var', (45, 60))	('tumor', 'Disease', (141, 146))	('men', 'Species', '9606', (102, 105))
35990	26005633	DNA hypomethylation appears to be a late event in prostate cancer contrary to other cancers.	('hypomethylation', 'Var', (4, 19))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('prostate cancer', 'Disease', (50, 65))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
35992	26005633	Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) has been observed in prostate cancer.	('WNT5A', 'Gene', (62, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('observed', 'Reg', (153, 161))	('Hypomethylation', 'Var', (0, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('WNT5A', 'Gene', '7474', (62, 67))	('CRIP1', 'Gene', '1396', (137, 142))	('prostate cancer', 'Disease', (165, 180))	('CRIP1', 'Gene', (137, 142))	('S100P', 'Gene', '6286', (102, 107))	('cysteine', 'Chemical', 'MESH:D003545', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('S100P', 'Gene', (102, 107))	('wingless-related MMTV integration site 5A', 'Gene', '7474', (19, 60))	('wingless-related MMTV integration site 5A', 'Gene', (19, 60))
35994	26005633	Hypomethylation has been found to cause re-expression of previously hypermethylated genes, such as the HRAS, BCL2, ABCB1, S100A4, SNCG, and CCND2, and numerous cancer/testis associated genes in testicular cancer.	('BCL2', 'Gene', (109, 113))	('numerous cancer', 'Disease', (151, 166))	('S100A4', 'Gene', '6275', (122, 128))	('testicular cancer', 'Disease', (194, 211))	('testicular cancer', 'Phenotype', 'HP:0010788', (194, 211))	('SNCG', 'Gene', (130, 134))	('re-expression', 'MPA', (40, 53))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('S100A4', 'Gene', (122, 128))	('numerous cancer', 'Disease', 'MESH:D009369', (151, 166))	('BCL2', 'Gene', '596', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('HRAS', 'Gene', '3265', (103, 107))	('testicular cancer', 'Disease', 'MESH:D013736', (194, 211))	('HRAS', 'Gene', (103, 107))	('CCND2', 'Gene', (140, 145))	('ABCB1', 'Gene', (115, 120))	('ABCB1', 'Gene', '5243', (115, 120))	('CCND2', 'Gene', '894', (140, 145))
35996	26005633	Hypomethylation of satellite DNA has been observed in ovarian cancer and found to increase with stage and grade of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ovarian cancer', 'Disease', 'MESH:D010051', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Hypomethylation', 'Var', (0, 15))	('ovarian cancer', 'Disease', (54, 68))	('ovarian cancer', 'Disease', (115, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (115, 129))	('satellite DNA', 'Gene', (19, 32))	('increase', 'PosReg', (82, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (115, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (54, 68))	('observed', 'Reg', (42, 50))
35998	26005633	Heparanase, an enzyme that acts both on cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides is also regulated by hypomethylation in bladder cancer.	('oligosaccharides', 'Chemical', 'MESH:D009844', (162, 178))	('Heparanase', 'Gene', '10855', (0, 10))	('regulated', 'Reg', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (219, 233))	('Heparanase', 'Gene', (0, 10))	('hypomethylation', 'Var', (200, 215))	('heparan sulfate', 'Chemical', 'MESH:D006497', (110, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (219, 233))	('degrade polymeric heparan sulfate molecules', 'MPA', (92, 135))	('bladder cancer', 'Disease', (219, 233))
36006	26005633	Despite its ability to demethylate p16INK4a gene promoter in colon cancer cells, its ability to modulate DNA methylation in genitourinary cancers remains to be vigorously tested.	('colon cancer', 'Phenotype', 'HP:0003003', (61, 73))	('colon cancer', 'Disease', 'MESH:D015179', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('genitourinary cancers', 'Disease', 'MESH:D014565', (124, 145))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('p16INK4a', 'Gene', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('colon cancer', 'Disease', (61, 73))	('demethylate', 'Var', (23, 34))	('genitourinary cancers', 'Disease', (124, 145))	('p16INK4a', 'Gene', '1029', (35, 43))
36020	26005633	Genistein-mediated modulation of methylation of pro-tumorigenic miRNA-1260b, its targets sFRP1 and Smad4 inhibits prostate cancer cell proliferation, invasion and TCF reporter activity.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('sFRP1', 'Gene', (89, 94))	('tumor', 'Disease', (52, 57))	('sFRP1', 'Gene', '6422', (89, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (114, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('prostate cancer', 'Disease', (114, 129))	('miRNA-1260b', 'Gene', (64, 75))	('TCF', 'Gene', '3172', (163, 166))	('modulation', 'Var', (19, 29))	('Smad4', 'Gene', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('methylation', 'MPA', (33, 44))	('inhibits', 'NegReg', (105, 113))	('Genistein', 'Chemical', 'MESH:D019833', (0, 9))	('TCF', 'Gene', (163, 166))	('invasion', 'CPA', (150, 158))	('Smad4', 'Gene', '4089', (99, 104))
36027	26005633	Curcumin was also observed to decrease CpG promoter methylation of Neurog1, a highly hypermethylated marker in prostate cancer and also the hypermethylation at the promoter region of tumor suppressor retinoic acid receptor 2 gene in cervical cancer.	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (111, 126))	('Neurog1', 'Gene', '4762', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('decrease', 'NegReg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cervical cancer', 'Disease', 'MESH:D002583', (233, 248))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('cervical cancer', 'Disease', (233, 248))	('tumor', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Neurog1', 'Gene', (67, 74))	('CpG promoter methylation', 'MPA', (39, 63))	('hypermethylation', 'Var', (140, 156))
36096	31001201	A possible underlying cause may be the induction of iatrogenic hypogonadism: in fact, orchiectomy, chemotherapy, and radiotherapy may all induce gonadal dysfunction.	('gonadal dysfunction', 'Disease', 'MESH:D006058', (145, 164))	('iatrogenic hypogonadism', 'Disease', (52, 75))	('orchiectomy', 'Disease', (86, 97))	('gonadal dysfunction', 'Disease', (145, 164))	('induce', 'Reg', (138, 144))	('hypogonadism', 'Phenotype', 'HP:0000135', (63, 75))	('radiotherapy', 'Var', (117, 129))	('iatrogenic hypogonadism', 'Disease', 'MESH:D007049', (52, 75))	('chemotherapy', 'Var', (99, 111))
36110	31001201	Radiotherapy can cause sexual dysfunctions by inducing damage to the cavernous nerve and/or progressive fibrosis of the cavernous tissue and endothelial damage, which can become clinically evident through the onset of erectile dysfunction even several years post-treatment.	('erectile dysfunction', 'Phenotype', 'HP:0000802', (218, 238))	('Radiotherapy', 'Var', (0, 12))	('men', 'Species', '9606', (268, 271))	('cause', 'Reg', (17, 22))	('fibrosis', 'Disease', 'MESH:D005355', (104, 112))	('fibrosis', 'Disease', (104, 112))	('damage', 'CPA', (55, 61))	('erectile dysfunction', 'Disease', (218, 238))	('inducing', 'Reg', (46, 54))	('sexual dysfunctions', 'Disease', 'MESH:D012735', (23, 42))	('erectile dysfunction', 'Disease', 'MESH:D007172', (218, 238))	('sexual dysfunctions', 'Disease', (23, 42))
36167	33535586	Gonadal dysfunction with subnormal testosterone levels in TC survivors is common after treatment, which has a major impact on quality of life.	('testosterone', 'Chemical', 'MESH:D013739', (35, 47))	('Gonadal dysfunction', 'Disease', (0, 19))	('subnormal', 'Var', (25, 34))	('men', 'Species', '9606', (92, 95))	('Gonadal dysfunction', 'Disease', 'MESH:D006058', (0, 19))	('TC', 'Phenotype', 'HP:0010788', (58, 60))	('subnormal testosterone levels', 'Phenotype', 'HP:0030087', (25, 54))
36534	24294176	Furthermore, breast cancer risk is associated with presence of single nucleotide polymorphisms (SNP) of KLK2 (Ex5 th 118C>T) or KLK4 (4207C>G).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('4207C>G', 'Mutation', 'g.4207C>G', (134, 141))	('118C>T', 'Mutation', 'c.118C>T', (117, 123))	('Ex5 th 118C>T', 'Var', (110, 123))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('single nucleotide polymorphisms', 'Var', (63, 94))	('KLK2', 'Gene', '3817', (104, 108))	('KLK4', 'Gene', '9622', (128, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('KLK4', 'Gene', (128, 132))	('KLK2', 'Gene', (104, 108))	('4207C>G', 'Var', (134, 141))	('presence', 'Var', (51, 59))
36566	24294176	We envision that selective inhibitors to certain KLKs will be developed for future therapeutic application, that aim at blocking their enzymatic activity, in order to interfere with KLK-mediated degradation or activation of other proteins.	('proteins', 'Protein', (230, 238))	('interfere', 'NegReg', (167, 176))	('enzymatic activity', 'MPA', (135, 153))	('KLK', 'Gene', '3816;5655;11012;26085;43847;55554;3817;354;9622;25818;5653;5653;5650;11202;284366', (182, 185))	('inhibitors', 'Var', (27, 37))	('KLK', 'Gene', (182, 185))	('KLK', 'Gene', '3816;5655;11012;26085;43847;55554;3817;354;9622;25818;5653;5653;5650;11202;284366', (49, 52))	('degradation', 'MPA', (195, 206))	('KLK', 'Gene', (49, 52))	('activation', 'PosReg', (210, 220))
36647	32399369	Unfortunately, there are no specific guidelines when it comes to the management of KS patients with testicular GCTs (embryonal cell carcinoma) with aberrant histological markers and normal serum tumor markers.	('GCT', 'Gene', (111, 114))	('tumor', 'Disease', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('GCT', 'Gene', '25797', (111, 114))	('men', 'Species', '9606', (75, 78))	('embryonal cell carcinoma', 'Disease', (117, 141))	('aberrant', 'Var', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('embryonal cell carcinoma', 'Phenotype', 'HP:0002898', (117, 141))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('embryonal cell carcinoma', 'Disease', 'MESH:C538614', (117, 141))	('patients', 'Species', '9606', (86, 94))
36745	32399369	The uncommon presentation, including normal serum tumor markers, aberrant histological markers, and chemotherapeutic resistance made our case even more challenging to diagnose and treat.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('aberrant', 'Var', (65, 73))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
36746	32399369	Unfortunately, there are no specific guidelines when it comes to the management of KS patients with testicular GCTs with aberrant histological markers and normal serum tumor markers.	('GCT', 'Gene', (111, 114))	('tumor', 'Disease', (168, 173))	('GCT', 'Gene', '25797', (111, 114))	('aberrant', 'Var', (121, 129))	('men', 'Species', '9606', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('patients', 'Species', '9606', (86, 94))
36890	31291913	We considered the following variables to describe the tumour characteristics: method of detection (symptoms, fortuitous, routine check-up, autopsy or unknown); stage, categorized in four classes based on the pathologic tumor-node-metastasis (TNM) classification or, when absent, the clinical TNM classification; and morphology grouped in two classes: seminoma (International Classification of Diseases in Oncology version 10: 9060-9064) and non-seminoma (including embryonal carcinoma ICD-O 10: 9070, yolk sac tumor ICD-O 10: 9071, teratoma ICD-O 10: 9080, 9082, 9083, 9102, teratocarcinoma ICD-O 10: 9081, choriocarcinoma ICD-O 10: 9100, 9101, mixed germ-cell tumor ICD-O10: 9085).	('carcinoma', 'Phenotype', 'HP:0030731', (581, 590))	('carcinoma', 'Phenotype', 'HP:0030731', (613, 622))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (219, 224))	('tumour', 'Disease', (54, 60))	('Oncology', 'Phenotype', 'HP:0002664', (405, 413))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (465, 484))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('teratoma ICD', 'Disease', 'OMIM:252500', (532, 544))	('teratocarcinoma ICD', 'Disease', 'OMIM:252500', (575, 594))	('embryonal carcinoma ICD', 'Disease', 'OMIM:252500', (465, 488))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (607, 622))	('choriocarcinoma ICD', 'Disease', 'OMIM:252500', (607, 626))	('choriocarcinoma ICD', 'Disease', (607, 626))	('non-seminoma', 'Disease', (441, 453))	('tumor', 'Disease', (510, 515))	('teratoma ICD', 'Disease', (532, 544))	('tumor', 'Disease', (661, 666))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (475, 484))	('tumor', 'Disease', 'MESH:D009369', (510, 515))	('tumor', 'Disease', 'MESH:D009369', (661, 666))	('teratocarcinoma ICD', 'Disease', (575, 594))	('embryonal carcinoma ICD', 'Disease', (465, 488))	('seminoma', 'Disease', (351, 359))	('9083', 'Var', (563, 567))	('seminoma', 'Disease', (445, 453))	('seminoma', 'Disease', 'MESH:D018239', (351, 359))	('seminoma', 'Disease', 'MESH:D018239', (445, 453))	('tumor', 'Phenotype', 'HP:0002664', (661, 666))	('germ-cell tumor', 'Phenotype', 'HP:0100728', (651, 666))	('tumor', 'Phenotype', 'HP:0002664', (510, 515))	('teratoma', 'Phenotype', 'HP:0009792', (532, 540))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('non-seminoma', 'Disease', 'MESH:D018239', (441, 453))
36944	31291913	Cryptorchidism, environmental exposures, epigenetic aberrations and genetic susceptibility are the suggested etiologic mechanisms for the development of this cancer.	('Cryptorchidism', 'Disease', (0, 14))	('men', 'Species', '9606', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('Cryptorchidism', 'Phenotype', 'HP:0000028', (0, 14))	('men', 'Species', '9606', (23, 26))	('epigenetic aberrations', 'Var', (41, 63))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
36962	30027931	Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group).	('rs995030', 'Mutation', 'rs995030', (153, 161))	('rs6897876', 'Var', (193, 202))	('TGFBR3', 'Gene', '7049', (239, 245))	('men', 'Species', '9606', (337, 340))	('SPRY4', 'Gene', '81848', (175, 180))	('TGCT', 'Disease', (289, 293))	('TGFBR3', 'Gene', (239, 245))	('KITLG', 'Gene', (146, 151))	('rs4624820', 'Mutation', 'rs4624820', (182, 191))	('rs12082710', 'Mutation', 'rs12082710', (247, 257))	('TM', 'Phenotype', 'HP:0012215', (308, 310))	('rs17198432', 'Mutation', 'rs17198432', (270, 280))	('HOXD', 'Gene', (264, 268))	('rs210138', 'Mutation', 'rs210138', (211, 219))	('KITLG', 'Gene', '4254', (146, 151))	('rs12082710', 'Var', (247, 257))	('men', 'Species', '9606', (48, 51))	('HOXD', 'Gene', '3230', (264, 268))	('rs388286', 'Mutation', 'rs388286', (228, 236))	('rs6897876', 'Mutation', 'rs6897876', (193, 202))	('BAK1', 'Gene', '578', (205, 209))	('rs4624820', 'Var', (182, 191))	('rs1508595', 'Mutation', 'rs1508595', (163, 172))	('BAK1', 'Gene', (205, 209))	('rs17198432', 'Var', (270, 280))	('SPRY4', 'Gene', (175, 180))	('rs1508595', 'Var', (163, 172))	('patients', 'Species', '9606', (294, 302))	('rs995030', 'Var', (153, 161))	('rs388286', 'Var', (228, 236))	('rs210138', 'Var', (211, 219))	('patients', 'Species', '9606', (311, 319))
36963	30027931	We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control.	('GG_rs995030', 'Var', (46, 57))	('KITLG', 'Gene', '4254', (40, 45))	('differences', 'Reg', (21, 32))	('TM', 'Phenotype', 'HP:0012215', (70, 72))	('KITLG', 'Gene', (40, 45))	('rs995030', 'Mutation', 'rs995030', (49, 57))	('TGCT', 'Disease', (88, 92))	('patients', 'Species', '9606', (93, 101))
36966	30027931	HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001).	('rs17198432', 'Mutation', 'rs17198432', (56, 66))	('HOXD', 'Gene', '3230', (0, 4))	('rs17198432 A', 'Var', (56, 68))	('HOXD', 'Gene', (0, 4))	('TGCTs', 'Disease', (49, 54))
36969	30027931	In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.	('associated', 'Reg', (123, 133))	('KITLG', 'Gene', '4254', (16, 21))	('KITLG', 'Gene', (16, 21))	('rs210138', 'Mutation', 'rs210138', (99, 107))	('HOXD', 'Gene', (67, 71))	('BAK1', 'Gene', (91, 95))	('GG_rs210138', 'Var', (96, 107))	('rs388286', 'Mutation', 'rs388286', (57, 65))	('TGCT development', 'CPA', (154, 170))	('rs995030', 'Mutation', 'rs995030', (25, 33))	('rs1508595', 'Mutation', 'rs1508595', (38, 47))	('rs17198432', 'Mutation', 'rs17198432', (75, 85))	('men', 'Species', '9606', (166, 169))	('HOXD', 'Gene', '3230', (67, 71))	('GG_rs1508595', 'Gene', (35, 47))	('GG_rs995030', 'Var', (22, 33))	('BAK1', 'Gene', '578', (91, 95))
36994	30027931	Using PCR-RFLP analysis, we developed a detection method (Figure 1) and investigated the KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) loci in 142 patients with TGCTs, 137 patients with TM, and 153 fertile men.	('men', 'Species', '9606', (296, 299))	('rs6897876', 'Var', (136, 145))	('TGFBR3', 'Gene', '7049', (182, 188))	('SPRY4', 'Gene', (118, 123))	('patients', 'Species', '9606', (237, 245))	('rs210138', 'Var', (154, 162))	('TGFBR3', 'Gene', (182, 188))	('TM', 'Phenotype', 'HP:0012215', (276, 278))	('rs4624820', 'Mutation', 'rs4624820', (125, 134))	('rs12082710', 'Mutation', 'rs12082710', (190, 200))	('rs17198432', 'Mutation', 'rs17198432', (213, 223))	('HOXD', 'Gene', (207, 211))	('SPRY4', 'Gene', '81848', (118, 123))	('rs12082710', 'Var', (190, 200))	('HOXD', 'Gene', '3230', (207, 211))	('rs388286', 'Mutation', 'rs388286', (171, 179))	('KITLG', 'Gene', (89, 94))	('rs6897876', 'Mutation', 'rs6897876', (136, 145))	('rs995030', 'Var', (96, 104))	('rs4624820', 'Var', (125, 134))	('rs17198432', 'Var', (213, 223))	('rs210138', 'Mutation', 'rs210138', (154, 162))	('BAK1', 'Gene', '578', (148, 152))	('rs1508595', 'Mutation', 'rs1508595', (106, 115))	('KITLG', 'Gene', '4254', (89, 94))	('rs1508595', 'Var', (106, 115))	('rs995030', 'Mutation', 'rs995030', (96, 104))	('rs388286', 'Var', (171, 179))	('patients', 'Species', '9606', (262, 270))	('BAK1', 'Gene', (148, 152))
36995	30027931	We found significant differences in the prevalence of the KITLG genotype GG rs995030 in patients with TM (P = 0.01) and TGCTs (P = 0.0005) compared with the level in the control group.	('rs995030', 'Mutation', 'rs995030', (76, 84))	('rs995030', 'Var', (76, 84))	('patients', 'Species', '9606', (88, 96))	('TM', 'Phenotype', 'HP:0012215', (102, 104))	('KITLG', 'Gene', '4254', (58, 63))	('KITLG', 'Gene', (58, 63))	('GG rs995030', 'Var', (73, 84))
36996	30027931	Strong associations of TM with KITLG (rs1508595) were detected for both the G allele (P = 0.003) and the GG genotype (P = 0.01) and also for TGCTs with the G allele (P = 0.0001) and the GG genotype (P = 0.0007).	('TM', 'Phenotype', 'HP:0012215', (23, 25))	('rs1508595', 'Mutation', 'rs1508595', (38, 47))	('KITLG', 'Gene', '4254', (31, 36))	('rs1508595', 'Var', (38, 47))	('KITLG', 'Gene', (31, 36))
36997	30027931	For BMP7 (rs388286), significant differences from the control group were found for both the TGCT group (T allele, P = 0.00004; TT genotype, P = 0.00006) and the TM group (T allele, P = 0.04).	('BMP7', 'Gene', (4, 8))	('differences', 'Reg', (33, 44))	('TM', 'Phenotype', 'HP:0012215', (161, 163))	('rs388286', 'Mutation', 'rs388286', (10, 18))	('rs388286', 'Var', (10, 18))	('TGCT', 'Disease', (92, 96))
36998	30027931	For HOXD (rs17198432), significant associations were demonstrated only with TGCTs (A allele, P = 0.0001; AA genotype, P = 0.001).	('TGCTs', 'Disease', (76, 81))	('rs17198432', 'Mutation', 'rs17198432', (10, 20))	('HOXD', 'Gene', '3230', (4, 8))	('associations', 'Interaction', (35, 47))	('rs17198432', 'Var', (10, 20))	('HOXD', 'Gene', (4, 8))
36999	30027931	For BAK1 (rs210138), significant differences were also found for the G allele (P = 0.03) and the GG genotype (P = 0.01) in the TGCT group compared with the control.	('TGCT', 'Disease', (127, 131))	('rs210138', 'Var', (10, 18))	('differences', 'Reg', (33, 44))	('BAK1', 'Gene', '578', (4, 8))	('rs210138', 'Mutation', 'rs210138', (10, 18))	('BAK1', 'Gene', (4, 8))
37000	30027931	However, there were no remarkable differences in TGFBR3 (rs12082710) and SPRY4 (rs4624820, rs6897876) allele and genotype frequencies between the TGCT/TM groups and the control.	('TGFBR3', 'Gene', '7049', (49, 55))	('TGFBR3', 'Gene', (49, 55))	('rs4624820', 'Mutation', 'rs4624820', (80, 89))	('rs12082710', 'Var', (57, 67))	('rs6897876', 'Var', (91, 100))	('SPRY4', 'Gene', (73, 78))	('SPRY4', 'Gene', '81848', (73, 78))	('TM', 'Phenotype', 'HP:0012215', (151, 153))	('rs6897876', 'Mutation', 'rs6897876', (91, 100))	('rs12082710', 'Mutation', 'rs12082710', (57, 67))	('rs4624820', 'Var', (80, 89))
37005	30027931	Recently, several GWASs have revealed a number of genetic variations with important roles in TGCT development, including variations in KITLG, SPRY4, BAK1, Doublesex- and mab-3-related transcription factor 1 gene (DMRT1), telomerase reverse transcriptase gene (TERT), activating transcription factor 7 interacting protein gene (ATF7IP), hematopoietic prostaglandin D synthase gene (HPGDS), mitotic arrest deficient 1 like 1 gene (MAD1L1), ring finger and WD repeat domain 3 gene (RFWD3), testis expressed 14, intercellular bridge forming factor gene (TEX14), and protein phosphatase, Mg2+/Mn2+ dependent 1E gene (PPM1E).	('prostaglandin D synthase', 'Gene', '5730', (350, 374))	('BAK1', 'Gene', (149, 153))	('variations', 'Var', (58, 68))	('variations', 'Var', (121, 131))	('men', 'Species', '9606', (105, 108))	('SPRY4', 'Gene', '81848', (142, 147))	('HPGDS', 'Gene', '27306', (381, 386))	('mitotic arrest deficient', 'Disease', (389, 413))	('TERT', 'Gene', (260, 264))	('TERT', 'Gene', '7015', (260, 264))	('activating transcription factor 7 interacting protein', 'Gene', '55729', (267, 320))	('PPM1E', 'Gene', (612, 617))	('BAK1', 'Gene', '578', (149, 153))	('mitotic arrest deficient', 'Disease', 'MESH:D006323', (389, 413))	('MAD1L1', 'Gene', '8379', (429, 435))	('Doublesex- and mab-3-related transcription factor 1', 'Gene', '1761', (155, 206))	('ATF7IP', 'Gene', (327, 333))	('DMRT1', 'Gene', '1761', (213, 218))	('TEX14', 'Gene', (550, 555))	('ring finger and WD repeat domain 3', 'Gene', '55159', (438, 472))	('KITLG', 'Gene', (135, 140))	('RFWD3', 'Gene', (479, 484))	('prostaglandin D synthase', 'Gene', (350, 374))	('HPGDS', 'Gene', (381, 386))	('SPRY4', 'Gene', (142, 147))	('RFWD3', 'Gene', '55159', (479, 484))	('PPM1E', 'Gene', '22843', (612, 617))	('ATF7IP', 'Gene', '55729', (327, 333))	('MAD1L1', 'Gene', (429, 435))	('TEX14', 'Gene', '56155', (550, 555))	('DMRT1', 'Gene', (213, 218))	('KITLG', 'Gene', '4254', (135, 140))
37009	30027931	The signaling pathway KIT/KITLG (Kit receptor signaling pathway) is critical for the migration and survival of primordial germ cells (PGCs), and its deregulation leads to the appearance of ectopically migrated PGCs.	('KITLG', 'Gene', '4254', (26, 31))	('ectopically migrated PGCs', 'CPA', (189, 214))	('leads to', 'Reg', (162, 170))	('KITLG', 'Gene', (26, 31))	('deregulation', 'Var', (149, 161))
37016	30027931	According to the GWAS data, BMP7 (rs388286) and HOXD (rs17198432) are genetic factors unrelated to TGCTs but related to TDS development.	('related', 'Reg', (109, 116))	('TDS', 'Disease', (120, 123))	('HOXD', 'Gene', '3230', (48, 52))	('men', 'Species', '9606', (131, 134))	('rs17198432', 'Mutation', 'rs17198432', (54, 64))	('rs388286', 'Mutation', 'rs388286', (34, 42))	('HOXD', 'Gene', (48, 52))	('rs388286', 'Var', (34, 42))	('rs17198432', 'Var', (54, 64))
37017	30027931	Interestingly, the HOXD locus (rs17198432 alleles and genotypes) is associated with TGCT development.	('men', 'Species', '9606', (96, 99))	('rs17198432', 'Mutation', 'rs17198432', (31, 41))	('HOXD', 'Gene', (19, 23))	('associated', 'Reg', (68, 78))	('TGCT development', 'CPA', (84, 100))	('rs17198432', 'Var', (31, 41))	('HOXD', 'Gene', '3230', (19, 23))
37024	30027931	Deletions of HOXD genes or their 5'-regions lead to severe abnormalities of limbs and gonads; point mutations in the HOXD13 gene result in synpolydactyly and brachydactyly.	('HOXD13', 'Gene', '3239', (117, 123))	('lead to', 'Reg', (44, 51))	('abnormalities of limbs', 'Phenotype', 'HP:0040064', (59, 81))	('HOXD', 'Gene', '3230', (117, 121))	('HOXD13', 'Gene', (117, 123))	('result in', 'Reg', (129, 138))	('brachydactyly', 'Phenotype', 'HP:0001156', (158, 171))	('HOXD', 'Gene', (13, 17))	('point mutations', 'Var', (94, 109))	('synpolydactyly and brachydactyly', 'Disease', 'MESH:C538153', (139, 171))	('HOXD', 'Gene', '3230', (13, 17))	('Deletions', 'Var', (0, 9))	('HOXD', 'Gene', (117, 121))
37036	30027931	Therefore, the KITLG and BMP7 ligands play important roles in PGC development and differentiation in human embryos, but their deregulation could lead to the activation of cell proliferation and consequently to TGCTs in adulthood.	('deregulation', 'Var', (126, 138))	('cell proliferation', 'CPA', (171, 189))	('KITLG', 'Gene', '4254', (15, 20))	('men', 'Species', '9606', (73, 76))	('KITLG', 'Gene', (15, 20))	('TGCTs', 'CPA', (210, 215))	('human', 'Species', '9606', (101, 106))	('activation', 'PosReg', (157, 167))	('lead to', 'Reg', (145, 152))
37044	30027931	The FDR test in the TGCT group confirmed the data for BMP7 (rs388286), KITLG (rs1508595), HOXD (rs17198432), and KITLG (rs995030) alleles and genotypes, but none of the evaluated polymorphisms in the TM group fulfilled the requirements of the FDR test (Table 3).	('TM', 'Phenotype', 'HP:0012215', (200, 202))	('HOXD', 'Gene', (90, 94))	('men', 'Species', '9606', (230, 233))	('KITLG', 'Gene', '4254', (71, 76))	('rs388286', 'Mutation', 'rs388286', (60, 68))	('rs1508595', 'Mutation', 'rs1508595', (78, 87))	('rs388286', 'Var', (60, 68))	('KITLG', 'Gene', '4254', (113, 118))	('KITLG', 'Gene', (71, 76))	('rs995030', 'Mutation', 'rs995030', (120, 128))	('rs17198432', 'Var', (96, 106))	('rs1508595', 'Var', (78, 87))	('KITLG', 'Gene', (113, 118))	('HOXD', 'Gene', '3230', (90, 94))	('rs995030', 'Var', (120, 128))	('rs17198432', 'Mutation', 'rs17198432', (96, 106))
37046	30027931	In conclusion, the present study demonstrated that variants of certain genes related to the KIT/KITLG and BMP/TGFbeta signaling pathways and important for the development of TGCTs are more common in TM patients than in fertile men.	('KITLG', 'Gene', (96, 101))	('BMP', 'Gene', (106, 109))	('common', 'Reg', (189, 195))	('men', 'Species', '9606', (227, 230))	('variants', 'Var', (51, 59))	('men', 'Species', '9606', (166, 169))	('patients', 'Species', '9606', (202, 210))	('TM', 'Phenotype', 'HP:0012215', (199, 201))	('BMP', 'Gene', '649', (106, 109))	('KITLG', 'Gene', '4254', (96, 101))
37059	28815058	TML has been suggested to be associated with testicular cancer, but this relationship remains debatable.	('TML', 'Phenotype', 'HP:0012215', (0, 3))	('testicular cancer', 'Disease', (45, 62))	('TML', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('testicular cancer', 'Phenotype', 'HP:0010788', (45, 62))	('testicular cancer', 'Disease', 'MESH:D013736', (45, 62))	('associated', 'Reg', (29, 39))
37108	24059746	Interestingly, following treatment with low doses of H2O2, the silencing of CCDC6 in GC1 cells caused a decrease in the oxidized form of cytochrome c and low detection of Bad, PARP-1 and Caspase 3 proteins.	('Caspase 3', 'Gene', (187, 196))	('Bad', 'Protein', (171, 174))	('low', 'NegReg', (154, 157))	('PARP-1', 'Gene', (176, 182))	('CCDC6', 'Gene', (76, 81))	('Caspase 3', 'Gene', '836', (187, 196))	('PARP-1', 'Gene', '142', (176, 182))	('cytochrome c', 'Gene', '54205', (137, 149))	('men', 'Species', '9606', (30, 33))	('decrease', 'NegReg', (104, 112))	('cytochrome c', 'Gene', (137, 149))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))	('silencing', 'Var', (63, 72))
37118	24059746	CCDC6 was originally identified upon rearrangement with RET in thyroid and lung tumours, and with genes other than RET in solid and not solid tumours.	('RET', 'Gene', '5979', (56, 59))	('men', 'Species', '9606', (46, 49))	('RET', 'Gene', (56, 59))	('RET', 'Gene', '5979', (115, 118))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('solid tumours', 'Disease', 'MESH:D009369', (136, 149))	('CCDC6', 'Gene', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('rearrangement', 'Var', (37, 50))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('solid tumours', 'Disease', (136, 149))	('RET', 'Gene', (115, 118))	('thyroid and lung tumours', 'Disease', 'MESH:D013964', (63, 87))
37119	24059746	In most cancers harbouring CCDC6 gene rearrangements, the product of the normal allele is supposed to be functionally impaired or absent.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('rearrangements', 'Var', (38, 52))	('cancers', 'Disease', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('men', 'Species', '9606', (47, 50))	('CCDC6', 'Gene', (27, 32))
37124	24059746	Here, we intend to gain more insights into the CCDC6 tissue biology and its relation to testicular cancer in order to unravel a role for CCDC6 as a new DDR component that participates in genome stability maintenance and whose malfunction may contribute to the pathogenesis of germ cell tumours.	('contribute', 'Reg', (242, 252))	('testicular cancer', 'Phenotype', 'HP:0010788', (88, 105))	('testicular cancer', 'Disease', 'MESH:D013736', (88, 105))	('tumours', 'Phenotype', 'HP:0002664', (286, 293))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('participates', 'Reg', (171, 183))	('CCDC6', 'Gene', (137, 142))	('malfunction', 'Var', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('testicular cancer', 'Disease', (88, 105))	('germ cell tumours', 'Disease', (276, 293))	('germ cell tumours', 'Disease', 'MESH:D009373', (276, 293))
37129	24059746	GC-1 cells were transfected with mission shCCDC6 or a control non-targeting scrambled sh, after 48h were treated with H2O2 at different doses (range of 1, 2, 5 and 10 muM) for 1h, as indicated.	('GC-1', 'CellLine', 'CVCL:8872', (0, 4))	('muM', 'Gene', (167, 170))	('H2O2', 'Chemical', 'MESH:D006861', (118, 122))	('shCCDC6', 'Var', (41, 48))	('1h', 'Chemical', '-', (176, 178))	('muM', 'Gene', '56925', (167, 170))
37133	24059746	GC-1 cells were transfected with mission shCCDC6 or a control non-targeting scrambled sh, after 48 h this cells were treated with H2O2 at 10 muM for 1 h and apoptosis was quantified by measuring Caspase 3/7 activation using the Caspase-Glo 3/7 assay (Promega) according to the manufacturer's instructions.	('GC-1', 'CellLine', 'CVCL:8872', (0, 4))	('activation', 'PosReg', (207, 217))	('muM', 'Gene', '56925', (141, 144))	('shCCDC6', 'Var', (41, 48))	('Caspase 3', 'Gene', (195, 204))	('H2O2', 'Chemical', 'MESH:D006861', (130, 134))	('Caspase 3', 'Gene', '836', (195, 204))	('muM', 'Gene', (141, 144))
37163	24059746	In order to investigate if the loss of CCDC6 could affect hydrogen peroxide-induced apoptosis in CCDC6-expressing primordial GC1 cells, we silenced its expression by the transient transfection of specific shRNAs directed against murine CCDC6 and exposed the cells to different doses of hydrogen peroxide for 1 hour (Figure 2A, right).	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (58, 75))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (286, 303))	('CCDC6', 'Gene', (39, 44))	('affect', 'Reg', (51, 57))	('murine', 'Species', '10090', (229, 235))	('silenced', 'NegReg', (139, 147))	('loss', 'Var', (31, 35))	('hydrogen peroxide-induced', 'MPA', (58, 83))	('expression', 'MPA', (152, 162))
37164	24059746	We observed a reversion of an antiproliferative effects following hydrogen peroxide exposure in CCDC6 silenced- compared to control GC1 cells.	('silenced-', 'Var', (102, 111))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (66, 83))	('antiproliferative', 'MPA', (30, 47))	('rat', 'Species', '10116', (41, 44))	('CCDC6', 'Gene', (96, 101))
37166	24059746	Indeed, by western blot analysis, we observed that the oxidized form of cytochrome c was significantly decreased in GC1-shCCDC6, compared to controls (Figure 2A, right).	('decreased', 'NegReg', (103, 112))	('GC1-shCCDC6', 'Var', (116, 127))	('cytochrome c', 'Gene', (72, 84))	('cytochrome c', 'Gene', '54205', (72, 84))
37168	24059746	By this assay we found that 48 hours after the transient silencing of shCCDC6 and shCTRL in GC1 cells the cytochrome c release in the cytosol of the GC1 shCCDC6 cells showed a slightly increase, compared to the significant high levels detected in the shCTRL GC1 cells, following one hour exposure to 10 muM H2O2, after washing out the hydrogen peroxide and leaving the cells an additional hour before the lysis.	('increase', 'PosReg', (185, 193))	('cytochrome c', 'Gene', '54205', (106, 118))	('H2O2', 'Chemical', 'MESH:D006861', (307, 311))	('shCCDC6', 'Gene', (70, 77))	('muM', 'Gene', '56925', (303, 306))	('silencing', 'Var', (57, 66))	('muM', 'Gene', (303, 306))	('cytochrome c', 'Gene', (106, 118))	('shCTRL', 'Gene', (82, 88))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (335, 352))
37172	24059746	To determine whether the H2O2-induced redox imbalance and the subsequent GC1 cell apoptosis were associated with changes in pro- and anti-apoptotic proteins, the expression of these proteins was analyzed by western blot.	('imbalance', 'Phenotype', 'HP:0002172', (44, 53))	('changes', 'Reg', (113, 120))	('redox imbalance', 'MPA', (38, 53))	('redox imbalance', 'Phenotype', 'HP:0025463', (38, 53))	('GC1 cell apoptosis', 'CPA', (73, 91))	('H2O2-induced', 'Var', (25, 37))	('H2O2', 'Chemical', 'MESH:D006861', (25, 29))
37177	24059746	To investigate whether CCDC6 silencing was able to confer protection by H2O2 induced apoptosis in testicular germ cells, we studied caspase -3 activity.	('caspase -3', 'Gene', (132, 142))	('H2O2', 'Chemical', 'MESH:D006861', (72, 76))	('H2O2', 'Gene', (72, 76))	('CCDC6', 'Gene', (23, 28))	('silencing', 'Var', (29, 38))	('caspase -3', 'Gene', '836', (132, 142))
37178	24059746	We found that caspase -3 activity was reduced in shCCDC6 compared to shCTRL GC1 cells, upon 10 muM H2O2 treatment for 1 hour (Figure 2D).	('caspase -3', 'Gene', (14, 24))	('reduced', 'NegReg', (38, 45))	('shCCDC6', 'Var', (49, 56))	('muM', 'Gene', '56925', (95, 98))	('caspase -3', 'Gene', '836', (14, 24))	('H2O2', 'Chemical', 'MESH:D006861', (99, 103))	('men', 'Species', '9606', (109, 112))	('muM', 'Gene', (95, 98))	('activity', 'MPA', (25, 33))
37179	24059746	We reported that stable CCDC6 depletion in HeLa cells affected the phosphorylation of histone H2AX on S139, upon IR and etoposide exposure.	('affected', 'Reg', (54, 62))	('H2AX', 'Gene', '3014', (94, 98))	('H2AX', 'Gene', (94, 98))	('depletion', 'Var', (30, 39))	('HeLa', 'CellLine', 'CVCL:0030', (43, 47))	('etoposide', 'Chemical', 'MESH:D005047', (120, 129))	('phosphorylation', 'MPA', (67, 82))
37180	24059746	In the same cells, CCDC6 silencing affects the levels of histone H2AX phosphorylation, upon H2O2 treatment (data not shown).	('silencing', 'Var', (25, 34))	('H2AX', 'Gene', (65, 69))	('CCDC6', 'Gene', (19, 24))	('H2O2', 'Chemical', 'MESH:D006861', (92, 96))	('affects', 'Reg', (35, 42))	('H2AX', 'Gene', '3014', (65, 69))	('men', 'Species', '9606', (102, 105))
37181	24059746	Interestingly, in the stable CCDC6-interfered HeLa cells, the re-expression of the wild type protein but not of the CCDC6 protein mutated in the T434A residue, an ATM kinase phosphorylation target, restored pS139_H2AX levels in response to genotoxic stress.	('H2AX', 'Gene', (213, 217))	('ATM', 'Gene', '472', (163, 166))	('response to genotoxic stress', 'MPA', (228, 256))	('HeLa', 'CellLine', 'CVCL:0030', (46, 50))	('T434A', 'Mutation', 'c.434T>A', (145, 150))	('mutated', 'Var', (130, 137))	('ATM', 'Gene', (163, 166))	('H2AX', 'Gene', '3014', (213, 217))	('restored', 'PosReg', (198, 206))
37183	24059746	Notably, the overexpression of the CCDC6 T434A mutant, that behaved as a dominant negative of the wild type protein, affected the phosphorylation status of the histone H2AX in the absence or presence of H2O2, in comparison to the empty vector transfected cells (Figure 2E).	('H2O2', 'Chemical', 'MESH:D006861', (203, 207))	('T434A', 'Mutation', 'c.434T>A', (41, 46))	('H2AX', 'Gene', (168, 172))	('overexpression', 'PosReg', (13, 27))	('T434A', 'Var', (41, 46))	('affected', 'Reg', (117, 125))	('phosphorylation status', 'MPA', (130, 152))	('H2AX', 'Gene', '3014', (168, 172))	('CCDC6', 'Gene', (35, 40))
37185	24059746	By immunoblot analysis of CCDC6, we could also observe that the protein was stabilized in response to H2O2 in the sh-ctrl and in the empty vector transfected GC-1 cells, compared to the T434A overexpressing cells, where the H2O2 treatments did not stabilize the CCDC6 protein (Figure 2E).	('GC-1', 'CellLine', 'CVCL:8872', (158, 162))	('T434A', 'Mutation', 'c.434T>A', (186, 191))	('men', 'Species', '9606', (234, 237))	('stabilized', 'MPA', (76, 86))	('H2O2', 'Chemical', 'MESH:D006861', (102, 106))	('H2O2', 'Var', (102, 106))	('H2O2', 'Chemical', 'MESH:D006861', (224, 228))
37186	24059746	As a control, in the lanes where CCDC6 was silenced in the GC1 cells (-/+H2O2), the anti-CCDC6 hybridization allows a verification of the efficiency of the silencing (Figure 2E).	('anti-CCDC6', 'Var', (84, 94))	('H2O2', 'Chemical', 'MESH:D006861', (73, 77))	('silencing', 'Var', (156, 165))
37187	24059746	Overall, these experiments have showed that, in the GC1 cells, the loss of CCDC6 or its functional impairment by mutation of a single residue limited the amount of S139_pH2AX that then influenced the sensing of DNA damage induced by H2O2, relative to the control cells.	('mutation', 'Var', (113, 121))	('H2AX', 'Gene', '3014', (170, 174))	('H2AX', 'Gene', (170, 174))	('sensing of DNA damage induced by H2O2', 'MPA', (200, 237))	('CCDC6', 'Gene', (75, 80))	('limited', 'NegReg', (142, 149))	('men', 'Species', '9606', (105, 108))	('loss', 'NegReg', (67, 71))	('influenced', 'Reg', (185, 195))	('functional', 'MPA', (88, 98))	('men', 'Species', '9606', (21, 24))	('H2O2', 'Chemical', 'MESH:D006861', (233, 237))
37190	24059746	In the same cells, the transient expression of the mutant CCDC6 T434A counteracted the ROS production, compared to the control (# p <= 0.05) (Figure 2G).	('mutant', 'Var', (51, 57))	('T434A', 'Var', (64, 69))	('ROS production', 'MPA', (87, 101))	('ROS', 'Chemical', 'MESH:D017382', (87, 90))	('T434A', 'Mutation', 'c.434T>A', (64, 69))	('CCDC6', 'Gene', (58, 63))
37193	24059746	In the testicular tissues adjacent to the tumour, normal or atrophic and not affected by neoplastic transformation, it was possible to appreciate the CCDC6 positivity mainly in the nucleus of the spermatogonial cells identified, on the basis of the morphological features, at the basal layer of the tubules.	('atrophic', 'Disease', 'MESH:D020966', (60, 68))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('atrophic', 'Disease', (60, 68))	('CCDC6', 'Gene', (150, 155))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('positivity', 'Var', (156, 166))
37201	24059746	An aberrant reduction or a lack of MDC1 has been reported in a significant proportion of carcinomas supporting its candidacy as a tumor suppressor.	('carcinomas', 'Disease', (89, 99))	('MDC1', 'Gene', (35, 39))	('MDC1', 'Gene', '9656', (35, 39))	('aberrant', 'Var', (3, 11))	('reduction', 'NegReg', (12, 21))	('lack', 'NegReg', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('tumor', 'Disease', (130, 135))	('carcinomas', 'Disease', 'MESH:D002277', (89, 99))
37208	24059746	Quantitative real time PCR analysis showed low levels of transcripts for CCDC6 in these cells, compared to the expression levels detected in the GC1 cells (Figure 5B), suggesting that the loss of CCDC6 in the neoplastic seminoma cells might not be dependent on a post-transcriptional mechanism.	('CCDC6', 'Gene', (73, 78))	('neoplastic seminoma', 'Disease', 'MESH:D018239', (209, 228))	('CCDC6', 'Gene', (196, 201))	('loss', 'Var', (188, 192))	('neoplastic seminoma', 'Phenotype', 'HP:0100617', (209, 228))	('neoplastic seminoma', 'Disease', (209, 228))
37222	24059746	A few CCDC6 somatic mutations have been reported in some tumours (http://www.sanger.ac.uk/genetics/CGP/cosmic), but they are still in need of characterization.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('CCDC6', 'Gene', (6, 11))	('reported', 'Reg', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (20, 29))
37230	24059746	Nevertheless, we can assume that in different tissues, other than the testis, CCDC6 may be inactivated or lost by different mechanisms, such as post-translational modifications, and also at different stages of tumour development, initiation or progression.	('men', 'Species', '9606', (224, 227))	('lost', 'NegReg', (106, 110))	('CCDC6', 'Gene', (78, 83))	('initiation', 'Disease', (230, 240))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('post-translational modifications', 'Var', (144, 176))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('initiation', 'Disease', 'MESH:D007319', (230, 240))	('tumour', 'Disease', (210, 216))
37233	24059746	The progressively decreasing levels of CCDC6 during the spermatocytic differentiation process could reflect the different levels of control needed for the mitotically proliferating testicular cells rather than during meiotic recombination where CCDC6 could probably induce inadequate apoptosis and undermine spermatogenesis.	('apoptosis', 'CPA', (284, 293))	('undermine', 'NegReg', (298, 307))	('levels', 'MPA', (29, 35))	('CCDC6', 'Var', (245, 250))	('rat', 'Species', '10116', (198, 201))	('rat', 'Species', '10116', (174, 177))	('induce', 'Reg', (266, 272))	('spermatogenesis', 'CPA', (308, 323))	('decreasing', 'NegReg', (18, 28))
37243	24059746	Moreover, we found that, upon H2O2 treatment, the silencing of CCDC6 or the mutation in the recognition site for the ATM kinase in primary GC1 germ cells increases the rate of survival, impairs the phosphorylation of histone H2AX on S139, affects ROS production and makes the cells more resistant to oxidative damage.	('increases', 'PosReg', (154, 163))	('phosphorylation', 'MPA', (198, 213))	('ROS', 'Chemical', 'MESH:D017382', (247, 250))	('ATM', 'Gene', '472', (117, 120))	('ROS production', 'MPA', (247, 261))	('affects', 'Reg', (239, 246))	('H2O2', 'Chemical', 'MESH:D006861', (30, 34))	('impairs', 'NegReg', (186, 193))	('silencing', 'Var', (50, 59))	('H2AX', 'Gene', '3014', (225, 229))	('H2AX', 'Gene', (225, 229))	('rat', 'Species', '10116', (168, 171))	('men', 'Species', '9606', (40, 43))	('survival', 'CPA', (176, 184))	('CCDC6', 'Gene', (63, 68))	('mutation', 'Var', (76, 84))	('ATM', 'Gene', (117, 120))
37245	24059746	In conclusion, our results suggest that the loss of CCDC6 in tumour testes could represent a specific event that helps testicular germ cell tumours formation.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour testes', 'Disease', (61, 74))	('tumour testes', 'Disease', 'MESH:D013736', (61, 74))	('helps', 'PosReg', (113, 118))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('testicular germ cell tumours', 'Disease', 'MESH:C563236', (119, 147))	('loss', 'Var', (44, 48))	('testicular germ cell tumours', 'Disease', (119, 147))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('CCDC6', 'Gene', (52, 57))
37269	21851623	Inactivation of the Dnd1 gene results in sterility in vertebrates as well as causes development of testicular germ cell tumors in mice.	('mice', 'Species', '10090', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('causes', 'Reg', (77, 83))	('sterility', 'CPA', (41, 50))	('germ cell tumors', 'Phenotype', 'HP:0100728', (110, 126))	('results in', 'Reg', (30, 40))	('germ cell tumor', 'Phenotype', 'HP:0100728', (110, 125))	('Dnd1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Dnd1', 'Gene', '213236', (20, 24))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (99, 126))	('testicular germ cell tumors', 'Disease', (99, 126))	('Inactivation', 'Var', (0, 12))
37271	21851623	Mice with inactivated Dnd1 show progressive reduction in germ cell numbers starting around embryonic day (E) 8 and are therefore rendered sterile at birth.	('germ cell numbers', 'CPA', (57, 74))	('Dnd1', 'Gene', (22, 26))	('Dnd1', 'Gene', '213236', (22, 26))	('reduction', 'NegReg', (44, 53))	('inactivated', 'Var', (10, 21))	('Mice', 'Species', '10090', (0, 4))
37272	21851623	In addition, when inactivation of Dnd1 occurs in 129 strain mouse background, these mice have a very high incidence of testicular germ cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('germ cell tumors', 'Phenotype', 'HP:0100728', (130, 146))	('inactivation', 'Var', (18, 30))	('Dnd1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Dnd1', 'Gene', '213236', (34, 38))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (119, 146))	('mouse', 'Species', '10090', (60, 65))	('testicular germ cell tumors', 'Disease', (119, 146))	('germ cell tumor', 'Phenotype', 'HP:0100728', (130, 145))	('mice', 'Species', '10090', (84, 88))
37276	21851623	Mutations engineered in the RRM prevent interaction of DND1 with mRNAs and have also been reported to prevent nucleo-cytoplasmic translocation of zebrafish DND1.	('nucleo-cytoplasmic translocation', 'MPA', (110, 142))	('zebrafish', 'Species', '7955', (146, 155))	('DND1', 'Gene', (55, 59))	('prevent', 'NegReg', (102, 109))	('Mutations', 'Var', (0, 9))	('interaction', 'Interaction', (40, 51))	('prevent', 'NegReg', (32, 39))
37277	21851623	In addition, a disease associated nucleotide polymorphism in the highly conserved RRM of DND1 was detected in a human patient with germ cell tumor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('DND1', 'Gene', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('disease associated', 'Reg', (15, 33))	('tumor', 'Disease', (141, 146))	('germ cell tumor', 'Phenotype', 'HP:0100728', (131, 146))	('patient', 'Species', '9606', (118, 125))	('nucleotide polymorphism', 'Var', (34, 57))	('human', 'Species', '9606', (112, 117))
37283	21851623	In the case of P27, Nanos1 and TDRD7, the U-rich sequences are found adjacent to miRNA binding sites.	('Nanos1', 'Var', (20, 26))	('P27', 'Var', (15, 18))	('miR', 'Gene', (81, 84))	('miR', 'Gene', '735281', (81, 84))
37316	21851623	PCR cycles for each transcript was as follows: P27 (30 or 35 cycles), HPRT1 (35 or 24 cycles), OCT4, SOX2 and NANOG (26 cycles), LIN28, KLF4, MYC, TP53, LATS2, BAX and BCLX (35 cycles).	('BCLX', 'Gene', (168, 172))	('TP53', 'Gene', (147, 151))	('HPRT1', 'Gene', '15452', (70, 75))	('KLF4', 'Gene', (136, 140))	('MYC', 'Gene', (142, 145))	('BCLX', 'Gene', '12048', (168, 172))	('MYC', 'Gene', '17869', (142, 145))	('KLF4', 'Gene', '16600', (136, 140))	('HPRT1', 'Gene', (70, 75))	('TP53', 'Gene', '22059', (147, 151))	('P27', 'Var', (47, 50))	('BAX', 'Gene', '12028', (160, 163))	('BAX', 'Gene', (160, 163))
37324	21851623	We established lentiviral modified hES lines that express HA-tagged human DND1 (hES/HA-DND1) in an inducible manner.	('hES', 'Gene', (80, 83))	('human', 'Species', '9606', (68, 73))	('hES', 'Gene', '6238', (35, 38))	('HA-tagged', 'Var', (58, 67))	('hES', 'Gene', (35, 38))	('DND1', 'Gene', (74, 78))	('hES', 'Gene', '6238', (80, 83))
37329	21851623	First, we performed RIP to test whether HA-tagged DND1, induced to be expressed in the hES/HA-DND1 cell line, can pull down P27 mRNA.	('pull down', 'NegReg', (114, 123))	('P27', 'Var', (124, 127))	('HA-tagged', 'Var', (40, 49))	('hES', 'Gene', '6238', (87, 90))	('DND1', 'Gene', (50, 54))	('hES', 'Gene', (87, 90))
37340	21851623	In the case of OCT4, SOX2, NANOG (Figure 3b) we observe specific pull down of the transcripts in lane 13 (anti-HA, dox +, RT +) compared to lane 14 (anti-HA, dox -, RT +).	('dox', 'Chemical', 'MESH:D004318', (158, 161))	('dox', 'Chemical', 'MESH:D004318', (115, 118))	('pull down', 'NegReg', (65, 74))	('anti-HA', 'Var', (106, 113))	('transcripts', 'MPA', (82, 93))
37346	21851623	This indicates that LIN28 is more efficiently pulled down with DND1 compared to TP53 and LATS2.	('DND1', 'Var', (63, 67))	('TP53', 'Gene', '22059', (80, 84))	('TP53', 'Gene', (80, 84))	('LIN28', 'Protein', (20, 25))
37359	21851623	This observation is corroborated by a recent study where RIP technique was applied to NIH3T3 cells and showed that tagged DND1 is able to pull down a number of cell cycle regulators including Lats2 and p53 .	('Lats2', 'Gene', '50523', (192, 197))	('Lats2', 'Gene', (192, 197))	('cell cycle regulators', 'MPA', (160, 181))	('NIH3T3', 'CellLine', 'CVCL:0594', (86, 92))	('p53', 'Gene', '22059', (202, 205))	('pull down', 'NegReg', (138, 147))	('p53', 'Gene', (202, 205))	('DND1', 'Gene', (122, 126))	('tagged', 'Var', (115, 121))
37365	21851623	Interestingly, our observation that DND1 interacts with pluripotency and anti-apoptotic factor mRNAs may explain why lack of DND1 results in the death of germ cells in mice.	('death', 'CPA', (145, 150))	('DND1', 'Gene', (125, 129))	('mice', 'Species', '10090', (168, 172))	('lack', 'Var', (117, 121))
37379	20411342	Screening for germline DND1 mutations in testicular cancer patients Although several observations suggest that a strong genetic predisposition to developing testicular germ cell tumors (TGCT) exists, no associated, highly penetrant germline mutations have been identified so far.	('testicular germ cell tumors', 'Disease', (157, 184))	('DND1', 'Gene', '373863', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('germ cell tumors', 'Phenotype', 'HP:0100728', (168, 184))	('germ cell tumor', 'Phenotype', 'HP:0100728', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('testicular cancer', 'Phenotype', 'HP:0010788', (41, 58))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('DND1', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (157, 184))
37380	20411342	In the 129/Sv mouse strain, a germline mutation in the DND1 gene has been shown to strongly increase the TGCT risk.	('mouse', 'Species', '10090', (14, 19))	('DND1', 'Gene', (55, 59))	('germline mutation', 'Var', (30, 47))	('increase', 'PosReg', (92, 100))	('TGCT', 'Disease', (105, 109))	('129/Sv', 'Species', '10090', (7, 13))
37382	20411342	A single nucleotide substitution c.657C > G (p.Asp219Glu) was observed in a non-familial case of testicular embryonal carcinoma.	('testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (97, 127))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (108, 127))	('c.657C > G', 'Mutation', 'c.657C>G', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('testicular embryonal carcinoma', 'Disease', (97, 127))	('c.657C > G', 'Var', (33, 43))	('p.Asp219Glu', 'Mutation', 'p.D219E', (45, 56))
37385	20411342	We conclude that germline DND1 mutations are unlikely to contribute significantly to human testicular germ cell tumor susceptibility.	('mutations', 'Var', (31, 40))	('germ cell tumor', 'Phenotype', 'HP:0100728', (102, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('DND1', 'Gene', (26, 30))	('human', 'Species', '9606', (85, 90))
37388	20411342	Although low to mild penetrant gene variants have been identified, including cKIT mutations, linkage analysis, genome-wide association studies and a candidate gene approach have not yet been successful in identifying highly penetrant germline mutations as the cause of familial TGCT.	('cKIT', 'Gene', (77, 81))	('cause', 'Reg', (260, 265))	('cKIT', 'Gene', '3815', (77, 81))	('familial TGCT', 'Disease', (269, 282))	('variants', 'Var', (36, 44))
37389	20411342	Animal models may help to identify disease-predisposing mutations in humans, for example, in the 129/Sv mouse model, a germline mutation in DND1 (Dead-end 1) has been shown to cause TGCT.	('DND1', 'Gene', (140, 144))	('humans', 'Species', '9606', (69, 75))	('Dead-end 1', 'Gene', '213236', (146, 156))	('TGCT', 'Disease', (182, 186))	('mouse', 'Species', '10090', (104, 109))	('germline mutation', 'Var', (119, 136))	('129/Sv', 'Species', '10090', (97, 103))	('cause', 'Reg', (176, 181))	('Dead-end 1', 'Gene', (146, 156))
37391	20411342	A recent study, the first to analyze germline human DND1 (MIM 609385) in a clinical disorder, therefore screened the gene for mutations in a series of 263 familial and sporadic TGCT patients and found a possibly pathogenic missense p.Glu86Ala mutation in a single case.	('p.Glu86Ala', 'Mutation', 'p.E86A', (232, 242))	('human', 'Species', '9606', (46, 51))	('patients', 'Species', '9606', (182, 190))	('p.Glu86Ala', 'Var', (232, 242))	('pathogenic', 'Reg', (212, 222))	('missense p.Glu86Ala', 'Var', (223, 242))
37392	20411342	These findings could neither confirm nor reject a role for germline DND1 mutations in human TGCT.	('human', 'Species', '9606', (86, 91))	('germline', 'Var', (59, 67))	('DND1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('TGCT', 'Disease', (92, 96))
37393	20411342	We therefore searched for germline DND1 mutations in an independent set of sporadic and familial cases of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('testicular cancer', 'Phenotype', 'HP:0010788', (106, 123))	('DND1', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('testicular cancer', 'Disease', 'MESH:D013736', (106, 123))	('testicular cancer', 'Disease', (106, 123))
37399	20411342	We tested 210 control chromosomes for any DND1 variant we detected in the patients if it was not reported as a common polymorphism in NCBI dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/).	('patients', 'Species', '9606', (74, 82))	('DND1', 'Gene', (42, 46))	('variant', 'Var', (47, 54))
37402	20411342	One patient was found to have an exon 4 missense mutation (see "Results" section) so the paraffin blocks of his tumor were sampled for DNA extraction and subsequent sequencing of the relevant part of DND1 to search for loss of heterozygosity.	('paraffin', 'Chemical', 'MESH:D010232', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('DND1', 'Gene', (200, 204))	('tumor', 'Disease', (112, 117))	('exon', 'Var', (33, 37))	('missense mutation', 'Var', (40, 57))
37404	20411342	In exon 4 of DND1 we observed a single base substitution c.657C > G (p.Asp219Glu) (Fig.	('c.657C > G', 'Mutation', 'c.657C>G', (57, 67))	('p.Asp219Glu', 'Mutation', 'p.D219E', (69, 80))	('c.657C > G', 'Var', (57, 67))	('DND1', 'Gene', (13, 17))
37413	20411342	This variant has no effect on the function of the splice acceptor site, nor does it create a novel splice site (Netgene and Berkeley Drosophila Genome Project tools).	('splice acceptor site', 'MPA', (50, 70))	('function', 'MPA', (34, 42))	('variant', 'Var', (5, 12))	('Drosophila', 'Species', '7227', (133, 143))
37419	20411342	The NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) reports a high heterozygosity frequency for both variants: 0.499 for c.363T > C and 0.497 for c.604 + 47G > A, and both are regarded as normal population variants.	('47G > A', 'Var', (170, 177))	('0.497', 'Var', (152, 157))	('c.363T > C', 'Mutation', 'rs2563333', (137, 147))	('c.363T > C', 'Var', (137, 147))	('47G > A', 'SUBSTITUTION', 'None', (170, 177))	('0.499', 'Var', (127, 132))
37421	20411342	From a clinical point of view, his family history was negative for cancer and the fact that both his father and brothers carry the variant suggests either low penetrance or that the variant makes no contribution to the tumor development.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('variant', 'Var', (131, 138))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (219, 224))	('men', 'Species', '9606', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
37425	20411342	The other variants, c.363T > C and c.604 + 47G > A, observed frequently in our patients, have been reported as common polymorphisms by NCBI dbSNP and are not therefore suspected of contributing to TGCT development.	('contributing', 'Reg', (181, 193))	('47G > A', 'Var', (43, 50))	('c.363T > C', 'Var', (20, 30))	('patients', 'Species', '9606', (79, 87))	('men', 'Species', '9606', (209, 212))	('47G > A', 'SUBSTITUTION', 'None', (43, 50))	('TGCT', 'Disease', (197, 201))	('c.363T > C', 'Mutation', 'rs2563333', (20, 30))
37426	20411342	The p.Glu86Ala DND1 variant detected in a single TGCT case by Linger et al.	('p.Glu86Ala', 'Var', (4, 14))	('p.Glu86Ala', 'Mutation', 'p.E86A', (4, 14))	('DND1', 'Gene', (15, 19))
37429	20411342	A role for germline or somatic DND1 mutations in human cancer, and in particular in TGCT, cannot be ruled out.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('DND1', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('TGCT', 'Disease', (84, 88))
37432	20411342	However, the vast majority of germline mutations in the known human tumor syndromes are truncating mutations, or in some cases missense mutations, e.g.	('tumor', 'Disease', (68, 73))	('truncating', 'MPA', (88, 98))	('missense mutations', 'Var', (127, 145))	('human', 'Species', '9606', (62, 67))	('germline mutations', 'Var', (30, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
37434	20411342	It is therefore reasonable to conclude that germline DND1 mutations are unlikely to contribute to tumor development in the majority of testicular germ cell tumors diagnosed in juveniles and adults.	('contribute', 'Reg', (84, 94))	('mutations', 'Var', (58, 67))	('testicular germ cell tumors', 'Disease', 'MESH:C563236', (135, 162))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('men', 'Species', '9606', (111, 114))	('testicular germ cell tumors', 'Disease', (135, 162))	('germ cell tumors', 'Phenotype', 'HP:0100728', (146, 162))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('germ cell tumor', 'Phenotype', 'HP:0100728', (146, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (98, 103))	('DND1', 'Gene', (53, 57))
37435	20411342	Whether this is also true for the very rare group of teratomas and yolk-sac tumors of neonates and infants, that more closely resemble the tumors observed in mice with germline DND1 mutations, remains to be investigated.	('teratomas', 'Disease', (53, 62))	('teratomas', 'Disease', 'MESH:D013724', (53, 62))	('infants', 'Species', '9606', (99, 106))	('mice', 'Species', '10090', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('teratoma', 'Phenotype', 'HP:0009792', (53, 61))	('tumors', 'Disease', (139, 145))	('DND1', 'Gene', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('teratomas', 'Phenotype', 'HP:0009792', (53, 62))	('mutations', 'Var', (182, 191))
37488	21951524	The loss of Blimp1 in mutant mice results in reduced somatic gene silencing, loss of founder PGCs, and lack of PGC migration.	('reduced', 'NegReg', (45, 52))	('somatic gene silencing', 'MPA', (53, 75))	('lack', 'NegReg', (103, 107))	('PGC', 'Gene', (93, 96))	('PGC', 'Gene', '109820', (111, 114))	('PGC', 'Gene', (111, 114))	('mutant', 'Var', (22, 28))	('loss', 'NegReg', (77, 81))	('mice', 'Species', '10090', (29, 33))	('loss', 'NegReg', (4, 8))	('Blimp1', 'Gene', (12, 18))	('PGC', 'Gene', '109820', (93, 96))
37489	21951524	By E7.25, there are approximately 40 Blimp1 positive, specified PGCs..	('PGC', 'Gene', '109820', (64, 67))	('PGC', 'Gene', (64, 67))	('E7.25', 'Var', (3, 8))
37506	21951524	It was demonstrated that PGCs will migrate to ectopic locations in response to aberrant SDF-1a secreting cells.	('PGC', 'Gene', (25, 28))	('migrate', 'CPA', (35, 42))	('SDF-1a', 'Gene', '352944', (88, 94))	('aberrant', 'Var', (79, 87))	('PGC', 'Gene', '109820', (25, 28))	('SDF-1a', 'Gene', (88, 94))
37536	21951524	Disruption of this regulation can lead to disorders such as infertility, chromosomal abnormalities, and germ cell tumors.	('germ cell tumors', 'Disease', (104, 120))	('germ cell tumors', 'Phenotype', 'HP:0100728', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('germ cell tumors', 'Disease', 'MESH:D009373', (104, 120))	('germ cell tumor', 'Phenotype', 'HP:0100728', (104, 119))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (73, 98))	('lead to', 'Reg', (34, 41))	('chromosomal abnormalities', 'Disease', (73, 98))	('infertility', 'Disease', 'MESH:D007247', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('infertility', 'Phenotype', 'HP:0000789', (60, 71))	('infertility', 'Disease', (60, 71))	('Disruption', 'Var', (0, 10))
37553	21951524	Mutations in Dead-end/Ter in the 129-strain mice cause significant PGC loss and increased type I testicular germ cell tumor susceptibility.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('PGC loss', 'Disease', (67, 75))	('increased', 'PosReg', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Dead-end/Ter', 'Gene', (13, 25))	('germ cell tumor', 'Phenotype', 'HP:0100728', (108, 123))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (118, 123))	('PGC loss', 'Disease', 'MESH:D015431', (67, 75))	('mice', 'Species', '10090', (44, 48))
37554	21951524	Targeted deletion of Pten in mouse PGCs leads to greater risk for testicular teratomas, increased germ cell proliferation, and greater capacity to generate embryonic germ cells in culture; thus indicating an important role for Pten in regulating germ cell proliferation and differentiation.	('greater', 'PosReg', (127, 134))	('testicular teratomas', 'Phenotype', 'HP:0100616', (66, 86))	('germ cell proliferation', 'CPA', (98, 121))	('testicular teratomas', 'Disease', (66, 86))	('deletion', 'Var', (9, 17))	('PGC', 'Gene', (35, 38))	('teratomas', 'Phenotype', 'HP:0009792', (77, 86))	('increased', 'PosReg', (88, 97))	('Pten', 'Gene', (21, 25))	('testicular teratomas', 'Disease', 'MESH:C562472', (66, 86))	('mouse', 'Species', '10090', (29, 34))	('Pten', 'Gene', '19211', (21, 25))	('Pten', 'Gene', (227, 231))	('PGC', 'Gene', '109820', (35, 38))	('Pten', 'Gene', '19211', (227, 231))
37577	21951524	Very few mutations associated with TGCT development have been identified, primarily due to lack of large pedigrees for analysis and the lack of suitable animal models for type II TGCTs.	('GCT', 'Gene', (180, 183))	('GCT', 'Gene', (36, 39))	('mutations', 'Var', (9, 18))	('GCT', 'Gene', '25797', (180, 183))	('GCT', 'Gene', '25797', (36, 39))	('men', 'Species', '9606', (47, 50))
37578	21951524	However, activating mutations in c-Kit exon17, in particular at codon 816, are associated predominantly with bilateral TGCTs, which only account for up to 5% of TGCTs.	('c-Kit', 'Gene', (33, 38))	('at codon 816', 'Var', (61, 73))	('GCT', 'Gene', '25797', (120, 123))	('associated', 'Reg', (79, 89))	('GCT', 'Gene', '25797', (162, 165))	('GCT', 'Gene', (120, 123))	('activating', 'PosReg', (9, 19))	('c-Kit', 'Gene', '30256', (33, 38))	('GCT', 'Gene', (162, 165))
37587	21951524	Bauer and Goetz identified 11 mutations that caused gonadal phenotypes in either males or females during a mutational screen using N-ethyl N-nitrosourea.	('gonadal', 'Disease', (52, 59))	('caused', 'Reg', (45, 51))	('mutations', 'Var', (30, 39))	('N-ethyl N-nitrosourea', 'Chemical', 'MESH:D005038', (131, 152))
37589	21951524	During a forward genetic screen to identify cancer susceptibility mutations, we identified a highly heritable testicular germ cell tumor (tgct) mutant.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('germ cell tumor', 'Phenotype', 'HP:0100728', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Disease', (131, 136))	('mutant', 'Var', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
37592	21951524	In the Medaka fish mutant, hotei, a nonsense mutation in anti-Mullerian hormone receptor II (AMHRII) impairs gonadal development and results in a phenotype somewhat overlapping that of the zebrafish tgct mutant.	('AMHRII', 'Gene', (93, 99))	('zebrafish', 'Species', '7955', (189, 198))	('nonsense mutation', 'Var', (36, 53))	('gonadal development', 'CPA', (109, 128))	('men', 'Species', '9606', (124, 127))	('impairs gonadal development', 'Phenotype', 'HP:0008373', (101, 128))	('results in', 'Reg', (133, 143))	('Medaka', 'Species', '8090', (7, 13))	('impairs', 'NegReg', (101, 108))
37593	21951524	Hotei (hot) mutant fish develop enlarged gonads; males exhibit hypertrophic testes with disorganized spermatogenesis, whereas females display arrested follicular development.	('men', 'Species', '9606', (169, 172))	('hypertrophic', 'Disease', (63, 75))	('mutant', 'Var', (12, 18))	('hypertrophic', 'Disease', 'MESH:D006984', (63, 75))	('hypertrophic testes', 'Phenotype', 'HP:0000053', (63, 82))
37602	21951524	Recently, Leu and Draper achieved robust and specific expression of transgenes in the early cells of the testis and ovary using the ziwi promoter (Leu and Draper).	('ziwi', 'Gene', '368200', (132, 136))	('ovary', 'Disease', (116, 121))	('ovary', 'Disease', 'MESH:D010051', (116, 121))	('transgenes', 'Var', (68, 78))	('ziwi', 'Gene', (132, 136))
37643	31191602	For testicular germ cell tumors (GCT), circulating microRNAs 371a-3p and 372-3p in serum and plasma have been proposed as biomarkers for diagnostic and disease monitoring purposes.	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('GCT', 'Phenotype', 'HP:0100728', (33, 36))	('germ cell tumors', 'Phenotype', 'HP:0100728', (15, 31))	('372-3p', 'Var', (73, 79))	('microRNAs 371a-3p', 'Var', (51, 68))
37658	31191602	Lysis of blood cells during phlebotomy or sample handling can therefore yield false high levels of miRNAs not reflecting the actual levels in circulation.	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('amp', 'Chemical', 'MESH:D000249', (43, 46))	('yield', 'Reg', (72, 77))	('Lysis', 'Var', (0, 5))
37678	31191602	TotalRNA including small RNAs was extracted from all samples using the miRNeasy kit (Qiagen P/N 217004, protocol RY43).	('miR', 'Gene', (71, 74))	('amp', 'Chemical', 'MESH:D000249', (54, 57))	('P/N 217004', 'Var', (92, 102))	('miR', 'Gene', '220972', (71, 74))	('P/N 217004', 'SUBSTITUTION', 'None', (92, 102))
37729	31191602	We also based our choice of A414 as the preferred method for hemolysis detection on the finding of Shah et al where A414 detects hemolysis down to 0.004% and correlates well with the miR-451a/23a ratio.	('A414', 'Chemical', '-', (116, 120))	('A414', 'Var', (116, 120))	('detects', 'Reg', (121, 128))	('hemolysis', 'Disease', (129, 138))	('A414', 'Chemical', '-', (28, 32))	('hemolysis', 'Disease', (61, 70))	('miR-451a', 'Gene', (183, 191))	('miR-451a', 'Gene', '574411', (183, 191))	('hemolysis', 'Disease', 'MESH:D006461', (129, 138))	('hemolysis', 'Disease', 'MESH:D006461', (61, 70))
37770	30634670	This model fits TGCTs genesis and places epigenetic deregulation as the perfect culprit mechanism for mediating this environment-genetics interaction and for explaining clinical findings that compose the TDS and that associate with increased risk of TGCTs.	('men', 'Species', '9606', (124, 127))	('TGCTs', 'Disease', (250, 255))	('fits TGCTs genesis', 'Disease', 'MESH:D012640', (11, 29))	('epigenetic deregulation', 'Var', (41, 64))	('fits TGCTs genesis', 'Disease', (11, 29))
37772	30634670	Importantly, these studies have put in evidence the polygenic character of the TGCT tumor model, identifying candidate culprit single nucleotide polymorphisms (SNPs) implicated in several distinct pathways, from the well-known KIT-KITL to DNA damage repair (namely RAD51C and BRCA1), from sex determination/germ cell specification (namely DMRT1, ZFPM1, and PRDM14) to apoptosis/cell cycle (including GSPT1 and CHEK2), from telomere maintenance (including TERT and ATFIP) to centrosome organization/microtubule assembly (TEX14, PMF1, and CENPE).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('RAD51C', 'Gene', (265, 271))	('PRDM14', 'Gene', (357, 363))	('CHEK2', 'Gene', '11200', (410, 415))	('GSPT1', 'Gene', '2935', (400, 405))	('CENPE', 'Gene', (537, 542))	('PRDM14', 'Gene', '63978', (357, 363))	('PMF1', 'Gene', (527, 531))	('GSPT1', 'Gene', (400, 405))	('DMRT1', 'Gene', (339, 344))	('PMF1', 'Gene', '11243', (527, 531))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TEX14', 'Gene', (520, 525))	('KITL', 'Gene', '4254', (231, 235))	('TERT', 'Gene', (455, 459))	('TERT', 'Gene', '7015', (455, 459))	('ZFPM1', 'Gene', '161882', (346, 351))	('CENPE', 'Gene', '1062', (537, 542))	('KITL', 'Gene', (231, 235))	('BRCA1', 'Gene', '672', (276, 281))	('BRCA1', 'Gene', (276, 281))	('TEX14', 'Gene', '56155', (520, 525))	('ZFPM1', 'Gene', (346, 351))	('implicated', 'Reg', (166, 176))	('single nucleotide polymorphisms', 'Var', (127, 158))	('RAD51C', 'Gene', '5889', (265, 271))	('tumor', 'Disease', (84, 89))	('DMRT1', 'Gene', '1761', (339, 344))	('CHEK2', 'Gene', (410, 415))
37776	30634670	Other risk factors include perinatal factors, such as low and high birthweight, decreased gestational age, maternal bleeding, and low parity.	('high birthweight', 'Phenotype', 'HP:0001520', (62, 78))	('low', 'Var', (54, 57))	('decreased', 'NegReg', (80, 89))	('low and high birthweight', 'Phenotype', 'HP:0001518', (54, 78))	('maternal bleeding', 'Disease', 'MESH:D006470', (107, 124))	('decreased gestational age', 'Phenotype', 'HP:0001518', (80, 105))	('low parity', 'CPA', (130, 140))	('gestational age', 'CPA', (90, 105))	('maternal bleeding', 'Disease', (107, 124))
37795	30634670	In the germline, however, GI needs to be early erased during PGCs migration, by means of demethylation of CpG sites, allowing for genesis of germ cells with no parental-specific epigenetic modifications.	('PGC', 'Gene', '5225', (61, 64))	('PGC', 'Gene', (61, 64))	('CpG', 'Gene', (106, 109))	('demethylation', 'Var', (89, 102))
37800	30634670	According to the proposed and above-mentioned model, errors in regulation of the developmental potential of embryonic stem and early PGCs may give rise essentially to extragonadal tumors early in life, whereas deregulation of the developmental potential already in the germline originates a multitude of tumors preferentially located in the gonads which are primarily diagnosed after childhood.	('tumors', 'Disease', (304, 310))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('men', 'Species', '9606', (36, 39))	('errors', 'Var', (53, 59))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('men', 'Species', '9606', (237, 240))	('men', 'Species', '9606', (88, 91))	('PGC', 'Gene', '5225', (133, 136))	('PGC', 'Gene', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('give rise', 'Reg', (142, 151))
37812	30634670	Polyploidization, in addition to a hypomethylated genome, contribute to chromosomal instability in these neoplasms, which further drives tumor progression; however, mutations and amplifications of oncogenes are rather rare in TGCTs, with KIT mutation being the most common, especially in SEs and in bilateral cases.	('KIT', 'Gene', (238, 241))	('tumor', 'Disease', (137, 142))	('amplifications', 'Var', (179, 193))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('drives', 'Reg', (130, 136))	('chromosomal instability', 'Phenotype', 'HP:0040012', (72, 95))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('common', 'Reg', (266, 272))	('TGCTs', 'Disease', (226, 231))	('neoplasm', 'Phenotype', 'HP:0002664', (105, 113))	('SEs', 'Disease', (288, 291))	('mutations', 'Var', (165, 174))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))	('mutation', 'Var', (242, 250))	('neoplasms', 'Disease', (105, 114))
37813	30634670	has showed, by use of whole genome and targeted-sequencing, that NSTs are initiated by genome duplication, followed by chromosome copy number alterations in cancer stem cells, with very low accumulation of somatic mutations, even in cases resistant to therapy.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('genome duplication', 'Var', (87, 105))	('cancer', 'Disease', (157, 163))	('NSTs', 'Disease', (65, 69))	('chromosome', 'CPA', (119, 129))	('initiated by', 'Reg', (74, 86))
37826	30634670	findings reflect, once again, a developmental model for TGCTs, with GCNIS and SEs showing XIST expression still not accompanied by methylation of the inactive X chromosome (a status typical of early germ cells), with more differentiated NSTs exhibiting both XIST expression and methylation of the inactive X chromosome (similar to female and extraembryonic tissues), and finally ECs displaying an intermediate pattern between the two.	('methylation', 'Var', (278, 289))	('GCNIS', 'Chemical', '-', (68, 73))	('XIST', 'Gene', '7503', (258, 262))	('XIST', 'Gene', '7503', (90, 94))	('men', 'Species', '9606', (39, 42))	('XIST', 'Gene', (258, 262))	('XIST', 'Gene', (90, 94))
37831	30634670	Region IV was frequently unmethylated in TGCTs, especially in SEs and patients with advanced disease, and no demethylated signals were detected in somatic cancers in males (serum samples of kidney and bladder cancer patients).	('unmethylated', 'Var', (25, 37))	('SEs', 'Disease', (62, 65))	('patients', 'Species', '9606', (70, 78))	('bladder cancer', 'Disease', 'MESH:D001749', (201, 215))	('advanced disease', 'Disease', 'MESH:D020178', (84, 100))	('TGCTs', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('patients', 'Species', '9606', (216, 224))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('cancers', 'Disease', (155, 162))	('advanced disease', 'Disease', (84, 100))	('kidney and bladder cancer', 'Phenotype', 'HP:0009726', (190, 215))
37838	30634670	Finally, the authors reported partial demethylation also in non-cancerous testicular parenchyma adjacent to TGCTs (without evidence of GCNIS); this somewhat unexpected finding is possibly due to epigenetic abnormalities related to defects in spermatogenesis and those occurring in stromal cells, similar to previous findings in gastric cancer.	('non-cancerous testicular parenchyma', 'Disease', (60, 95))	('defects in spermatogenesis', 'Phenotype', 'HP:0008669', (231, 257))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('gastric cancer', 'Disease', (328, 342))	('gastric cancer', 'Disease', 'MESH:D013274', (328, 342))	('defects', 'Var', (231, 238))	('spermatogenesis', 'CPA', (242, 257))	('gastric cancer', 'Phenotype', 'HP:0012126', (328, 342))	('GCNIS', 'Chemical', '-', (135, 140))	('non-cancerous testicular parenchyma', 'Disease', 'MESH:D013736', (60, 95))	('epigenetic abnormalities', 'Var', (195, 219))	('partial demethylation', 'MPA', (30, 51))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
37839	30634670	These findings might point towards an impact of field-cancerization, with cancer-associated stromal cells sharing epigenetic changes with the accompanying tumor epithelial cells, and being biologically different from normal stroma unrelated to the tumor bulk.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', (155, 160))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('epigenetic changes', 'Var', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
37847	30634670	This way, the authors uncovered a hypomethylation locus which proved to be consistently present in TGCTs (both SEs and NSTs), corresponding to hypomethylation of the DPPA3 (also known as STELLA) gene promoter.	('DPPA3', 'Gene', '359787', (166, 171))	('DPPA3', 'Gene', (166, 171))	('hypomethylation', 'Var', (143, 158))	('STELLA', 'Gene', '359787', (187, 193))	('TGCTs', 'Gene', (99, 104))	('STELLA', 'Gene', (187, 193))
37848	30634670	This maternal-effect gene implicated in protecting parental imprints from erasure in the post-fertilization demethylation process, is expressed in both TGCTs and PGCs, and was shown to be hypomethylated in TGCTs (irrespective of the histology:SEs or NSTs:reflecting the pattern observed in PGCs), but always (hyper)methylated in all tested somatic tissues.	('hyper', 'Disease', (309, 314))	('PGC', 'Gene', '5225', (162, 165))	('PGC', 'Gene', (162, 165))	('PGC', 'Gene', '5225', (290, 293))	('PGC', 'Gene', (290, 293))	('hypomethylated', 'Var', (188, 202))	('hyper', 'Disease', 'MESH:D053307', (309, 314))
37855	30634670	After data processing (assuring exclusion of confounders such as cross hybridization, SNPs, poor probe performance) a total of 437,882 valid probes were employed, with additional annotation including small nuclear RNAs (snRNAs) and miRs, repetitive elements and imprinted segments.	('men', 'Species', '9606', (275, 278))	('repetitive elements', 'Var', (238, 257))	('small', 'Var', (200, 205))	('men', 'Species', '9606', (252, 255))	('miR', 'Gene', '220972', (232, 235))	('miR', 'Gene', (232, 235))
37862	30634670	In their study, they have profiled six pure ECs (metastatic and non-metastatic) with methylated DNA immunoprecipitation (MeDIP) followed by DNA-tiling hybridization (using Human Tiling Array 2.0R Chips), identifying hypermethylated DMRs in this tumor subtype, including X- and Y-linked genes and others related to metabolism.	('hyper', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('Human', 'Species', '9606', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('hyper', 'Disease', 'MESH:D053307', (216, 221))	('tumor', 'Disease', (245, 250))	('DMRs', 'Chemical', '-', (232, 236))	('DMRs', 'Var', (232, 236))
37876	30634670	This mechanism constitutes an explanation for tumor progression in TGCTs, which typically show absence of p53 mutations (i.e., they harbor wild-type p53).	('p53', 'Gene', '7157', (106, 109))	('p53', 'Gene', (149, 152))	('mutations', 'Var', (110, 119))	('absence', 'NegReg', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('p53', 'Gene', '7157', (149, 152))	('TGCTs', 'Disease', (67, 72))	('tumor', 'Disease', (46, 51))	('p53', 'Gene', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
37893	30634670	Soon, novel miRs were also uncovered by high-throughput methods, including miR-511, -26b, -769, -23a, -106b, -365, -598, -340, and let-7a.	('miR', 'Gene', '220972', (75, 78))	('let-7a', 'Var', (131, 137))	('miR', 'Gene', (75, 78))	('miR-511', 'Gene', '574445', (75, 82))	('miR-511', 'Gene', (75, 82))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
37900	30634670	The largest series evaluated thus far identified (with ampTSmiR test) miR-371a-3p, 373-3p, and 367-3p as highly sensitive and specific in TGCTs diagnosis (joint AUC of 0.96).	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('miR-371a', 'Gene', '442916', (70, 78))	('373-3p', 'Var', (83, 89))	('367-3p', 'Var', (95, 101))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('TGCTs', 'Disease', (138, 143))	('miR-371a', 'Gene', (70, 78))
37912	30634670	A summary of the mentioned studies on TGCT biomarkers regarding both methylation and miRs is depicted in Table 4.	('miR', 'Gene', '220972', (85, 88))	('men', 'Species', '9606', (17, 20))	('methylation', 'Var', (69, 80))	('miR', 'Gene', (85, 88))
37972	21499930	Health risk factors, such as high blood pressure, high cholesterol, and obesity, have had negative impacts on SF-36 scores, factors which could be affecting this population, but were not directly assessed in the current study.	('high cholesterol', 'Var', (50, 66))	('obesity', 'Phenotype', 'HP:0001513', (72, 79))	('high blood pressure', 'Phenotype', 'HP:0000822', (29, 48))	('negative', 'NegReg', (90, 98))	('obesity', 'Disease', 'MESH:D009765', (72, 79))	('high', 'Disease', (29, 33))	('SF-36', 'Gene', (110, 115))	('obesity', 'Disease', (72, 79))	('cholesterol', 'Chemical', 'MESH:D002784', (55, 66))	('high cholesterol', 'Phenotype', 'HP:0003124', (50, 66))
38063	20648226	Program: T0 min 100% A; T10 min 100% A; T25 min 30% A; T30 min 30% A; T45 min 0% A; T55 min 0% A; T58 min as described in Faucet-Marquis et al., 2006.	('T10', 'Gene', '27883', (24, 27))	('T25', 'Gene', (40, 43))	('T0 min 100', 'Var', (9, 19))	('T25', 'Gene', '21838', (40, 43))	('T10', 'Gene', (24, 27))	('T30 min 30% A; T45 min 0% A; T55 min 0% A; T58 min', 'Var', (55, 105))
38085	20648226	In the case of high exposure, the amount of C-C8dG OTA was 25% higher in testis than in kidney.	('higher', 'PosReg', (63, 69))	('C-C8dG', 'Var', (44, 50))	('C-C8dG', 'Chemical', '-', (44, 50))
38106	20648226	The amount of C-C8dG OTA was significantly higher in testis compared to kidney.	('C-C8dG', 'Var', (14, 20))	('C-C8dG', 'Chemical', '-', (14, 20))	('higher', 'PosReg', (43, 49))
38120	20648226	The C-C8dGMP OTA adduct is the same adduct consistently observed in kidney tumors from patients with BEN in the Balkans and in other European countries.	('kidney tumors', 'Disease', (68, 81))	('C-C8dGMP', 'Var', (4, 12))	('kidney tumors', 'Disease', 'MESH:D007674', (68, 81))	('kidney tumors', 'Phenotype', 'HP:0009726', (68, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('C-C8dGMP', 'Chemical', '-', (4, 12))	('patients', 'Species', '9606', (87, 95))
38138	31600388	The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles.	('inducing', 'Reg', (122, 130))	('cisplatin', 'Var', (54, 63))	('premature ovarian insufficiency', 'Disease', (87, 118))	('activation', 'CPA', (156, 166))	('doxorubicin', 'Chemical', 'MESH:D004317', (68, 79))	('primordial follicles', 'CPA', (170, 190))	('premature ovarian insufficiency', 'Disease', 'MESH:D010051', (87, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('accelerated', 'PosReg', (144, 155))	('atresia', 'Disease', (205, 212))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (36, 52))	('rat', 'Species', '10116', (150, 153))	('cyclophosphamide', 'Var', (36, 52))	('doxorubicin', 'Var', (68, 79))	('increased', 'PosReg', (195, 204))	('premature ovarian insufficiency', 'Phenotype', 'HP:0008209', (87, 118))	('atresia', 'Disease', 'MESH:D018633', (205, 212))
38172	31600388	This will require studies to ensure that the protectants do not interfere with the efficacy of the cancer treatment and that they do not impair the developmental competence of oocytes or lead to the survival of oocytes with DNA damage in the form of genetic or epigenetic mutations.	('genetic', 'Var', (250, 257))	('impair', 'NegReg', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('developmental competence', 'CPA', (148, 172))	('cancer', 'Disease', (99, 105))	('epigenetic mutations', 'Var', (261, 281))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lead to', 'Reg', (187, 194))
38181	31600388	Nonetheless, there is strong clinical evidence that ovarian damage is particularly severe after administration of alkylating and alkylating-like agents, while DOX, which is used to treat a wide range of cancers, is amongst the non-alkylating agents most closely linked to female reproductive problems.	('alkylating', 'Var', (114, 124))	('rat', 'Species', '10116', (104, 107))	('DOX', 'Chemical', 'MESH:D004317', (159, 162))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('ovarian damage', 'Disease', 'MESH:D010049', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('reproductive problems', 'Phenotype', 'HP:0000078', (279, 300))	('ovarian damage', 'Disease', (52, 66))	('cancers', 'Disease', (203, 210))
38182	31600388	Consequently, many of the chemicals currently being investigated as potential protectants have been specifically tested to ameliorate damage induced by CPM, CIS or DOX.	('CPM', 'Chemical', 'MESH:D003520', (152, 155))	('damage', 'MPA', (134, 140))	('rat', 'Species', '10116', (129, 132))	('CPM', 'Var', (152, 155))	('DOX', 'Chemical', 'MESH:D004317', (164, 167))
38194	31600388	From these, it is difficult to determine the precise effects of CPM on PMFs: while the PMF population has been shown to be reduced in size following CPM-exposure, there are reports both of direct damage to this follicle population and of a reduction in PMF numbers following accelerated activation, with the authors also suggesting that phosphoramide mustard itself may even directly induce accelerated PMF activation.	('rat', 'Species', '10116', (397, 400))	('CPM', 'Chemical', 'MESH:D003520', (64, 67))	('CPM', 'Chemical', 'MESH:D003520', (149, 152))	('phosphoramide', 'Chemical', 'MESH:C005438', (337, 350))	('reduction', 'NegReg', (240, 249))	('rat', 'Species', '10116', (281, 284))	('CPM-exposure', 'Var', (149, 161))	('PMF', 'Gene', (253, 256))	('reduced', 'NegReg', (123, 130))
38195	31600388	Direct effects have, however, been clearly demonstrated on PMFs in the mouse (see below) and on growing follicles in human ovarian tissue examined in vitro, with CPM inducing increased granulosa cell apoptosis and follicular atresia.	('CPM', 'Var', (162, 165))	('human', 'Species', '9606', (117, 122))	('rat', 'Species', '10116', (50, 53))	('mouse', 'Species', '10090', (71, 76))	('follicular atresia', 'Disease', 'MESH:D005497', (214, 232))	('follicular atresia', 'Disease', (214, 232))	('inducing', 'Reg', (166, 174))	('increased', 'PosReg', (175, 184))	('granulosa cell apoptosis', 'CPA', (185, 209))	('CPM', 'Chemical', 'MESH:D003520', (162, 165))
38198	31600388	Exposure of growing follicles to CPM, particularly at earlier stages, has also been linked to embryo abnormalities and to malformation in the next generation in later pregnancies (, respectively).	('CPM', 'Var', (33, 36))	('CPM', 'Chemical', 'MESH:D003520', (33, 36))	('linked', 'Reg', (84, 90))	('rat', 'Species', '10116', (151, 154))	('embryo abnormalities', 'Disease', (94, 114))	('embryo abnormalities', 'Disease', 'MESH:D020964', (94, 114))
38204	31600388	Most of our understanding of precisely how CPM induces ovarian damage has come from studies trying to prevent that damage (Table 1).	('induces', 'Reg', (47, 54))	('ovarian damage', 'Disease', (55, 69))	('CPM', 'Var', (43, 46))	('CPM', 'Chemical', 'MESH:D003520', (43, 46))	('ovarian damage', 'Disease', 'MESH:D010049', (55, 69))
38205	31600388	As expected, given what is known about its action on cancer cells, there is clear evidence that CPM leads to an upregulation in apoptosis in the ovary, as is evident from the rapid induction of DNA breaks and from a change in the expression levels of pro- and anti-apoptotic genes.	('expression levels', 'MPA', (230, 247))	('DNA', 'MPA', (194, 197))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('change', 'Reg', (216, 222))	('CPM', 'Var', (96, 99))	('upregulation', 'PosReg', (112, 124))	('CPM', 'Chemical', 'MESH:D003520', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('apoptosis', 'CPA', (128, 137))
38206	31600388	Recent studies have demonstrated that the DNA damage-induced pro-apoptotic protein PUMA plays a key role in inducing oocyte apoptosis in rodents following CPM treatment, as is also the case following irradiation.	('inducing', 'Reg', (108, 116))	('oocyte apoptosis', 'CPA', (117, 133))	('rat', 'Species', '10116', (27, 30))	('CPM', 'Var', (155, 158))	('CPM', 'Chemical', 'MESH:D003520', (155, 158))
38210	31600388	One study has now demonstrated that CPM specifically induces apoptosis in the oocytes of primordial follicles, while also not finding increased activation of such follicles.	('CPM', 'Chemical', 'MESH:D003520', (36, 39))	('apoptosis', 'CPA', (61, 70))	('rat', 'Species', '10116', (25, 28))	('CPM', 'Var', (36, 39))	('induces', 'Reg', (53, 60))
38219	31600388	The immunomodulator AS101 is a non-toxic, tellurium-based compound that modulates the PI3K/PTEN/Akt pathway, reducing the Akt and rpS6 phosphorylation that is induced by CPM.	('rpS6', 'Gene', '20104', (130, 134))	('CPM', 'Chemical', 'MESH:D003520', (170, 173))	('AS101', 'Var', (20, 25))	('modulates', 'Reg', (72, 81))	('PI3K/PTEN/Akt pathway', 'Pathway', (86, 107))	('Akt and', 'Pathway', (122, 129))	('rpS6', 'Gene', (130, 134))	('reducing', 'NegReg', (109, 117))
38221	31600388	In vivo treatment of mice with AS101 lowers CPM-induced loss of PMFs, as well as apoptosis of granulosa cells in growing follicles, leading to improved reproductive outcomes.	('reproductive outcomes', 'CPA', (152, 173))	('improved', 'PosReg', (143, 151))	('loss', 'NegReg', (56, 60))	('mice', 'Species', '10090', (21, 25))	('CPM', 'Chemical', 'MESH:D003520', (44, 47))	('PMFs', 'Protein', (64, 68))	('AS101', 'Var', (31, 36))	('lowers', 'NegReg', (37, 43))
38223	31600388	Importantly, it has been demonstrated that not only does AS101 not interfere with the primary anti-neoplastic activity of CPM in vivo, but, in fact, it also may improve the efficiency of the anti-cancer activity of CPM, possibly due to reduced inflammation.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('AS101', 'Var', (57, 62))	('CPM', 'Chemical', 'MESH:D003520', (215, 218))	('rat', 'Species', '10116', (32, 35))	('improve', 'PosReg', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('CPM', 'Chemical', 'MESH:D003520', (122, 125))	('cancer', 'Disease', (196, 202))	('inflammation', 'Disease', 'MESH:D007249', (244, 256))	('inflammation', 'Disease', (244, 256))
38229	31600388	Deletion of components of the mTOR pathway, including PTEN- and TSC1-negative regulators, can induce accelerated PMF activation in mice.	('accelerated', 'PosReg', (101, 112))	('mTOR', 'Gene', '56717', (30, 34))	('TSC1', 'Gene', '64930', (64, 68))	('TSC1', 'Gene', (64, 68))	('rat', 'Species', '10116', (107, 110))	('PTEN-', 'Gene', (54, 59))	('mice', 'Species', '10090', (131, 135))	('PTEN-', 'Gene', '19211', (54, 59))	('mTOR', 'Gene', (30, 34))	('PMF activation', 'MPA', (113, 127))	('Deletion', 'Var', (0, 8))
38232	31600388	Both treatments preserved the ovarian reserve, with ovaries containing PMF numbers that were comparable to those in control mice; furthermore, fertility was restored.	('ovaries', 'Disease', 'MESH:D010051', (52, 59))	('mice', 'Species', '10090', (124, 128))	('ovarian reserve', 'CPA', (30, 45))	('fertility', 'CPA', (143, 152))	('ovaries', 'Disease', (52, 59))	('PMF numbers', 'Var', (71, 82))
38261	31600388	CIS-exposure also leads to increased reactive oxygen species and a decrease in the ovarian antioxidant capacity.	('increased', 'PosReg', (27, 36))	('CIS-exposure', 'Var', (0, 12))	('decrease', 'NegReg', (67, 75))	('ovarian antioxidant capacity', 'MPA', (83, 111))	('reactive oxygen species', 'MPA', (37, 60))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))
38268	31600388	Recently, CHK2 and the executioner kinase CK1 have been identified as important for the elimination of mouse oocytes following double-stranded breaks in DNA, and their function is essential for downstream activation of TAp63.	('CK1', 'Species', '2498238', (42, 45))	('mouse', 'Species', '10090', (103, 108))	('double-stranded breaks', 'Var', (127, 149))	('p63', 'Gene', '22061', (221, 224))	('CHK2', 'Gene', (10, 14))	('p63', 'Gene', (221, 224))	('CHK2', 'Gene', '50883', (10, 14))
38269	31600388	In vitro, pharmacological inhibition of CHK2/CK1 was shown to be effective at rescuing oocytes from TAp63-mediated apoptosis induced by CIS or by DOX (see below) or following gamma-irradiation.	('CHK2', 'Gene', '50883', (40, 44))	('CK1', 'Species', '2498238', (45, 48))	('DOX', 'Chemical', 'MESH:D004317', (146, 149))	('p63', 'Gene', '22061', (102, 105))	('pharmacological inhibition', 'Var', (10, 36))	('p63', 'Gene', (102, 105))	('CHK2', 'Gene', (40, 44))
38276	31600388	The same conclusion was reached in another study which generated a conditional knockout mouse with an oocyte-specific deletion of Abl1 and Abl2; ovaries from these mice treated with CIS show no protection against apoptosis.	('ovaries', 'Disease', 'MESH:D010051', (145, 152))	('Abl1', 'Gene', (130, 134))	('mice', 'Species', '10090', (164, 168))	('Abl2', 'Gene', '11352', (139, 143))	('Abl2', 'Gene', (139, 143))	('apoptosis', 'CPA', (213, 222))	('ovaries', 'Disease', (145, 152))	('rat', 'Species', '10116', (59, 62))	('mouse', 'Species', '10090', (88, 93))	('deletion', 'Var', (118, 126))	('Abl1', 'Gene', '11350', (130, 134))
38310	31600388	Furthermore, DOX decreases the ovulation rate, and although the ovulated oocytes appear morphologically normal, blastocyst number, litter size, and pup birth weight are reduced.	('blastocyst number', 'CPA', (112, 129))	('pup birth weight', 'CPA', (148, 164))	('decreases', 'NegReg', (17, 26))	('ovulation rate', 'CPA', (31, 45))	('reduced', 'NegReg', (169, 176))	('litter size', 'CPA', (131, 142))	('ovulated oocytes', 'CPA', (64, 80))	('rat', 'Species', '10116', (41, 44))	('DOX', 'Var', (13, 16))	('DOX', 'Chemical', 'MESH:D004317', (13, 16))
38317	31600388	Double-strand breaks and gammaH2AX are also increased in antral follicles in marmoset monkey ovary exposed to DOX, as are metaphase II oocytes which undergo apoptosis after DOX exposure in vitro.	('antral follicles', 'CPA', (57, 73))	('gammaH2AX', 'Gene', (25, 34))	('DOX', 'Chemical', 'MESH:D004317', (110, 113))	('marmoset', 'Species', '9483', (77, 85))	('DOX', 'Chemical', 'MESH:D004317', (173, 176))	('gammaH2AX', 'Gene', '15270', (25, 34))	('increased', 'PosReg', (44, 53))	('Double-strand', 'Var', (0, 13))
38344	31600388	More recently,) also found that AMH reduced the loss of follicles induced by CPM, with protection against the reduction in number of oocytes that could be recovered following ovarian stimulation, although an effect on fertility was not shown.	('CPM', 'Chemical', 'MESH:D003520', (77, 80))	('CPM', 'Var', (77, 80))	('loss', 'CPA', (48, 52))	('reduced', 'NegReg', (36, 43))
38345	31600388	That study also provided data suggesting that AMH regulates FOXO3a phosphorylation and induces autophagy in ovaries.	('ovaries', 'Disease', 'MESH:D010051', (108, 115))	('AMH', 'Var', (46, 49))	('regulates', 'Reg', (50, 59))	('FOXO3a', 'Gene', (60, 66))	('induces', 'Reg', (87, 94))	('ovaries', 'Disease', (108, 115))	('autophagy', 'CPA', (95, 104))	('phosphorylation', 'CPA', (67, 82))	('FOXO3a', 'Gene', '56484', (60, 66))
38350	31600388	An effect has also been seen against CIS in the rat, where all follicle counts (primordial, primary, secondary and tertiary) and serum AMH levels were significantly increased in the G-CSF-CIS treated group compared to the control group.	('rat', 'Species', '10116', (48, 51))	('serum AMH levels', 'MPA', (129, 145))	('CIS', 'Disease', (37, 40))	('increased', 'PosReg', (165, 174))	('G-CSF-CIS', 'Var', (182, 191))
38356	31600388	These results are supported by other studies, where the inhibition of MDR transporters in human and mouse oocytes, as well as deletion of the gene in mice, has led to increased susceptibility to CPM toxicity.	('inhibition', 'NegReg', (56, 66))	('mice', 'Species', '10090', (150, 154))	('mouse', 'Species', '10090', (100, 105))	('toxicity', 'Disease', 'MESH:D064420', (199, 207))	('toxicity', 'Disease', (199, 207))	('human', 'Species', '9606', (90, 95))	('susceptibility', 'MPA', (177, 191))	('deletion', 'Var', (126, 134))	('MDR', 'Enzyme', (70, 73))	('CPM', 'Chemical', 'MESH:D003520', (195, 198))
38365	31600388	A number of potential protectants under current investigation involve manipulating the Akt pathway, stressing the importance of greater understanding of its role, including in the human ovary.	('Akt pathway', 'Pathway', (87, 98))	('human', 'Species', '9606', (180, 185))	('manipulating', 'Var', (70, 82))
38481	26265202	TGCT is thought to be a polygenic disorder caused by the combined effects of multiple, common genetic variants, perhaps acting in concert with certain environmental exposures.	('variants', 'Var', (102, 110))	('polygenic disorder', 'Disease', 'MESH:D030342', (24, 42))	('polygenic disorder', 'Disease', (24, 42))	('TGCT', 'Disease', (0, 4))	('caused by', 'Reg', (43, 52))	('men', 'Species', '9606', (158, 161))
38482	26265202	However, the traditional genetic perspective has been that polygenic disorders should not present as familial clusters, presumably because the penetrance of such variants is low.	('variants', 'Var', (162, 170))	('polygenic disorders', 'Disease', (59, 78))	('polygenic disorders', 'Disease', 'MESH:D030342', (59, 78))
38517	26265202	Within the constraints imposed by the small number of events, none of these features identified a subset of study participants as being at markedly greater risk of developing incident TGCT, although the presence of either microlithiasis (O/E=29.3; 95%CI=10.7-63.7) or UDT (O/E=31.1; 95%CI=8.5-79.7) in the family suggested higher risks.	('microlithiasis', 'Disease', 'MESH:C566478', (222, 236))	('microlithiasis', 'Disease', (222, 236))	('participants', 'Species', '9606', (114, 126))	('UDT', 'Var', (268, 271))	('TGCT', 'Disease', (184, 188))
38530	26265202	Potential mechanisms for this phenomenon include (a) the existence of intermediate-risk variants, like KITLG; (b) the presence of common, low-penetrance variants acting as modifiers of the risks associated with as yet undiscovered rare, high-penetrance variants; and (c) common variants proving to be highly-active functionally.	('men', 'Species', '9606', (35, 38))	('KITLG', 'Gene', '4254', (103, 108))	('variants', 'Var', (153, 161))	('variants', 'Var', (253, 261))	('KITLG', 'Gene', (103, 108))
38556	26265202	These findings support the notion that the combined effect of common, low-penetrance mutations can confer a significant risk of cancer, and provide a rationale for developing more sophisticated risk stratification strategies that might unambiguously identify subsets of men which warrant enhanced education and TGCT surveillance.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('men', 'Species', '9606', (270, 273))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('low-penetrance', 'NegReg', (70, 84))	('cancer', 'Disease', (128, 134))
38660	31652641	Disrupted foetal hormone signalling during foetal development due to the influence of various xenobiotics as well as misbalanced maternal hormone levels is thought to be the cause of multiple disorders linked to TC.	('misbalanced', 'Var', (117, 128))	('Disrupted', 'Reg', (0, 9))	('multiple disorders', 'Disease', (183, 201))	('cause', 'Reg', (174, 179))	('multiple disorders', 'Disease', 'MESH:D009105', (183, 201))	('TC', 'Disease', 'MESH:D013736', (212, 214))	('men', 'Species', '9606', (57, 60))	('TC', 'Phenotype', 'HP:0010788', (212, 214))
38694	31652641	The larger subunit beta (145 amino acids) contains two N-glycans (Asn13 and Asn30) and 4 O-glycans (Ser121, Ser127, Ser132 and Ser138) (Figure 2a).	('Ser121', 'Chemical', 'MESH:C530429', (100, 106))	('Ser132', 'Var', (116, 122))	('Asn13', 'Chemical', 'MESH:C528802', (66, 71))	('Ser127', 'Var', (108, 114))	('Ser', 'Chemical', 'MESH:C530429', (100, 103))	('Ser', 'Chemical', 'MESH:C530429', (116, 119))	('Ser', 'Chemical', 'MESH:C530429', (127, 130))	('Ser', 'Chemical', 'MESH:C530429', (108, 111))	('Ser121', 'Var', (100, 106))	('Ser127', 'Chemical', 'MESH:C530429', (108, 114))	('Ser132', 'Chemical', 'MESH:C530429', (116, 122))	('O-glycans', 'Chemical', 'MESH:D011134', (89, 98))	('Ser138', 'Var', (127, 133))
38695	31652641	Of those 4 O-glycans, three are type 1 O-glycans (Ser127, Ser132, and Ser138) and one is a type 2 O-glycan (Ser121) (Figure 2a).	('O-glycans', 'Chemical', 'MESH:D011134', (11, 20))	('Ser', 'Chemical', 'MESH:C530429', (58, 61))	('O-glycan', 'Chemical', 'MESH:D011134', (11, 19))	('Ser127', 'Var', (50, 56))	('Ser', 'Chemical', 'MESH:C530429', (108, 111))	('Ser', 'Chemical', 'MESH:C530429', (70, 73))	('O-glycans', 'Chemical', 'MESH:D011134', (39, 48))	('Ser132', 'Var', (58, 64))	('O-glycan', 'Chemical', 'MESH:D011134', (39, 47))	('Ser132', 'Chemical', 'MESH:C530429', (58, 64))	('O-glycan', 'Chemical', 'MESH:D011134', (98, 106))	('Ser', 'Chemical', 'MESH:C530429', (50, 53))	('Ser138', 'Var', (70, 76))	('Ser127', 'Chemical', 'MESH:C530429', (50, 56))	('Ser121', 'Chemical', 'MESH:C530429', (108, 114))
38705	31652641	seven semi-independent molecules, when considering functional roles:  significant structural variability involving numerous isoforms combining glycosylation (14 major variants for hCGalpha and 12 major variants for hCGbeta) and structural (nicked forms of hCG, hCGbeta, hCG-H, hCGbeta-H; hCG forms without a terminal CTP tail (beta113-145 containing all 4 O-glycans); beta-core fragment (beta6-40 and beta55-92 linked by a disulphide bond)) variations.	('hCG', 'Gene', '3342', (288, 291))	('hCGbeta', 'Gene', (261, 268))	('hCG', 'Gene', '3342', (256, 259))	('hCG', 'Gene', (256, 259))	('hCG', 'Gene', (288, 291))	('hCGbeta', 'Gene', '1113', (215, 222))	('hCGbeta', 'Gene', (277, 284))	('hCG', 'Gene', '3342', (270, 273))	('hCG', 'Gene', '3342', (215, 218))	('beta-core fragment', 'MPA', (368, 386))	('hCGbeta', 'Gene', '1113', (261, 268))	('hCG', 'Gene', (215, 218))	('men', 'Species', '9606', (382, 385))	('hCG', 'Gene', (270, 273))	('hCG', 'Gene', '3342', (261, 264))	('hCGbeta', 'Gene', '1113', (277, 284))	('disulphide', 'Chemical', 'MESH:C109673', (423, 433))	('variants', 'Var', (167, 175))	('hCG', 'Gene', (261, 264))	('hCGalpha', 'Gene', '1113', (180, 188))	('mole', 'Phenotype', 'HP:0003764', (23, 27))	('hCG', 'Gene', '3342', (277, 280))	('hCG-H', 'Gene', (270, 275))	('hCG-H', 'Gene', '3342', (270, 275))	('hCG', 'Gene', (277, 280))	('hCG', 'Gene', '3342', (180, 183))	('hCGalpha', 'Gene', (180, 188))	('hCG', 'Gene', (180, 183))	('hCGbeta', 'Gene', (215, 222))	('O-glycans', 'Chemical', 'MESH:D011134', (356, 365))
38752	31652641	For example, TC patients negative for microRNA-371a-3p had a better progression-free survival and an overall survival compared to the TC patients with microRNA-371a-3p present in serum.	('microRNA-371a-3p', 'Var', (38, 54))	('better', 'PosReg', (61, 67))	('negative', 'NegReg', (25, 33))	('patients', 'Species', '9606', (16, 24))	('overall survival', 'CPA', (101, 117))	('patients', 'Species', '9606', (137, 145))	('TC', 'Disease', 'MESH:D013736', (134, 136))	('TC', 'Phenotype', 'HP:0010788', (134, 136))	('TC', 'Disease', 'MESH:D013736', (13, 15))	('TC', 'Phenotype', 'HP:0010788', (13, 15))	('progression-free survival', 'CPA', (68, 93))
38756	31652641	The changes/alterations in glycosylation can be successfully applied to the discovery of novel cancer-related biomarkers.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('rat', 'Species', '10116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('changes/alterations', 'Var', (4, 23))	('cancer', 'Disease', (95, 101))	('changes/alterations', 'Reg', (4, 23))	('glycosylation', 'MPA', (27, 40))
38757	31652641	It is estimated that 70+% of all proteins are post-translationally modified by glycosylation with the involvement of glycans in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('men', 'Species', '9606', (142, 145))	('glycosylation', 'Var', (79, 92))	('involvement', 'Reg', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('proteins', 'Protein', (33, 41))	('men', 'Species', '9606', (109, 112))	('cancer', 'Disease', (128, 134))
38768	31652641	With regard to N-glycan analysis, triantennary glycans and fucosylation increased at Asn13 and Asn30 of hCGbeta isolated from the cancer samples.	('Asn30', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('increased', 'PosReg', (72, 81))	('hCGbeta', 'Gene', (104, 111))	('cancer', 'Disease', (130, 136))	('hCGbeta', 'Gene', '1113', (104, 111))	('triantennary glycans', 'Protein', (34, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('fucosylation', 'MPA', (59, 71))	('Asn13', 'Chemical', 'MESH:C528802', (85, 90))
38769	31652641	With regard to O-glycans, type 2 O-glycans, in particular, were enriched at Ser127 and Ser132 in cancer and especially, in TC.	('type 2 O-glycans', 'Protein', (26, 42))	('Ser127', 'Var', (76, 82))	('cancer', 'Disease', (97, 103))	('Ser132', 'Chemical', 'MESH:C530429', (87, 93))	('O-glycans', 'Chemical', 'MESH:D011134', (15, 24))	('Ser127', 'Chemical', 'MESH:C530429', (76, 82))	('O-glycans', 'Chemical', 'MESH:D011134', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('TC', 'Disease', 'MESH:D013736', (123, 125))	('TC', 'Phenotype', 'HP:0010788', (123, 125))	('Ser132', 'Var', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
38770	31652641	The other important difference between O-glycosylation at Ser127 and Ser132 is a complete absence of short O-glycans, like Tn (N-acetygalactosamine attached to serine/threonine), T (galactose-beta-1,3-N-acetygalactosamine attached to serine/threonine) and sialyl T antigen on hCGbeta from TC patients in comparison with an invasive mole patient and pregnant women.	('hCGbeta', 'Gene', (276, 283))	('galactose', 'Chemical', 'MESH:D005690', (182, 191))	('patients', 'Species', '9606', (292, 300))	('Ser132', 'Chemical', 'MESH:C530429', (69, 75))	('serine', 'Chemical', 'MESH:C047902', (160, 166))	('O-glycans', 'Chemical', 'MESH:D011134', (107, 116))	('women', 'Species', '9606', (358, 363))	('N-acetygalactosamine', 'Chemical', 'MESH:D009584', (127, 147))	('patient', 'Species', '9606', (292, 299))	('hCGbeta', 'Gene', '1113', (276, 283))	('Ser132', 'Var', (69, 75))	('Ser127', 'Chemical', 'MESH:C530429', (58, 64))	('mole', 'Phenotype', 'HP:0003764', (332, 336))	('threonine', 'Chemical', 'MESH:C061951', (241, 250))	('absence', 'NegReg', (90, 97))	('threonine', 'Chemical', 'MESH:C061951', (167, 176))	('TC', 'Phenotype', 'HP:0010788', (289, 291))	('TC', 'Disease', 'MESH:D013736', (289, 291))	('sialyl T antigen', 'Protein', (256, 272))	('serine', 'Chemical', 'MESH:C047902', (234, 240))	('patient', 'Species', '9606', (337, 344))	('Ser127', 'Var', (58, 64))	('beta-1,3', 'Gene', '28888;28881;28883', (192, 200))	('N-acetygalactosamine', 'Chemical', 'MESH:D009584', (201, 221))
38771	31652641	The authors suggest that these glycan differences might facilitate the application of lectins to the diagnosis of malignancies (including TC), but a larger number of samples need to be analysed to confirm such results.	('differences', 'Var', (38, 49))	('TC', 'Disease', 'MESH:D013736', (138, 140))	('TC', 'Phenotype', 'HP:0010788', (138, 140))	('facilitate', 'PosReg', (56, 66))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('application', 'MPA', (71, 82))	('malignancies', 'Disease', (114, 126))
38848	31652641	Accordingly, it can be stated that an analysis of the changes of the other three O-glycans (Ser121, Ser127 and Ser138) and four N-glycans, so far underexplored, is worth investigating to identify additional promising glycans as TC biomarkers for diagnostic and prognostic purposes and for disease recurrence evaluation.	('Ser127', 'Var', (100, 106))	('Ser', 'Chemical', 'MESH:C530429', (92, 95))	('TC', 'Disease', 'MESH:D013736', (228, 230))	('Ser', 'Chemical', 'MESH:C530429', (100, 103))	('Ser121', 'Chemical', 'MESH:C530429', (92, 98))	('TC', 'Phenotype', 'HP:0010788', (228, 230))	('Ser127', 'Chemical', 'MESH:C530429', (100, 106))	('Ser', 'Chemical', 'MESH:C530429', (111, 114))	('O-glycans', 'Chemical', 'MESH:D011134', (81, 90))	('Ser138', 'Var', (111, 117))	('Ser121', 'Var', (92, 98))
38863	31533343	The percentage of demethylated XIST fragment in cell lines reflected their chromosomal constitution (number of extra X chromosomes).	('demethylated', 'Var', (18, 30))	('XIST', 'Gene', (31, 35))	('XIST', 'Gene', '7503', (31, 35))
38865	31533343	Conclusions: The X chromosome inactivation event and demethylated XIST promoter are promising biomarkers for TGCTs and for assessing spermatogenesis quality.	('GCTs', 'Phenotype', 'HP:0100728', (110, 114))	('X chromosome inactivation', 'Var', (17, 42))	('TGCTs', 'Disease', (109, 114))	('XIST', 'Gene', '7503', (66, 70))	('XIST', 'Gene', (66, 70))	('demethylated', 'Var', (53, 65))
38868	31533343	Epigenetic deregulation plays an important role in their genesis, which is in line with this developmental model, since few recurrent mutations are found in these neoplasms.	('neoplasms', 'Disease', (163, 172))	('neoplasms', 'Disease', 'MESH:D009369', (163, 172))	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('Epigenetic deregulation', 'Var', (0, 23))
38878	31533343	studied in detail the XIST promoter (by bisulfite sequencing, followed by conventional polymerase chain reaction (PCR) with primers specific for the methylated and demethylated XIST promoter), finding that region IV was frequently demethylated in TGCTs (again, especially in SEs).	('XIST', 'Gene', (177, 181))	('XIST', 'Gene', '7503', (177, 181))	('XIST', 'Gene', '7503', (22, 26))	('bisulfite', 'Chemical', 'MESH:C042345', (40, 49))	('XIST', 'Gene', (22, 26))	('demethylated', 'Var', (231, 243))	('GCTs', 'Phenotype', 'HP:0100728', (248, 252))	('SE', 'Disease', 'None', (275, 277))
38884	31533343	The aim of this work is to explore the role of demethylated and methylated XIST promoter as a candidate biomarker for both TGCTs as well as extensiveness of spermatogenesis.	('XIST', 'Gene', '7503', (75, 79))	('demethylated', 'Var', (47, 59))	('GCTs', 'Phenotype', 'HP:0100728', (124, 128))	('XIST', 'Gene', (75, 79))
38894	31533343	Moreover, we found no significant association with patients' stage, metastatic dissemination or the International Germ Cell Cancer Collaborative Group (IGCCCG) category (data not shown), which is in line with publicly available TCGA data, showing hypermethylation of the XIST promoter both in SE as well as in NS.	('SE', 'Disease', 'None', (293, 295))	('Germ Cell Cancer', 'Phenotype', 'HP:0100728', (114, 130))	('XIST', 'Gene', (271, 275))	('XIST', 'Gene', '7503', (271, 275))	('patients', 'Species', '9606', (51, 59))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('hypermethylation', 'Var', (247, 263))
38896	31533343	We then focused on the demethylated XIST promoter fragment, which we studied in two independent cohorts.	('XIST', 'Gene', (36, 40))	('XIST', 'Gene', '7503', (36, 40))	('demethylated', 'Var', (23, 35))
38905	31533343	Moreover, demethylated XIST was also detected in 16 of 17 (94.1%) GCNIS lesions.	('XIST', 'Gene', '7503', (23, 27))	('XIST', 'Gene', (23, 27))	('demethylated', 'Var', (10, 22))	('detected', 'Reg', (37, 45))	('GCNIS lesions', 'Disease', (66, 79))
38908	31533343	Regarding (T)GCT cell lines, demethylated XIST was detected in all four cell lines.	('XIST', 'Gene', (42, 46))	('XIST', 'Gene', '7503', (42, 46))	('demethylated', 'Var', (29, 41))
38909	31533343	The percentage of demethylated XIST was significantly higher in NT2 as compared with the remaining cell lines (adjusted p-values of 0.0079, 0.0021, and 0.0108 as compared with TCam-2, NCCIT, and 2102Ep, respectively) (Figure 7).	('higher', 'PosReg', (54, 60))	('NT2', 'Var', (64, 67))	('demethylated', 'MPA', (18, 30))	('XIST', 'Gene', '7503', (31, 35))	('XIST', 'Gene', (31, 35))	('TCam-2', 'Chemical', 'MESH:C485520', (176, 182))
38911	31533343	We found a significant and strong positive correlation between the relative levels of demethylated XIST promoter and the Johnsen's score attributed by the pathologist (rs = 0.75, p < 0.0001).	('XIST', 'Gene', (99, 103))	('XIST', 'Gene', '7503', (99, 103))	('demethylated', 'Var', (86, 98))	("Johnsen's score", 'Disease', (121, 136))
38913	31533343	Demethylated XIST fragment was able to discriminate among testicular parenchyma with a higher or lower (i.e., <4 or >=4) Johnsen's score with an AUC of 0.87 (Figure 8).	('XIST', 'Gene', '7503', (13, 17))	('XIST', 'Gene', (13, 17))	('lower', 'NegReg', (97, 102))	('Demethylated', 'Var', (0, 12))	('testicular parenchyma', 'Disease', (58, 79))
38921	31533343	Subsequent works have demonstrated quite convincingly the existence of X chromosome gains in TGCTs, both SE and NS alike, and XIST expression in both tumor types.	('GCTs', 'Phenotype', 'HP:0100728', (94, 98))	('gains', 'PosReg', (84, 89))	('X chromosome', 'Var', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('XIST', 'Gene', (126, 130))	('SE', 'Disease', 'None', (105, 107))	('XIST', 'Gene', '7503', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TGCTs', 'Disease', (93, 98))	('tumor', 'Disease', (150, 155))
38927	31533343	In a similar fashion, they also detected the methylated XIST fragment in several samples, always more frequently in NS as compared to SE (77% and 45% of NS tissues/plasma samples vs. 61% and 43% of SE tissues/plasma samples).	('SE', 'Disease', 'None', (134, 136))	('detected', 'Reg', (32, 40))	('methylated', 'Var', (45, 55))	('SE', 'Disease', 'None', (198, 200))	('XIST', 'Gene', (56, 60))	('XIST', 'Gene', '7503', (56, 60))
38931	31533343	The absence of associations with clinical variables might indicate that the methylation status of XIST relates more to the defined (developmental) biology of these tumors, limiting its value as a prognostic biomarker, although diagnostically of interest.	('limiting', 'NegReg', (172, 180))	('tumors', 'Disease', (164, 170))	('XIST', 'Gene', (98, 102))	('methylation status', 'Var', (76, 94))	('relates', 'Reg', (103, 110))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('XIST', 'Gene', '7503', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
38933	31533343	Our results are in line with those findings, since demethylated XIST was detected in 16 of 17 tested samples.	('XIST', 'Gene', (64, 68))	('XIST', 'Gene', '7503', (64, 68))	('demethylated', 'Var', (51, 63))	('detected', 'Reg', (73, 81))
38938	31533343	This is again in accordance with our data, showing that demethylated XIST was detected in all cell lines tested (both SE-like TCam-2 and NS-derived NCCIT, NT2, and 2102Ep), compatible with XIST expression, although with some variation in distinct cells (Figure 7).	('SE', 'Disease', 'None', (118, 120))	('demethylated', 'Var', (56, 68))	('TCam-2', 'Chemical', 'MESH:C485520', (126, 132))	('XIST', 'Gene', (189, 193))	('XIST', 'Gene', '7503', (69, 73))	('XIST', 'Gene', '7503', (189, 193))	('XIST', 'Gene', (69, 73))
38967	31533343	Primer annealing temperature was optimized at 64  C for methylated and demethylated XIST and 60  C for beta-actin.	('XIST', 'Gene', '7503', (84, 88))	('XIST', 'Gene', (84, 88))	('methylated', 'Var', (56, 66))	('beta-actin', 'Gene', (103, 113))	('beta-actin', 'Gene', '728378', (103, 113))	('demethylated', 'Var', (71, 83))
38968	31533343	For quantification purposes, five serial dilutions (in duplicate) of previously bisulfite treated CpGenomeTM Universal Methylated DNA and Unmethylated DNA (Merck Millipore, Burlingtone, MA, USA) were included for methylated and demethylated XIST, respectively.	('demethylated', 'Var', (228, 240))	('Burlingtone', 'Chemical', 'None', (173, 184))	('Methyl', 'Chemical', 'MESH:C031105', (119, 125))	('XIST', 'Gene', '7503', (241, 245))	('XIST', 'Gene', (241, 245))	('bisulfite', 'Chemical', 'MESH:C042345', (80, 89))
38988	31533343	For both methylated and demethylated XIST, the Youden's method was used to achieve a cutoff to maximize the sensitivity and specificity.	('XIST', 'Gene', (37, 41))	('XIST', 'Gene', '7503', (37, 41))	('demethylated', 'Var', (24, 36))	('methylated', 'Var', (9, 19))
38995	31533343	Demethylated XIST fragment relative amounts in testicular germ cell tumors and testicular parenchyma of the discovery cohort.	('tumors', 'Disease', (68, 74))	('XIST', 'Gene', '7503', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('germ cell tumors', 'Phenotype', 'HP:0100728', (58, 74))	('XIST', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Demethylated', 'Var', (0, 12))
39000	31533343	XIST methylation and expression and X chromosome inactivation in humans.	('methylation', 'Var', (5, 16))	('expression', 'MPA', (21, 31))	('XIST', 'Gene', '7503', (0, 4))	('XIST', 'Gene', (0, 4))	('humans', 'Species', '9606', (65, 71))
39065	28612337	We investigated 261 retrospective serum samples of six selected fully evaluated TGCC patients with a proven relapse using the ampTSmiR test for miR-371a-3p, miR-373-3p, and miR-367-3p and compared the results to those of the conventional protein biomarkers.	('miR-367', 'Gene', '442912', (173, 180))	('GCC', 'Phenotype', 'HP:0100728', (81, 84))	('patients', 'Species', '9606', (85, 93))	('miR-367', 'Gene', (173, 180))	('miR-373-3p', 'Var', (157, 167))	('miR-371a-3p', 'Var', (144, 155))
39083	28612337	In the current proof-of-concept study, we examined the levels of miR-371a-3p, miR-373-3p and miR-367-3p in serum samples of a follow-up series of selected TGCC patients ranging from the time of primary diagnosis to relapse and complete remission.	('GCC', 'Phenotype', 'HP:0100728', (156, 159))	('miR-367', 'Gene', '442912', (93, 100))	('patients', 'Species', '9606', (160, 168))	('miR-367', 'Gene', (93, 100))	('miR-371a-3p', 'Var', (65, 76))	('TGCC', 'Disease', (155, 159))	('miR-373-3p', 'Var', (78, 88))
39094	28612337	cDNA generation and quantification of miR levels were performed using TaqMan Micro RNA assays for the analysis of hsa-miR-371a-3p (002124), hsa-miR-373-3p (000561), hsa-miR-367-3p (000555), ath-miR-159a (000338) and hsa-miR-30b-5p (000602).	('000338', 'Var', (204, 210))	('miR-30b', 'Gene', '407030', (220, 227))	('miR-30b', 'Gene', (220, 227))	('hsa-miR-373', 'Gene', '442918', (140, 151))	('hsa-miR-373', 'Gene', (140, 151))	('hsa-miR-367', 'Gene', (165, 176))	('hsa-miR-367', 'Gene', '442912', (165, 176))
39096	28612337	This resulted in a 89% sensitivity and a 90% specificity for miR-371a-3p, a 70% sensitivity and a 89% specificity for miR-373-3p and a 79% sensitivity and a 85% specificity for miR-367-3p.	('miR-371a-3p', 'Var', (61, 72))	('miR-367', 'Gene', '442912', (177, 184))	('miR-367', 'Gene', (177, 184))	('miR-373-3p', 'Var', (118, 128))
39111	28612337	The ampTSmiR test revealed elevated levels of miR-371a-3p, miR-373-3p and miR-367-3p (Supplementary Table 1, Fig.	('miR-367', 'Gene', '442912', (74, 81))	('miR-371a-3p', 'Var', (46, 57))	('miR-367', 'Gene', (74, 81))	('miR-373-3p', 'Var', (59, 69))
39122	28612337	Remarkably, for as yet unknown reasons, positive ampTSmiR scores were found for miR-371a-3p, miR-373-3p and miR-367-3p (not shown) at 15 months after relapse.	('positive', 'PosReg', (40, 48))	('miR-373-3p', 'Var', (93, 103))	('miR-367', 'Gene', (108, 115))	('miR-371a-3p', 'Var', (80, 91))	('miR-367', 'Gene', '442912', (108, 115))
39134	28612337	The levels of both B-HCG and miR-371a-3p, miR-373-3p and miR-367 indicated the presence of a PILN, of which the first miR (as well as B-HCG, being borderline) were the first to be positive.	('miR-367', 'Gene', (57, 64))	('miR-371a-3p', 'Var', (29, 40))	('miR-367', 'Gene', '442912', (57, 64))	('miR-373-3p', 'Var', (42, 52))	('indicated', 'Reg', (65, 74))
39139	28612337	A single positive score for miR-373-3p and miR-371a-3p (just above cut-off level) was obtained seven years after primary diagnosis, but without known clinical consequences.	('miR-371a-3p', 'Var', (43, 54))	('clinical', 'Species', '191496', (150, 158))	('miR-373-3p', 'Var', (28, 38))
39150	28612337	The conventional biomarker tests showed highly elevated levels of B-HCG (88,915 U/L), AFP (2024 U/L) and LDH (3698 U/L) (Fig.	('elevated', 'PosReg', (47, 55))	('2024 U/L', 'Var', (91, 99))	('AFP', 'Gene', (86, 89))	('LDH', 'Gene', (105, 108))	('3698 U/L', 'Var', (110, 118))	('AFP', 'Gene', '174', (86, 89))
39151	28612337	Similarly, miR-371a-3p, miR-373-3p and miR-367-3p showed high levels (Supplementary Table 1, Fig.	('miR-367', 'Gene', (39, 46))	('miR-373-3p', 'Var', (24, 34))	('miR-367', 'Gene', '442912', (39, 46))	('miR-371a-3p', 'Var', (11, 22))
39174	28612337	Of the three selected miRs, miR-371a-3p was found to be the most sensitive and specific one and to outperform the others in detecting a relapse, which is in agreement with recently published results of larger series of patients with a shorter follow-up and less measure points.	('relapse', 'Disease', (136, 143))	('miR-371a-3p', 'Var', (28, 39))	('outperform', 'PosReg', (99, 109))	('patients', 'Species', '9606', (219, 227))
39188	21668838	In this comprehensive review of human epidemiologic studies which have tested for associations between organochlorines and facets of TDS, we find evidence for associations between the exposures p,p'-DDE, cis-nonachlor, and trans-nonachlor with TGCT.	('p', 'Chemical', 'MESH:D010758', (196, 197))	('associations', 'Interaction', (159, 171))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (204, 217))	("p'-DDE", 'Var', (196, 202))	('p', 'Chemical', 'MESH:D010758', (11, 12))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (194, 202))	('TDS', 'Chemical', '-', (133, 136))	('trans-nonachlor', 'Var', (223, 238))	('p', 'Chemical', 'MESH:D010758', (186, 187))	('p', 'Chemical', 'MESH:D010758', (194, 195))	('organochlorines', 'Chemical', 'MESH:D006843', (103, 118))	('human', 'Species', '9606', (32, 37))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (223, 238))	('p', 'Chemical', 'MESH:D010758', (39, 40))	('cis-nonachlor', 'Var', (204, 217))
39195	21668838	Organochlorines are also highly insoluble in water and accumulate in adipose tissue when ingested.	('insoluble', 'MPA', (32, 41))	('accumulate', 'PosReg', (55, 65))	('p', 'Chemical', 'MESH:D010758', (72, 73))	('Organochlorines', 'Var', (0, 15))	('water', 'Chemical', 'MESH:D014867', (45, 50))	('Organochlorines', 'Chemical', 'MESH:D006843', (0, 15))
39196	21668838	Combined, these properties make organochlorines persistent pollutants that bioaccumulate and biomagnify.	('organochlorines', 'Chemical', 'MESH:D006843', (32, 47))	('organochlorines', 'Var', (32, 47))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('p', 'Chemical', 'MESH:D010758', (48, 49))	('bioaccumulate', 'MPA', (75, 88))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('p', 'Chemical', 'MESH:D010758', (19, 20))
39202	21668838	Agricultural use of DDT is now banned by the Stockholm Convention on Persistent Organic Pollutants (United Nations Environment Programme (UNEP), 2001), although DDT continues to be used as an anti-malarial in parts of Africa and Asia.	('DDT', 'Chemical', 'MESH:D003634', (161, 164))	('DDT', 'Chemical', 'MESH:D003634', (20, 23))	('malaria', 'Disease', (197, 204))	('malaria', 'Disease', 'MESH:D008288', (197, 204))	('DDT', 'Var', (161, 164))	('men', 'Species', '9606', (122, 125))	('p', 'Chemical', 'MESH:D010758', (209, 210))
39205	21668838	The International Agency for Research on Cancer (IARC) classifies DDT as a Group 2B carcinogen (possibly carcinogenic to humans).	('DDT', 'Var', (66, 69))	('carcinogenic', 'Disease', (105, 117))	('DDT', 'Chemical', 'MESH:D003634', (66, 69))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('humans', 'Species', '9606', (121, 127))	('carcinogenic', 'Disease', 'MESH:D063646', (105, 117))
39209	21668838	PCBs are known to be able to cause hormonal perturbations and have been associated with urogenital maldevelopment in animal models.	('urogenital maldevelopment', 'Disease', (88, 113))	('associated', 'Reg', (72, 82))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('hormonal perturbations', 'MPA', (35, 57))	('urogenital maldevelopment', 'Phenotype', 'HP:0000119', (88, 113))	('PCBs', 'Var', (0, 4))	('PCBs', 'Chemical', 'MESH:D011078', (0, 4))	('cause', 'Reg', (29, 34))	('p', 'Chemical', 'MESH:D010758', (44, 45))
39232	21668838	Using a similar prospective study design, Bhatia and colleagues examined the association between maternal serum levels of p,p'-DDT and p,p'-DDE and cryptorchidism and hypospadias in the prospective Child Health and Development Studies (CHDS).	("p,p'-DDT", 'Chemical', 'MESH:D003634', (122, 130))	('p', 'Chemical', 'MESH:D010758', (151, 152))	('association', 'Interaction', (77, 88))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('p', 'Chemical', 'MESH:D010758', (172, 173))	('p', 'Chemical', 'MESH:D010758', (124, 125))	('p', 'Chemical', 'MESH:D010758', (186, 187))	("p'-DDT", 'Var', (124, 130))	('p', 'Chemical', 'MESH:D010758', (122, 123))	('cryptorchidism and hypospadias', 'Disease', 'MESH:D003456', (148, 178))	('p', 'Chemical', 'MESH:D010758', (169, 170))	('p', 'Chemical', 'MESH:D010758', (16, 17))	('Child', 'Species', '9606', (198, 203))	('p', 'Chemical', 'MESH:D010758', (137, 138))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (135, 143))	('hypospadias', 'Phenotype', 'HP:0000047', (167, 178))	('p', 'Chemical', 'MESH:D010758', (221, 222))	('p', 'Chemical', 'MESH:D010758', (135, 136))	('p', 'Chemical', 'MESH:D010758', (190, 191))	('cryptorchidism', 'Phenotype', 'HP:0000028', (148, 162))
39257	21668838	In summary, none reported a significant association with p,p'-DDT, o,p'-DDT or p,p'-DDE and either cryptorchidism or hypospadias.	('cryptorchidism', 'Phenotype', 'HP:0000028', (99, 113))	("p,p'-DDT", 'Chemical', 'MESH:D003634', (57, 65))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('cryptorchidism or hypospadias', 'Disease', 'MESH:D003456', (99, 128))	('p', 'Chemical', 'MESH:D010758', (79, 80))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('hypospadias', 'Phenotype', 'HP:0000047', (117, 128))	("p'-DDT", 'Var', (69, 75))	("o,p'-DDT", 'Chemical', 'MESH:C016340', (67, 75))	('p', 'Chemical', 'MESH:D010758', (57, 58))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('p', 'Chemical', 'MESH:D010758', (81, 82))	('cryptorchidism or hypospadias', 'Disease', (99, 128))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (79, 87))	('p', 'Chemical', 'MESH:D010758', (102, 103))	('p', 'Chemical', 'MESH:D010758', (122, 123))
39270	21668838	In a cross-sectional evaluation of East and West coast Swedish fishermen (n=195), Rignell-Hydbom and colleagues examined the association between serum levels of p,p'-DDE and testis volume, semen volume, sperm count, concentration, and motility ( p'-DDE and male reproductive function).	('semen volume', 'CPA', (189, 201))	('concentration', 'CPA', (216, 229))	("p'-DDE", 'Chemical', '-', (246, 252))	('sperm count', 'CPA', (203, 214))	('men', 'Species', '9606', (69, 72))	('p', 'Chemical', 'MESH:D010758', (264, 265))	('men', 'Species', '9606', (191, 194))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('association', 'Interaction', (125, 136))	("p'-DDE", 'Var', (163, 169))	('p', 'Chemical', 'MESH:D010758', (204, 205))	('male reproductive function', 'CPA', (257, 283))	('motility', 'CPA', (235, 243))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (161, 169))	("p'-DDE", 'Chemical', '-', (163, 169))	('p', 'Chemical', 'MESH:D010758', (246, 247))	('p', 'Chemical', 'MESH:D010758', (161, 162))	('testis volume', 'CPA', (174, 187))
39281	21668838	No associations were found between lipid-adjusted serum p,p'-DDT and semen volume, sperm count, sperm concentration, percent progressive motility or percent motile sperm, and percent normal morphology.	('p', 'Chemical', 'MESH:D010758', (165, 166))	('p', 'Chemical', 'MESH:D010758', (125, 126))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('p', 'Chemical', 'MESH:D010758', (149, 150))	('p', 'Chemical', 'MESH:D010758', (84, 85))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('semen volume', 'CPA', (69, 81))	('sperm count', 'CPA', (83, 94))	('men', 'Species', '9606', (71, 74))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	("p,p'-DDT", 'Chemical', 'MESH:D003634', (56, 64))	('percent progressive motility', 'CPA', (117, 145))	('p', 'Chemical', 'MESH:D010758', (58, 59))	('p', 'Chemical', 'MESH:D010758', (97, 98))	("p'-DDT", 'Var', (58, 64))	('percent motile sperm', 'CPA', (149, 169))	('p', 'Chemical', 'MESH:D010758', (193, 194))	('p', 'Chemical', 'MESH:D010758', (175, 176))	('p', 'Chemical', 'MESH:D010758', (56, 57))	('sperm concentration', 'CPA', (96, 115))
39304	21668838	In the study of Swedish fisherman, serum PCB-153 concentration was weakly associated with motility (mean difference 9.9%; 95% CI: -1% - 21%) but was not associated with the other semen variables (volume, count, and concentration) ( p'-DDE and male reproductive function).	("p'-DDE", 'Chemical', '-', (232, 238))	('serum', 'Var', (35, 40))	('associated', 'Interaction', (74, 84))	('motility', 'CPA', (90, 98))	('PCB', 'Gene', '5091', (41, 44))	('PCB', 'Gene', (41, 44))	('p', 'Chemical', 'MESH:D010758', (250, 251))	('p', 'Chemical', 'MESH:D010758', (232, 233))	('men', 'Species', '9606', (181, 184))
39312	21668838	reported that serum PCB-138 concentration was associated with decreased sperm motility (OR for less than 50% normal sperm motility: tertile 2 vs. 1 = 1.68; tertile 3 vs. 1 = 2.35; p-trend = 0.03) and decreased percent normal morphology (OR for less than 4% normal sperm morphology: tertile 2 vs. 1 = 1.36; tertile 3 vs. 1 = 2.53; p-trend = 0.04) ( p'-DDE).	('serum', 'Var', (14, 19))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('PCB', 'Gene', '5091', (20, 23))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('decreased', 'NegReg', (200, 209))	('p', 'Chemical', 'MESH:D010758', (348, 349))	('percent normal morphology', 'CPA', (210, 235))	('sperm motility', 'CPA', (72, 86))	('p', 'Chemical', 'MESH:D010758', (228, 229))	('decreased sperm motility', 'Phenotype', 'HP:0012207', (62, 86))	('p', 'Chemical', 'MESH:D010758', (330, 331))	('PCB', 'Gene', (20, 23))	('p', 'Chemical', 'MESH:D010758', (273, 274))	('decreased', 'NegReg', (62, 71))	('p', 'Chemical', 'MESH:D010758', (210, 211))	('p', 'Chemical', 'MESH:D010758', (265, 266))	('p', 'Chemical', 'MESH:D010758', (2, 3))	("p'-DDE", 'Chemical', '-', (348, 354))	('p', 'Chemical', 'MESH:D010758', (73, 74))
39330	21668838	TCDD exposure during early life was associated with decreased sperm concentration (p-value = 0.025), and motility (p-value = 0.018).	('exposure', 'Var', (5, 13))	('TCDD', 'Gene', (0, 4))	('p', 'Chemical', 'MESH:D010758', (63, 64))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('p', 'Chemical', 'MESH:D010758', (7, 8))	('decreased', 'NegReg', (52, 61))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('motility', 'CPA', (105, 113))	('TCDD', 'Chemical', 'MESH:D000072317', (0, 4))	('sperm concentration', 'CPA', (62, 81))
39339	21668838	Evidence indicates that TGCT may be more likely to be the result of maldevelopment than the result of an accumulation of mutations leading to uncontrolled mitosis and loss of the ability to induce apoptosis.	('mitosis', 'Disease', 'None', (155, 162))	('leading to', 'Reg', (131, 141))	('mutations', 'Var', (121, 130))	('TGCT', 'Disease', (24, 28))	('p', 'Chemical', 'MESH:D010758', (77, 78))	('uncontrolled', 'MPA', (142, 154))	('loss', 'NegReg', (167, 171))	('p', 'Chemical', 'MESH:D010758', (200, 201))	('p', 'Chemical', 'MESH:D010758', (198, 199))	('mitosis', 'Disease', (155, 162))
39369	21668838	Chlordane and its derivatives (oxychlordane, trans-nonachlor, cis-nonachlor, MC6) have been assessed by the four previously mentioned studies for association with TGCT (Table 5), and only the ATLAS Study failed to find at least one statistically significant association with these compounds.	('p', 'Chemical', 'MESH:D010758', (284, 285))	('oxychlordane', 'Var', (31, 43))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (62, 75))	('men', 'Species', '9606', (124, 127))	('cis-nonachlor', 'Var', (62, 75))	('trans-nonachlor', 'Var', (45, 60))	('MC6', 'Chemical', '-', (77, 80))	('Chlordane', 'Chemical', 'MESH:D002706', (0, 9))	('TGCT', 'Disease', (163, 167))	('association', 'Interaction', (146, 157))	('oxychlordane', 'Chemical', 'MESH:C008743', (31, 43))	('MC6', 'Var', (77, 80))	('p', 'Chemical', 'MESH:D010758', (113, 114))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (45, 60))
39373	21668838	These latter two studies, which indicated evidence for associations between trans-nonachlor, cis-nonachlor, total chlordanes and TGCT, also have the advantage of having assessed pre-diagnostic serum samples.	('p', 'Chemical', 'MESH:D010758', (178, 179))	('associations', 'Interaction', (55, 67))	('p', 'Chemical', 'MESH:D010758', (202, 203))	('trans-nonachlor', 'Var', (76, 91))	('TGCT', 'Gene', (129, 133))	('cis-nonachlor', 'Var', (93, 106))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (76, 91))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (93, 106))	('chlordanes', 'Chemical', 'MESH:D002706', (114, 124))
39374	21668838	Thus, overall it appears as though cis- and trans-nonachlor may be associated with TGCT.	('trans-nonachlor', 'Var', (44, 59))	('cis- and trans-nonachlor', 'Chemical', '-', (35, 59))	('TGCT', 'Disease', (83, 87))	('associated', 'Reg', (67, 77))	('cis-', 'Var', (35, 39))
39394	21668838	The study also found an association between the DDT:DDE ratio and conclude that this may represent either a slower metabolism of DDT to DDE or more recent exposure in mothers of TGCT cases compared with mothers of control subjects.	('metabolism', 'MPA', (115, 125))	('TGCT', 'Gene', (178, 182))	('p', 'Chemical', 'MESH:D010758', (192, 193))	('p', 'Chemical', 'MESH:D010758', (91, 92))	('DDE', 'Chemical', 'MESH:D003633', (136, 139))	('association', 'Interaction', (24, 35))	('DDT', 'Chemical', 'MESH:D003634', (48, 51))	('DDT', 'Chemical', 'MESH:D003634', (129, 132))	('DDE', 'Chemical', 'MESH:D003633', (52, 55))	('DDE', 'MPA', (52, 55))	('DDT', 'MPA', (48, 51))	('slower', 'NegReg', (108, 114))	('p', 'Chemical', 'MESH:D010758', (157, 158))	('cases', 'Var', (183, 188))
39401	21668838	Current epidemiological evidence would infer that p,p'-DDE and chlordane, particularly cis- and trans-nonachlor, are positively associated with TGCT.	('cis- and trans-nonachlor', 'Chemical', '-', (87, 111))	('TGCT', 'Disease', (144, 148))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (50, 58))	('chlordane', 'Chemical', 'MESH:D002706', (63, 72))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('p', 'Chemical', 'MESH:D010758', (52, 53))	('associated', 'Reg', (128, 138))	('p', 'Chemical', 'MESH:D010758', (9, 10))	('p', 'Chemical', 'MESH:D010758', (74, 75))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('cis-', 'Var', (87, 91))
39457	33072608	Conversely, patients with low PD-L1 expression showed a better outcome, namely, better progression-free survival and overall survival.	('patients', 'Species', '9606', (12, 20))	('low', 'Var', (26, 29))	('overall survival', 'CPA', (117, 133))	('progression-free survival', 'CPA', (87, 112))	('PD-L1', 'Gene', (30, 35))	('better', 'PosReg', (80, 86))	('expression', 'MPA', (36, 46))
39466	33072608	A favorable prognosis was possibly mediated by PD-L1 expression on TILs, which could reduce the proinflammatory environment, and vice versa.	('expression', 'Var', (53, 63))	('PD-L1', 'Gene', (47, 52))	('reduce', 'NegReg', (85, 91))	('proinflammatory environment', 'MPA', (96, 123))	('men', 'Species', '9606', (119, 122))
39471	33072608	These results are in line with data from Sadigh et al., where choriocarcinoma was the only GCT histological subtype expressing PD-L1 in tumor cells, whereas other subtypes primarily expressed varying levels of PD-L1 on tumor-associated macrophages (TAMs) without true PD-L1 expression on tumor cells themselves.	('tumor', 'Disease', (288, 293))	('PD-L1', 'Var', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('choriocarcinoma', 'Disease', (62, 77))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (62, 77))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('choriocarcinoma', 'Disease', 'MESH:D002822', (62, 77))	('GCT', 'Phenotype', 'HP:0100728', (91, 94))	('PD-L1', 'Var', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('TAMs', 'Chemical', '-', (249, 253))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (136, 141))
39473	33072608	The absence of PD-L1 positivity in ICs was also determined to be an independent predictor of worse relapse-free survival (RFS) when adjusting for several other clinical variables.	('PD-L1', 'Gene', (15, 20))	('positivity', 'Var', (21, 31))	('RFS', 'Disease', (122, 125))	('RFS', 'Disease', 'MESH:D005198', (122, 125))	('relapse-free survival', 'CPA', (99, 120))	('absence', 'Var', (4, 11))
39485	33072608	PD-L1 represents an important mechanism by which cancer cells are able to suppress antitumor immunity in the tumor microenvironment; therefore, alterations in the PD-1 signaling pathway have a great impact on immunological homeostasis.	('PD-1 signaling pathway', 'Pathway', (163, 185))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (87, 92))	('impact', 'Reg', (199, 205))	('suppress', 'NegReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('alterations', 'Var', (144, 155))	('men', 'Species', '9606', (127, 130))	('cancer', 'Disease', (49, 55))	('tumor', 'Disease', (109, 114))
39528	33072608	Furthermore, the antitumor effect of brentuximab-vedotin was also assessed in another phase II trial enrolling 24 patients with CD30+ germ cell tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('germ cell tumor', 'Phenotype', 'HP:0100728', (134, 149))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('germ cell tumors', 'Phenotype', 'HP:0100728', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('brentuximab', 'Chemical', 'MESH:C504717', (37, 48))	('vedotin', 'Chemical', '-', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('patients', 'Species', '9606', (114, 122))	('CD30+', 'Var', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
39567	33072608	A pathological vascular system in combination with an impaired blood-testis barrier is associated with an increased influx of cytotoxic immune cells into tumor tissue.	('vascular system', 'CPA', (15, 30))	('pathological', 'Var', (2, 14))	('pathological vascular system', 'Phenotype', 'HP:0002597', (2, 30))	('impaired blood-testis', 'Disease', (54, 75))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('impaired blood-testis', 'Disease', 'MESH:C564174', (54, 75))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('increased', 'PosReg', (106, 115))	('influx of cytotoxic immune cells into', 'MPA', (116, 153))	('tumor', 'Disease', (154, 159))
39569	33072608	Subsequently, an anti-angiogenic treatment might be responsible for the reduction of the anti-PD-L1/PD-1 treatment effect.	('reduction', 'NegReg', (72, 81))	('men', 'Species', '9606', (38, 41))	('anti-PD-L1/PD-1', 'Var', (89, 104))	('men', 'Species', '9606', (110, 113))
39692	23781896	Increasing evidence shows diverse regulatory roles of NATs such as RNA interference (RNAi), alternative splicing, trafficking, genomic imprinting and X-chromosome inactivation.	('X-chromosome inactivation', 'Var', (150, 175))	('RNA interference', 'MPA', (67, 83))	('trafficking', 'MPA', (114, 125))	('alternative', 'MPA', (92, 103))	('NAT', 'Gene', (54, 57))	('NAT', 'Gene', '6046', (54, 57))
39697	23781896	The expression of human cis-NATs transcribed by RNA Pol II is epigenetically regulated, and aberrant production of these transcripts has been linked with human disease.	('aberrant', 'Var', (92, 100))	('human', 'Species', '9606', (154, 159))	('NAT', 'Gene', (28, 31))	('RNA Pol II', 'Gene', (48, 58))	('linked', 'Reg', (142, 148))	('NAT', 'Gene', '6046', (28, 31))	('human', 'Species', '9606', (18, 23))
39701	23781896	LUC7L is expressed in the opposite direction from the aberrant expression of an antisense HBA2 transcript, which methylates the CpG island of HBA2 and results in silencing gene (Figure 2, action in cis).	('methylates', 'Var', (113, 123))	('HBA2', 'Gene', '3040', (142, 146))	('HBA2', 'Gene', '3040', (90, 94))	('silencing gene', 'MPA', (162, 176))	('LUC7L', 'Gene', (0, 5))	('HBA2', 'Gene', (142, 146))	('HBA2', 'Gene', (90, 94))	('LUC7L', 'Gene', '55692', (0, 5))
39704	23781896	Modarresi et al., demonstrated that inhibition of brain-derived neurotrophic factor antisense transcript (BDNF-AS) leads to upregulation of BDNF expression and induces neuronal outgrowth and differentiation both in vitro, and in vivo, which is essential for their function and survival.	('BDNF-AS', 'Gene', (106, 113))	('upregulation', 'PosReg', (124, 136))	('BDNF', 'Gene', '627', (106, 110))	('BDNF-AS', 'Gene', '497258', (106, 113))	('inhibition', 'Var', (36, 46))	('brain-derived neurotrophic factor', 'Gene', '627', (50, 83))	('BDNF', 'Gene', '627', (140, 144))	('neuronal outgrowth', 'CPA', (168, 186))	('expression', 'MPA', (145, 155))	('differentiation', 'CPA', (191, 206))	('brain-derived neurotrophic factor', 'Gene', (50, 83))	('BDNF', 'Gene', (106, 110))	('BDNF', 'Gene', (140, 144))	('induces', 'PosReg', (160, 167))
39713	23781896	SPRY4-IT1 is upregulated in melanoma cells, and its knockdown resulted in defects in cell growth, invasion, and elevated rates of apoptosis in melanoma cells.	('melanoma', 'Disease', (28, 36))	('apoptosis', 'CPA', (130, 139))	('invasion', 'CPA', (98, 106))	('SPRY4-IT1', 'Gene', (0, 9))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (0, 9))	('upregulated', 'PosReg', (13, 24))	('defects', 'NegReg', (74, 81))	('elevated', 'PosReg', (112, 120))	('cell growth', 'CPA', (85, 96))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('knockdown', 'Var', (52, 61))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
39730	23781896	Some of the functions in which lincRNAs have been implicated include genomic programming, maintenance of pluripotency and lineage commitment control and control of epigenetic changes.	('lineage commitment', 'CPA', (122, 140))	('ncRNA', 'Gene', '220202', (33, 38))	('epigenetic changes', 'Var', (164, 182))	('pluripotency', 'Disease', (105, 117))	('pluripotency', 'Disease', 'None', (105, 117))	('ncRNA', 'Gene', (33, 38))
39745	23781896	Therefore, any error that occurs in either step will lead to abnormal mRNA, and disrupt the open reading frame and result in human diseases, such as atypical cystic fibrosis, Frasier syndrome, spinal muscular atrophy, etc.	('Frasier syndrome', 'Disease', 'MESH:D052159', (175, 191))	('abnormal mRNA', 'MPA', (61, 74))	('lead to', 'Reg', (53, 60))	('atypical cystic fibrosis', 'Disease', (149, 173))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (193, 216))	('spinal muscular atrophy', 'Disease', (193, 216))	('open reading frame', 'MPA', (92, 110))	('human', 'Species', '9606', (125, 130))	('disrupt', 'NegReg', (80, 87))	('error', 'Var', (15, 20))	('atypical cystic fibrosis', 'Disease', 'MESH:D003550', (149, 173))	('Frasier syndrome', 'Disease', (175, 191))	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (193, 216))	('muscular atrophy', 'Phenotype', 'HP:0003202', (200, 216))	('result in', 'Reg', (115, 124))
39746	23781896	Faustino and Cooper provided comprehensive documentation on abnormal splicing mechanisms that lead to human disorders.	('human', 'Species', '9606', (102, 107))	('lead to', 'Reg', (94, 101))	('human disorders', 'Disease', (102, 117))	('abnormal splicing mechanisms', 'Var', (60, 88))
39758	23781896	These include C/D snoRNAs (U3, U8, U22) and H/ACA snoRNAs (snR10, snR30, E2 and E3).	('snoRNA', 'Gene', '85390', (18, 24))	('snoRNA', 'Gene', (50, 56))	('snoRNA', 'Gene', (18, 24))	('snoRNA', 'Gene', '85390', (50, 56))	('D snoRNA', 'Phenotype', 'HP:0025267', (16, 24))	('E2 and E3', 'Gene', '26765;84548', (73, 82))	('D snoRNAs', 'Phenotype', 'HP:0025267', (16, 25))	('snR10', 'Var', (59, 64))
39761	23781896	The Prader-Willi syndrome is linked to the deletion of region on chromosome 15 which contains a brain-specific C/D RNA (HBII-52) that processes serotonin-2c receptor (HTR2C) pre-mRNA.	('deletion', 'Var', (43, 51))	('HBII-52', 'Gene', '692218', (120, 127))	('linked', 'Reg', (29, 35))	('Prader-Willi syndrome', 'Disease', (4, 25))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (4, 25))	('HTR2C', 'Gene', '3358', (167, 172))	('serotonin-2c receptor', 'MPA', (144, 165))	('HTR2C', 'Gene', (167, 172))	('HBII-52', 'Gene', (120, 127))
39774	23781896	More recently it was shown that in a cellular model for myeloproliferative neoplasms, mutant SET2 cells express at least 58 moRNA at moderate to high level and 95% of these moRNAs correspond to the 5' arm of its miRNA.	('SET2', 'Gene', '29072', (93, 97))	('mutant', 'Var', (86, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (75, 84))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (56, 84))	('SET2', 'Gene', (93, 97))	('neoplasms', 'Disease', (75, 84))	('neoplasms', 'Disease', 'MESH:D009369', (75, 84))
39780	23781896	PiRNAs have been shown to act in the Piwi-dependent transposon silencing and heterochromatin modification in germinal cells to maintain the genomic integrity of these cells.	('Piwi', 'Gene', '9271', (37, 41))	('Piwi', 'Gene', (37, 41))	('maintain', 'Reg', (127, 135))	('genomic integrity', 'CPA', (140, 157))	('silencing', 'NegReg', (63, 72))	('heterochromatin modification', 'Var', (77, 105))	('transposon', 'Var', (52, 62))
39782	23781896	Also piRNAs and piwi proteins have recently been identified outside of germinal cell lines, e.g., in human cancer cells, suggesting a role for this ncRNAs in the epigenetic regulation of aberrant cancer "stem cell like" cells that are proposed to be critical for tumor initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('ncRNA', 'Gene', '220202', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('piwi', 'Gene', (16, 20))	('tumor initiation', 'Disease', 'MESH:D009369', (263, 279))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('human', 'Species', '9606', (101, 106))	('epigenetic regulation', 'MPA', (162, 183))	('cancer', 'Disease', (196, 202))	('aberrant', 'Var', (187, 195))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('piwi', 'Gene', '9271', (16, 20))	('tumor initiation', 'Disease', (263, 279))	('ncRNA', 'Gene', (148, 153))	('cancer', 'Disease', (107, 113))
39805	24155923	SRY mutations, can cause Testicular Dysgenesis Syndrome (TDS) but in most cases no mutations have been identified.	('cause', 'Reg', (19, 24))	('SRY', 'Gene', '6736', (0, 3))	('SRY', 'Gene', (0, 3))	('TDS', 'Disease', (57, 60))	('Testicular Dysgenesis Syndrome', 'Disease', (25, 55))	('TDS', 'Disease', 'None', (57, 60))	('Testicular Dysgenesis Syndrome', 'Disease', 'MESH:D013733', (25, 55))	('mutations', 'Var', (4, 13))	('Testicular Dysgenesis', 'Phenotype', 'HP:0008715', (25, 46))
39856	24155923	suggested that p,p'-DDE, oxychlordane, cis-nonachlor, trans-nonachlor and total chlordane serum levels are associated with TGCT risk, especially with seminomas.	("p,p'-DDE", 'Chemical', 'MESH:D003633', (15, 23))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (39, 52))	('associated', 'Reg', (107, 117))	('chlordane', 'Chemical', 'MESH:D002706', (28, 37))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (54, 69))	('TGCT', 'Disease', (123, 127))	('oxychlordane', 'Chemical', 'MESH:C008743', (25, 37))	('chlordane', 'Chemical', 'MESH:D002706', (80, 89))	('seminomas', 'Disease', 'MESH:D018239', (150, 159))	('seminomas', 'Disease', (150, 159))	('trans-nonachlor', 'Var', (54, 69))	('cis-nonachlor', 'Var', (39, 52))
39858	24155923	Two polymorphisms of the CYP1A1 gene (rs7495708 and rs1456432) were suspected to be associated with an increase of TGCT risk in men having elevated total chlordane serum levels.	('rs1456432', 'Mutation', 'rs1456432', (52, 61))	('CYP1A1', 'Gene', '1543', (25, 31))	('chlordane', 'Chemical', 'MESH:D002706', (154, 163))	('men', 'Species', '9606', (128, 131))	('total chlordane serum levels', 'MPA', (148, 176))	('rs7495708', 'Var', (38, 47))	('rs1456432', 'Var', (52, 61))	('associated', 'Reg', (84, 94))	('TGCT', 'Disease', (115, 119))	('rs7495708', 'Mutation', 'rs7495708', (38, 47))	('CYP1A1', 'Gene', (25, 31))
39859	24155923	Overall, no association was observed with serum levels of hexachlorohexane, hexachlorobenzene (HCB), pp'DDT, oxychlordane, op'DDT and mirex.	("pp'DDT", 'Var', (101, 107))	('DDT', 'Chemical', 'MESH:D003634', (126, 129))	('oxychlordane', 'Chemical', 'MESH:C008743', (109, 121))	("op'DDT", 'Var', (123, 129))	('DDT', 'Chemical', 'MESH:D003634', (104, 107))	('hexachlorobenzene', 'Chemical', 'MESH:D006581', (76, 93))	('oxychlordane', 'MPA', (109, 121))	('hexachlorobenzene', 'MPA', (76, 93))	('hexachlorohexane', 'MPA', (58, 74))
39868	24155923	No excess risk for TGCT was reported among the sons of farmers or pesticide applicators, except in one study in Norway that reported an increased risk for sons of agricultural workers using nitrate fertiliser, especially with a high nitrate/phosphate ratio.	('high', 'Var', (228, 232))	('nitrate', 'Chemical', 'MESH:D009566', (233, 240))	('TGCT', 'Disease', (19, 23))	('phosphate', 'Chemical', 'MESH:D010710', (241, 250))	('nitrate', 'Chemical', 'MESH:D009566', (190, 197))
39874	24155923	A positive association was found for hexachlorobenzene, PCBs, PBDE and chlordanes in maternal serum and the risk of TGCC among the women's sons.	('PCBs', 'Gene', (56, 60))	('TGCC', 'Disease', (116, 120))	('PBDE', 'Chemical', 'MESH:C086401', (62, 66))	('women', 'Species', '9606', (131, 136))	('chlordanes', 'Chemical', 'MESH:D002706', (71, 81))	('PCBs', 'Chemical', 'MESH:D011078', (56, 60))	('PBDE', 'Gene', (62, 66))	('hexachlorobenzene', 'Chemical', 'MESH:D006581', (37, 54))	('hexachlorobenzene', 'Var', (37, 54))
39924	18841155	Linkage analyses have revealed several potential genomic regions of interest, including 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 (Rapley et al, 2000; Crockford et al, 2006), and a specific deletion in the Y chromosome has also been identified as conferring an increased risk of both sporadic and familial testicular cancers in a small percentage of men (Nathanson et al, 2005).	('sporadic', 'Disease', (290, 298))	('testicular cancer', 'Phenotype', 'HP:0010788', (312, 329))	('familial testicular cancers', 'Disease', 'MESH:D013736', (303, 330))	('deletion', 'Var', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))	('testicular cancers', 'Phenotype', 'HP:0010788', (312, 330))	('men', 'Species', '9606', (356, 359))	('familial testicular cancers', 'Disease', (303, 330))
40005	32290859	These include psychological distress, impairment in pursuit of life goals, persistent physical side effects, elevated risk of secondary malignancies and chronic illness, and biobehavioral burden (e.g., enhanced inflammation, dysregulated diurnal stress hormones).	('psychological distress', 'CPA', (14, 36))	('chronic illness', 'Disease', (153, 168))	('impairment', 'Var', (38, 48))	('inflammation', 'Disease', 'MESH:D007249', (211, 223))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('enhanced', 'PosReg', (202, 210))	('dysregulated', 'Var', (225, 237))	('malignancies', 'Disease', (136, 148))	('inflammation', 'Disease', (211, 223))	('chronic illness', 'Disease', 'MESH:D002908', (153, 168))	('impairment in pursuit', 'Phenotype', 'HP:0007772', (38, 59))	('men', 'Species', '9606', (44, 47))
40159	24407180	We defined three major histologic groups of testicular cancer: seminoma (9060/3-9062/3, 9064/3), non-seminoma (9065/3, 9070/3-9073/3, 9080/3-9085/3, 9100/3-9102/3) and cancers of other or unspecified histological types (8000/3-8004/3) according to the 3rd edition of International Classification of Diseases for Oncology.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('non-seminoma', 'Disease', 'MESH:D018239', (97, 109))	('9060/3-9062/3, 9064/3', 'Var', (73, 94))	('unspecified', 'Species', '32644', (188, 199))	('seminoma', 'Disease', 'MESH:D018239', (63, 71))	('testicular cancer', 'Phenotype', 'HP:0010788', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Oncology', 'Phenotype', 'HP:0002664', (312, 320))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('seminoma', 'Disease', (63, 71))	('testicular cancer', 'Disease', 'MESH:D013736', (44, 61))	('seminoma', 'Disease', 'MESH:D018239', (101, 109))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('non-seminoma', 'Disease', (97, 109))	('testicular cancer', 'Disease', (44, 61))	('seminoma', 'Disease', (101, 109))	('9065/3, 9070/3-9073/3', 'Var', (111, 132))
40161	24407180	Second primary cancers were classified according to the rules for multiple primary cancers outlined by the International Agency for Research on Cancer and coded as 104-208 (ICD-9) or C00-80 (ICD-10).	('primary cancers', 'Disease', (7, 22))	('C00-80', 'Var', (183, 189))	('primary cancers', 'Disease', 'MESH:D009369', (7, 22))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('primary cancers', 'Disease', (75, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('primary cancers', 'Disease', 'MESH:D009369', (75, 90))
40199	24407180	The observation of a continued cumulative incidence increase, after 15 years in period (II) compared to period (I), supports the hypothesis that cisplatin delays tumor development as a result of its influence on the premalignant germ cell epithelium.	('cisplatin', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('delays tumor', 'Disease', 'MESH:D009369', (155, 167))	('influence', 'Reg', (199, 208))	('delays tumor', 'Disease', (155, 167))	('men', 'Species', '9606', (175, 178))
40352	17711579	Interestingly, the most over-represented biological processes comprising the up-regulated genes were sensory perception, cell surface receptor linked signal transduction, physiological response to stimulus, neurophysiological process, and potassium ion transport.	('potassium', 'Chemical', 'MESH:D011188', (239, 248))	('cell surface receptor', 'Gene', '57126', (121, 142))	('up-regulated', 'PosReg', (77, 89))	('cell surface receptor', 'Gene', (121, 142))	('genes', 'Var', (90, 95))	('potassium ion transport', 'MPA', (239, 262))
40388	17711579	Since NEO1 and LATS2 are tumor-suppressor genes and at the same time target genes for p53 and hsa-mir-372 and 373, both hsa-mir-372 and 373 may suppress the p53 pathway by destabilizing NEO1s and LATS2s transcript and/or by inhibiting their translation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('translation', 'MPA', (241, 252))	('LATS2', 'Gene', (15, 20))	('LATS2', 'Gene', '26524', (15, 20))	('NEO1', 'Gene', (6, 10))	('p53', 'Gene', '7157', (86, 89))	('NEO1', 'Gene', '4756', (6, 10))	('suppress', 'NegReg', (144, 152))	('p53', 'Gene', '7157', (157, 160))	('p53', 'Gene', (86, 89))	('hsa-mir-372', 'Gene', (120, 131))	('hsa-mir-372', 'Gene', (94, 105))	('tumor', 'Disease', (25, 30))	('LATS2', 'Gene', (196, 201))	('transcript', 'MPA', (203, 213))	('NEO1', 'Gene', (186, 190))	('inhibiting', 'NegReg', (224, 234))	('373', 'Var', (136, 139))	('LATS2', 'Gene', '26524', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('p53', 'Gene', (157, 160))	('NEO1', 'Gene', '4756', (186, 190))	('hsa-mir-372', 'Gene', '442917', (120, 131))	('destabilizing', 'NegReg', (172, 185))	('hsa-mir-372', 'Gene', '442917', (94, 105))
40391	17711579	Several reports have suggested that loss of Dicer1 causes embryonic lethality and loss of stem cell population.	('embryonic lethality', 'Disease', 'MESH:D020964', (58, 77))	('embryonic lethality', 'Disease', (58, 77))	('Dicer1', 'Gene', '23405', (44, 50))	('loss', 'Var', (36, 40))	('loss', 'NegReg', (82, 86))	('causes', 'Reg', (51, 57))	('Dicer1', 'Gene', (44, 50))
40396	17711579	However, the functionality of specific parts of the p53-dependent pathway may be suppressed through miRNA repression of some of the p53 target genes, such as NEO1 and LATS2.	('NEO1', 'Gene', (158, 162))	('suppressed', 'NegReg', (81, 91))	('p53', 'Gene', (132, 135))	('LATS2', 'Gene', (167, 172))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (132, 135))	('p53', 'Gene', '7157', (52, 55))	('NEO1', 'Gene', '4756', (158, 162))	('LATS2', 'Gene', '26524', (167, 172))	('functionality', 'MPA', (13, 26))	('miRNA repression', 'Var', (100, 116))
40405	17711579	Among different classes of anticancer agents, the senescent phenotype is induced most strongly by DNA-damaging agents such as doxorubicin, aphidicolin, cisplatin, etoposide and ionizing radiation.	('aphidicolin', 'Chemical', 'MESH:D016590', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('etoposide', 'Chemical', 'MESH:D005047', (163, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('doxorubicin', 'Chemical', 'MESH:D004317', (126, 137))	('senescent phenotype', 'CPA', (50, 69))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cisplatin', 'Var', (152, 161))
40418	17711579	The mutual effects of apoptosis, senescence-like phenotype, and mitotic catastrophe in tumors in response to treatment are illustrated by studies in which inhibition of apoptosis was shown to increase mitotic catastrophe, senescence, or both.	('mitotic catastrophe', 'CPA', (201, 220))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('senescence', 'CPA', (222, 232))	('men', 'Species', '9606', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'Protein', (169, 178))	('tumors', 'Disease', (87, 93))	('inhibition', 'Var', (155, 165))	('increase', 'PosReg', (192, 200))
40479	32210101	As an alternative, or in addition to, the STMs, a panel of circulating microRNAs (miR-367-3p, miR-371a-3p, miR-372-3p, and miR-373-3p) has been investigated intensively, due to their high expression in most TGCTs (except teratomas).	('STM', 'Gene', (42, 45))	('miR-367-3p', 'Chemical', '-', (82, 92))	('miR-372-3p', 'Var', (107, 117))	('TGCTs', 'Disease', (207, 212))	('expression', 'MPA', (188, 198))	('miR-367-3p', 'Var', (82, 92))	('STM', 'Gene', '6818', (42, 45))	('miR-371a-3p', 'Var', (94, 105))	('miR-372-3p', 'Chemical', '-', (107, 117))	('teratoma', 'Phenotype', 'HP:0009792', (221, 229))	('miR-373', 'Gene', (123, 130))	('teratoma', 'Disease', 'MESH:D013724', (221, 229))	('miR-373', 'Gene', '442918', (123, 130))	('teratomas', 'Phenotype', 'HP:0009792', (221, 230))	('teratoma', 'Disease', (221, 229))	('miR-371a-3p', 'Chemical', '-', (94, 105))
40481	32210101	A recent large multicenter study showed that serum miR-371a-3p had a sensitivity of 90% and specificity of 94% in the initial diagnosis of TGCTs, and hence greatly outperformed STMs.	('miR-371a-3p', 'Chemical', '-', (51, 62))	('TGCTs', 'Disease', (139, 144))	('STM', 'Gene', '6818', (177, 180))	('STM', 'Gene', (177, 180))	('serum miR-371a-3p', 'Var', (45, 62))
40482	32210101	The level of miR-371a-3p correlated with both primary tumor size and clinical stage.	('miR-371a-3p', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-371a-3p', 'Chemical', '-', (13, 24))	('tumor', 'Disease', (54, 59))	('correlated', 'Reg', (25, 35))
40487	32210101	They found pre-treatment miR-371a-3p levels to be associated with the spread of disease and favorable response to therapy.	('associated with', 'Reg', (50, 65))	('miR-371a-3p levels', 'Var', (25, 43))	('miR-371a-3p', 'Chemical', '-', (25, 36))	('spread of disease', 'CPA', (70, 87))	('men', 'Species', '9606', (20, 23))
40521	32210101	The patients with the highest levels of miRNA-367-3p, -371a-3p, and -373-3p before orchiectomy had CS II TGCTs (Figure 2b,c,e).	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('CS', 'Chemical', '-', (99, 101))	('patients', 'Species', '9606', (4, 12))	('and -373-3p', 'Var', (64, 75))
40630	29581795	Low 2D : 4D was associated with prostate cancer, gastric cancer, and brain tumors, while high 2D : 4D, with breast cancer risk and cervical dysplasia.	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associated', 'Reg', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('prostate cancer', 'Disease', (32, 47))	('cervical dysplasia', 'Disease', (131, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('high 2D : 4D', 'Var', (89, 101))	('brain tumors', 'Phenotype', 'HP:0030692', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breast cancer', 'Disease', (108, 121))	('brain tumor', 'Phenotype', 'HP:0030692', (69, 80))	('cervical dysplasia', 'Disease', 'MESH:D002575', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Low 2D : 4D', 'Var', (0, 11))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (131, 149))	('gastric cancer', 'Disease', (49, 63))	('brain tumors', 'Disease', (69, 81))
40644	29581795	Findings from the prospective Melbourne Collaborative Cohort Study with a median of 16 years of follow-up suggested that higher 2D : 4D might be associated with decreased prostate cancer risk before 60 years of age.	('higher 2D : 4D', 'Var', (121, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('decreased prostate', 'Phenotype', 'HP:0008687', (161, 179))	('decreased prostate cancer', 'Disease', 'MESH:D011471', (161, 186))	('decreased prostate cancer', 'Disease', (161, 186))
40654	29581795	Others also found that high 2D : 4D ratio was associated with better response to dutasteride treatment.	('response', 'MPA', (69, 77))	('dutasteride', 'Chemical', 'MESH:D000068538', (81, 92))	('high', 'Var', (23, 27))
40673	23050906	The deficiency of this enzyme causes desmosterolosis, an autosomal recessive disease characterized by elevated levels of desmosterol, the immediate Delta24-unsaturated precursor of cholesterol, in plasma and tissues, developmental malformations and neuropsychological alterations.	('developmental malformations', 'Disease', 'MESH:D000014', (217, 244))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (57, 84))	('causes', 'Reg', (30, 36))	('desmosterol', 'Chemical', 'MESH:D003897', (37, 48))	('elevated', 'PosReg', (102, 110))	('desmosterolosis', 'Disease', (37, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (181, 192))	('deficiency', 'Var', (4, 14))	('developmental malformations', 'Disease', (217, 244))	('desmosterol', 'Chemical', 'MESH:D003897', (121, 132))	('desmosterolosis', 'Disease', 'MESH:C566555', (37, 52))	('autosomal recessive disease', 'Disease', (57, 84))
40736	23050906	The primers for human LDLR-containing SRE, used as a positive control, were 5'-GTGGGAATCAGAGCTTCACG-3' for sense and 5'-GACCTGCTGTGTCCTAGCTG-3' for antisense.	('LDLR', 'Gene', '3949', (22, 26))	('human', 'Species', '9606', (16, 21))	("5'-GACCTGCTGTGTCCTAGCTG-3", 'Var', (117, 142))	('LDLR', 'Gene', (22, 26))
40747	23050906	Sequencing of nine RACE PCR clones revealed five potential TSSs (transcription start sites) upstream (C-60, G-56, C-55, A-47 and A-18) (Figure 2) and one downstream (T+38, not shown) of the ATG codon.	('A-18', 'Gene', (129, 133))	('A-47', 'CellLine', 'CVCL:L675', (120, 124))	('C-55', 'Var', (114, 118))	('A-18', 'Gene', '28920', (129, 133))	('G-56', 'Var', (108, 112))	('C-60', 'Var', (102, 106))	('A-47', 'Var', (120, 124))
40749	23050906	The transcription-factor-binding sites predicted with high score were: four GC-boxes (-57/-52, -109/-104, -202/-197 and -314/-309), three direct CCAAT-boxes (-70/-65, -166/-160 and -638/-634), one inverted CCAAT-box (-118/-114), four CACCC-boxes (-221/-217, -235/-231, -266/-262 and -797/-792) and one binding site for the following transcription factors: YY1 (-123/-115), EGR2 (early growth-response 2) (-207/-198), c-Myb (-274/-269), AP-1 (activator protein 1) (-388/-382), AREB6 (-607/-600), NFAT-1 (nuclear factor of activated T-cells 1) (-678/-673) and NF-A (-891/-884).	('early growth-response 2', 'Gene', (379, 402))	('-891/-884', 'Var', (564, 573))	('EGR2', 'Gene', (373, 377))	('-274/-269', 'Var', (424, 433))	('c-Myb', 'Gene', (417, 422))	('NF-A', 'Gene', (558, 562))	('-607/-600', 'Var', (483, 492))	('c-Myb', 'Gene', '4602', (417, 422))	('early growth-response 2', 'Gene', '1959', (379, 402))	('-123/-115', 'Var', (361, 370))	('YY1', 'Gene', '7528', (356, 359))	('NFAT-1 (nuclear factor of activated T-cells 1', 'Gene', '4772', (495, 540))	('-221/-217', 'Var', (247, 256))	('YY1', 'Gene', (356, 359))	('-207/-198', 'Var', (405, 414))	('AREB6', 'Gene', (476, 481))	('AP-1 (activator protein 1', 'Gene', '3726', (436, 461))	('AREB6', 'Gene', '6935', (476, 481))	('-678/-673', 'Var', (543, 552))
40755	23050906	Deletion of regions spanning nucleotides -1012 to -348 caused no significant change in either basal promoter activity or the response to lovastatin or LDL.	('response to lovastatin', 'MPA', (125, 147))	('lovastatin', 'Chemical', 'MESH:D008148', (137, 147))	('basal promoter activity', 'MPA', (94, 117))	('LDL', 'MPA', (151, 154))	('Deletion', 'Var', (0, 8))
40758	23050906	Deletion of the nucleotides between positions -166 and -149 caused a 4.3-fold reduction in the promoter basal activity, with no alteration of the ability to respond to cholesterol availability.	('promoter basal activity', 'MPA', (95, 118))	('cholesterol', 'Chemical', 'MESH:D002784', (168, 179))	('reduction', 'NegReg', (78, 87))	('Deletion', 'Var', (0, 8))
40759	23050906	The last deletion (up to -90) completely abrogated both the basal and the cholesterol-regulated activity of DHCR24.	('abrogated', 'NegReg', (41, 50))	('basal', 'MPA', (60, 65))	('cholesterol', 'Chemical', 'MESH:D002784', (74, 85))	('deletion', 'Var', (9, 17))	('cholesterol-regulated activity', 'MPA', (74, 104))	('DHCR24', 'Gene', (108, 114))
40762	23050906	In this region the presence of one YY1 (-123/-115), one inverted CCAAT-box (-118/-114), one GC-box (-109/-104) and one SRE (-98/-90) cis-acting elements was predicted.	('-118/-114', 'Var', (76, 85))	('YY1', 'Gene', (35, 38))	('YY1', 'Gene', '7528', (35, 38))
40763	23050906	HepG2 cells were transiently transfected with the wild-type promoter-reporter construct (pH DHCR24), the mutant promoter-reporter construct (mut SRE) or the empty vector (pGL3) and the response to the addition of LDL or lovastatin was analysed.	('pGL3', 'Gene', '6391', (171, 175))	('lovastatin', 'Chemical', 'MESH:D008148', (220, 230))	('HepG2', 'CellLine', 'CVCL:0027', (0, 5))	('mutant', 'Var', (105, 111))	('pGL3', 'Gene', (171, 175))
40764	23050906	As shown in Figure 4(B), mutation of the SRE decreased the basal activity of the DHCR24 promoter and abrogated the cholesterol-mediated regulation.	('abrogated', 'NegReg', (101, 110))	('cholesterol', 'Chemical', 'MESH:D002784', (115, 126))	('DHCR24 promoter', 'Gene', (81, 96))	('SRE', 'Gene', (41, 44))	('mutation', 'Var', (25, 33))	('decreased', 'NegReg', (45, 54))	('basal activity', 'MPA', (59, 73))	('cholesterol-mediated regulation', 'MPA', (115, 146))
40780	23050906	As shown in Figure 7(A), DHT produced a dose-dependent increase in DHCR24 mRNA levels.	('increase', 'PosReg', (55, 63))	('DHT', 'Chemical', 'MESH:D013196', (25, 28))	('DHT', 'Var', (25, 28))	('DHCR24', 'Gene', (67, 73))
40801	23050906	In agreement with previous work, we described the presence of four GC-boxes in the proximal region of the DHCR24 promoter, two of them located at the appropriate distance of the TSS (-57/-52 and -109/-104) and are conserved in human and mouse (Figure 1 and Supplementary Figure S1).	('-57/-52', 'Var', (183, 190))	('DHCR24', 'Gene', (106, 112))	('mouse', 'Species', '10090', (237, 242))	('human', 'Species', '9606', (227, 232))
40818	23050906	Another important region for DHCR24 promoter activity spans nucleotides -348 to -198, since its deletion markedly reduced the basal transcriptional activity, without affecting the cholesterol-mediated regulation.	('reduced', 'NegReg', (114, 121))	('basal transcriptional activity', 'MPA', (126, 156))	('DHCR24', 'Gene', (29, 35))	('deletion', 'Var', (96, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (180, 191))
40824	23050906	Although the DHCR24 regulation by EGR2 needs to be verified, the presence of an EGR2-binding site in the DHCR24 promoter is consistent with the important role of DHCR24 and desmosterol in brain development and the severe malformations produced by DHCR24 deficiency.	('DHCR24', 'Gene', (247, 253))	('deficiency', 'Var', (254, 264))	('malformations', 'Disease', 'MESH:D000014', (221, 234))	('malformations', 'Disease', (221, 234))	('desmosterol', 'Chemical', 'MESH:D003897', (173, 184))	('brain development', 'CPA', (188, 205))
40899	28654092	Some authors have hypothesised that disruption to hCG production may be associated with maldescent of the developing testes, with Chedane et al.	('hCG', 'Gene', '93659', (50, 53))	('disruption', 'Var', (36, 46))	('maldescent of the developing testes', 'CPA', (88, 123))	('associated', 'Reg', (72, 82))	('hCG', 'Gene', (50, 53))
40900	28654092	recently showing that the placentas of boys born with cryptorchidism had somewhat lower total hCG levels compared to controls (case mothers: 21.4 kilounits/litre, control mothers: 27.7 kilounits/litre).	('hCG', 'Gene', (94, 97))	('boys', 'Species', '9606', (39, 43))	('cryptorchidism', 'Phenotype', 'HP:0000028', (54, 68))	('hCG', 'Gene', '93659', (94, 97))	('cryptorchidism', 'Var', (54, 68))	('lower', 'NegReg', (82, 87))
40902	28654092	Like testosterone, the protein hormone INSL3 is crucial to testicular descent: cryptorchidism can be achieved in animal models by knocking out the gene that encodes INSL3.	('INSL3', 'Gene', (165, 170))	('cryptorchidism', 'Phenotype', 'HP:0000028', (79, 93))	('INSL3', 'Gene', '3640', (39, 44))	('knocking out', 'Var', (130, 142))	('INSL3', 'Gene', '3640', (165, 170))	('cryptorchidism', 'Disease', (79, 93))	('INSL3', 'Gene', (39, 44))	('testosterone', 'Chemical', 'MESH:D013739', (5, 17))
40921	28654092	However, there is limited evidence that 'heavy' drinking (relative to reported abstinence) might be associated with cryptorchidism development: whether via chronic exposure in terms of a relatively large number of drinks per week  or via binge drinking episodes.	('cryptorchidism', 'Phenotype', 'HP:0000028', (116, 130))	('cryptorchidism development', 'Disease', (116, 142))	('men', 'Species', '9606', (138, 141))	("'heavy'", 'Var', (40, 47))	('binge drinking', 'Phenotype', 'HP:0100739', (238, 252))
40923	28654092	had the greatest power to detect an association between 'heavy' drinking and cryptorchidism development, with a cohort of more than n=41,000 and n=1,598 cryptorchidism cases; still, they found no such association.	('cryptorchidism development', 'Disease', (77, 103))	('men', 'Species', '9606', (99, 102))	('cryptorchidism', 'Phenotype', 'HP:0000028', (153, 167))	('cryptorchidism', 'Phenotype', 'HP:0000028', (77, 91))	("'heavy' drinking", 'Var', (56, 72))
40928	28654092	Given a possible association between sustained heavy consumption or binge drinking and cryptorchidism development, standardisation of how these exposures are measured is necessary.	('binge drinking', 'Phenotype', 'HP:0100739', (68, 82))	('cryptorchidism', 'Phenotype', 'HP:0000028', (87, 101))	('cryptorchidism development', 'Disease', (87, 113))	('binge drinking', 'Var', (68, 82))	('men', 'Species', '9606', (109, 112))
40947	28654092	observed that the relationship between paternal smoking and cryptorchidism development did not disappear when additionally adjusted for maternal smoking; and it is conceivable that paternal smoking is associated with cryptorchidism via passive maternal exposure  or genetic 'damage' to the sperm involved in conception.	('cryptorchidism', 'Phenotype', 'HP:0000028', (60, 74))	('cryptorchidism', 'Phenotype', 'HP:0000028', (217, 231))	('maternal exposure', 'Phenotype', 'HP:0031437', (244, 261))	('associated', 'Reg', (201, 211))	('cryptorchidism', 'Disease', (217, 231))	('men', 'Species', '9606', (82, 85))	('genetic', 'Var', (266, 273))
40958	28654092	These studies have found little or no association between use of these medications and subsequent cryptorchidism risk - with the possible exception of Bartfai et al., who observed that boys born to mothers who reported using Prenoxdiazine (cough medicine) at some point during pregnancy appeared to be at increased risk of cryptorchidism (adjusted OR: 1.8, 95% CI 0.9-3.5).	('cryptorchidism', 'Disease', (323, 337))	('Prenoxdiazine', 'Chemical', 'MESH:C008277', (225, 238))	('Prenoxdiazine', 'Var', (225, 238))	('cough', 'Phenotype', 'HP:0012735', (240, 245))	('cryptorchidism', 'Phenotype', 'HP:0000028', (323, 337))	('cryptorchidism', 'Phenotype', 'HP:0000028', (98, 112))	('boys', 'Species', '9606', (185, 189))
41000	28654092	Genes that encode the molecules that facilitate testicular descent could be related to the risk of cyptorchdism; for example, experimental studies have shown that 'knocking-out' the gene that encodes INSL3 will result in bilateral cryptorchidism.	('INSL3', 'Gene', '3640', (200, 205))	('bilateral cryptorchidism', 'Disease', (221, 245))	('result in', 'Reg', (211, 220))	('men', 'Species', '9606', (132, 135))	("'knocking-out'", 'Var', (163, 177))	('INSL3', 'Gene', (200, 205))	('bilateral cryptorchidism', 'Phenotype', 'HP:0008689', (221, 245))	('cryptorchidism', 'Phenotype', 'HP:0000028', (231, 245))
41003	28654092	Variants in more than 15 genes have thus far been implicated in the development of cryptorchidism in humans via candidate gene studies (see Supplementary Material 2); however, only one genome-wide association study (GWAS) has been performed in 'non-syndromic' cryptorchidism (i.e.	("non-syndromic' cryptorchidism", 'Disease', (245, 274))	('cryptorchidism', 'Phenotype', 'HP:0000028', (260, 274))	('Variants', 'Var', (0, 8))	('humans', 'Species', '9606', (101, 107))	('cryptorchidism', 'Phenotype', 'HP:0000028', (83, 97))	('men', 'Species', '9606', (146, 149))	('men', 'Species', '9606', (75, 78))	("non-syndromic' cryptorchidism", 'Disease', 'MESH:D003456', (245, 274))
41007	28654092	With respect to the latter, rare mutations in INSL3 and its receptor RXFP2 have been reported at low frequencies (1-4%) in boys born with cryptorchidism, while rare mutations have also been found in NR5A1, which is involved in several reproductive processes.	('cryptorchidism', 'Disease', (138, 152))	('INSL3', 'Gene', '3640', (46, 51))	('boys', 'Species', '9606', (123, 127))	('mutations', 'Var', (33, 42))	('RXFP2', 'Gene', '122042', (69, 74))	('NR5A1', 'Gene', (199, 204))	('cryptorchidism', 'Phenotype', 'HP:0000028', (138, 152))	('INSL3', 'Gene', (46, 51))	('RXFP2', 'Gene', (69, 74))	('NR5A1', 'Gene', '2516', (199, 204))
41008	28654092	It is possible that inherited genetic variants may make an individual more or less susceptible to endocrine disruption via pathways such as exposure to chemicals, by disrupting the metabolism of these elements.	('metabolism of these elements', 'MPA', (181, 209))	('genetic variants', 'Var', (30, 46))	('men', 'Species', '9606', (204, 207))	('endocrine disruption', 'MPA', (98, 118))	('disrupting', 'NegReg', (166, 176))
41009	28654092	For example an (albeit un-replicated) association reported by Qin et al., was with a variant of the Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) gene (OR for minor homozygous genotype rs5000770 [AA vs. GG]: 3.5, 95% CI 1.7-7.3).	('ARNT2', 'Gene', (150, 155))	('rs5000770', 'Mutation', 'rs5000770', (196, 205))	('Aryl hydrocarbon receptor nuclear translocator 2', 'Gene', (100, 148))	('variant', 'Var', (85, 92))	('Qin', 'Gene', '2290', (62, 65))	('Aryl hydrocarbon receptor nuclear translocator 2', 'Gene', '9915', (100, 148))	('Qin', 'Gene', (62, 65))	('rs5000770', 'Var', (196, 205))	('ARNT2', 'Gene', '9915', (150, 155))
41020	28654092	Using this approach, researchers could use genetic variants known to influence the risk of smoking and alcohol consumption, and assess their association with cryptorchidism.	('cryptorchidism', 'Phenotype', 'HP:0000028', (158, 172))	('association', 'Interaction', (141, 152))	('variants', 'Var', (51, 59))	('influence', 'Reg', (69, 78))	('cryptorchidism', 'Disease', (158, 172))	('alcohol', 'Chemical', 'MESH:D000438', (103, 110))
41024	28654092	mutations at INSL3 ) Assisted reproduction  Diet during pregnancy  Birth presentation  Intrauterine exposure to high levels of endogenous hormones (e.g.	('INSL3', 'Gene', (13, 18))	('mutations', 'Var', (0, 9))	('Intrauterine exposure', 'Phenotype', 'HP:0031437', (87, 108))	('INSL3', 'Gene', '3640', (13, 18))
41077	25058491	Previous studies found that certain compounds in environmental tobacco smoke may pass through the placental barrier and interact with fetal DNA, resulting in DNA damage and mutation.	('men', 'Species', '9606', (56, 59))	('resulting in', 'Reg', (145, 157))	('tobacco', 'Species', '4097', (63, 70))	('DNA damage', 'MPA', (158, 168))	('interact', 'Interaction', (120, 128))	('mutation', 'Var', (173, 181))
41097	20053729	The analysis of DNA from tumoral versus normal tissue revealed that hypomethylation of U3 promoters in tumors is a prerequisite for their activation.	('hypomethylation', 'Var', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (25, 30))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('activation', 'PosReg', (138, 148))
41135	20053729	G6PD that appeared to be the most stable housekeeping gene between the tumoral and the normal adjacent tissues was chosen to normalize the experiments.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('G6PD', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
41165	20053729	Similarly, overexpression of six HERV-W loci in the testicular cancer was evidenced by their respective U5 LTR probesets, namely, HW28073.L5.U5_at, HW08822.L5.U5_at, HW33438.L5.U5_at, HW38223.L5.U5_at, HW13386.L5.U5_at and HW22795.LS.U5_at (fold change ranging from 5.90 to 12.80; Table 2).	('HW28073.L5.U5_at', 'Var', (130, 146))	('HW08822.L5.U5_at', 'Var', (148, 164))	('HW33438.L5.U5_at', 'Var', (166, 182))	('HERV-W', 'Species', '87786', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HW22795.LS.U5_at', 'Var', (223, 239))	('testicular cancer', 'Disease', (52, 69))	('HW38223.L5.U5_at', 'Var', (184, 200))	('HW13386.L5.U5_at', 'Var', (202, 218))	('overexpression', 'PosReg', (11, 25))	('testicular cancer', 'Phenotype', 'HP:0010788', (52, 69))	('testicular cancer', 'Disease', 'MESH:D013736', (52, 69))
41170	20053729	All the loci were overexpressed in the testicular tumor when compared with the normal adjacent section, with fold changes ranging from 71 for HW22795 up to 3226 for HW33438 (Figure 2B).	('HW22795', 'Var', (142, 149))	('overexpressed', 'PosReg', (18, 31))	('testicular tumor', 'Disease', 'MESH:D013736', (39, 55))	('testicular tumor', 'Phenotype', 'HP:0010788', (39, 55))	('testicular tumor', 'Disease', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HW33438', 'Var', (165, 172))
41183	20053729	Associated U3 probesets targeting 5'LTRs for HW08822, HW13386 and HW38223 and included in the microarray are poorly and not differentially expressed in the normal and tumoral testicular samples (Figure 4A).	('HW13386', 'Var', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('HW38223', 'Var', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('HW08822', 'Var', (45, 52))	('tumor', 'Disease', (167, 172))
41187	20053729	First, we observed a clear dichotomic expression between U3 and U5 regions for the loci HW08822, HW13386, HW38223 and HW28073/ERVWE1.	('ERVWE1', 'Gene', '30816', (126, 132))	('HW08822', 'Var', (88, 95))	('ERVWE1', 'Gene', (126, 132))	('HW38223', 'Var', (106, 113))	('HW13386', 'Var', (97, 104))
41190	20053729	In addition, in normal tissues, it is noticeable that the apparent level of U5 expression of these four loci varied among the samples, from a non-significant expression (<450 copies) for HW08822, HW13386 and HW38223 to a significant expression in three samples (from 1730 to 5000 copies) for ERVWE1.	('HW38223', 'Var', (208, 215))	('ERVWE1', 'Gene', '30816', (292, 298))	('ERVWE1', 'Gene', (292, 298))	('HW13386', 'Var', (196, 203))	('HW08822', 'Var', (187, 194))
41191	20053729	Thus, transcriptional profiles of HW08822, HW13386, HW38223 and ERVWE1 clearly suggest a transcriptional induction through the activation of the U3 promoter.	('ERVWE1', 'Gene', '30816', (64, 70))	('ERVWE1', 'Gene', (64, 70))	('HW13386', 'Var', (43, 50))	('HW08822', 'Var', (34, 41))	('activation', 'PosReg', (127, 137))	('HW38223', 'Var', (52, 59))	('transcriptional induction', 'MPA', (89, 114))
41192	20053729	Second, the HW33438 locus roughly presented the same dichotomic expression, that is, a relatively low expression of the U3 region when compared with a high expression of the U5 region in all the four tumoral samples.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('expression', 'MPA', (102, 112))	('HW33438', 'Var', (12, 19))	('low', 'NegReg', (98, 101))	('tumor', 'Disease', (200, 205))
41208	20053729	Precisely, the global amount of methylation was over 88.5% in the normal DNA and lower than 36.4% in the tumoral DNA for the loci HW36489 and HW35372.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('methylation', 'MPA', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HW36489', 'Var', (130, 137))	('HW35372', 'Var', (142, 149))	('tumor', 'Disease', (105, 110))
41210	20053729	For the locus HW21714, the percentage of methylation observed was 30.3% and 24.2% in normal and tumoral DNA, respectively, with a majority of fully unmethylated sequences in both the cases.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HW21714', 'Var', (14, 21))	('methylation', 'MPA', (41, 52))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
41211	20053729	To assess whether the testicular tumor-associated hypomethylation of HERV is restricted to the family W, we analyzed the HERV loci from other families, namely, HERV-H, HERV-E and HERV-FRD, that is, the loci HH34532 overexpressed in colorectal cancer, and HERV-E.PTN and ERVFRDE1 expressed in the placenta.	('colorectal cancer', 'Disease', (232, 249))	('HERV-FRD', 'Disease', (179, 187))	('testicular tumor', 'Disease', 'MESH:D013736', (22, 38))	('testicular tumor', 'Phenotype', 'HP:0010788', (22, 38))	('ERVFRDE1', 'Gene', (270, 278))	('testicular tumor', 'Disease', (22, 38))	('HERV-FRD', 'Disease', 'None', (179, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (232, 249))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('HH34532', 'Var', (207, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (232, 249))	('overexpressed', 'PosReg', (215, 228))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('HERV-H', 'Species', '57282', (160, 166))
41214	20053729	Altogether, these results suggest that the methylation deregulation in this tumoral context concerns neither the HERVs as a whole nor the differentially expressed HERV-W loci alone.	('deregulation', 'Var', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('HERVs', 'Species', '206037', (113, 118))	('HERV-W', 'Species', '87786', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('methylation', 'MPA', (43, 54))
41243	20053729	Most intriguingly, the presence of ERVWE1 3.1-kb transcript is presumed to lead to the production of the Syncytin-1 protein in seminoma, as observed quite frequently in other cancers.	('lead to', 'Reg', (75, 82))	('Syncytin-1', 'Gene', (105, 115))	('seminoma', 'Disease', (127, 135))	('ERVWE1', 'Gene', '30816', (35, 41))	('presence', 'Var', (23, 31))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('production', 'MPA', (87, 97))	('seminoma', 'Disease', 'MESH:D018239', (127, 135))	('ERVWE1', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Syncytin-1', 'Gene', '30816', (105, 115))
41247	20053729	This mode of control of expression was exclusive and preserved for HW08822, HW13386 and HW38223 and ERVWE1/HW28073 elements in all patients.	('patients', 'Species', '9606', (131, 139))	('HW13386', 'Var', (76, 83))	('HW08822', 'Var', (67, 74))	('HW38223', 'Var', (88, 95))	('ERVWE1', 'Gene', '30816', (100, 106))	('ERVWE1', 'Gene', (100, 106))
41254	20053729	U3 expression of both HW22795 and HW33438 LTR may either reflect a transcriptional terminator function (U3-R-polyA) or an antisense transcript, as HERV-W LTR was shown to possess a bi-directional promoter activity.	('HERV-W', 'Species', '87786', (147, 153))	('HW33438', 'Var', (34, 41))	('HW22795', 'Var', (22, 29))
41255	20053729	Alternatively, such features may reflect the heterogeneity of the tumor, leading to a combination of transcription factors targeting heterogeneously and independently in the subpopulation, HW22795 and HW33438 LTRs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HW22795', 'Var', (189, 196))	('HW33438 LTRs', 'Var', (201, 213))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
41256	20053729	In such situation, expression of HW08822, HW13386 and HW38223, as well as ERVWE1/HW28073 LTRs would not be affected by heterogeneity.	('ERVWE1', 'Gene', '30816', (74, 80))	('HW38223', 'Var', (54, 61))	('HW08822', 'Var', (33, 40))	('ERVWE1', 'Gene', (74, 80))	('HW13386', 'Var', (42, 49))
41260	20053729	Nevertheless, analyses of three additional HERV-W loci that were not expressed showed that hypomethylation was tumor-associated in two of them and was an intrinsic attribute in one of them.	('HERV-W', 'Species', '87786', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('hypomethylation', 'Var', (91, 106))
41261	20053729	In DNA isolated from a true normal testis tissue (fatal accident), CpG methylation of HW8822 active LTR and HW35372 inactive LTR were similar to the one observed in adjacent tissue (data not shown).	('HW8822', 'CellLine', 'CVCL:F560', (86, 92))	('HW35372', 'Var', (108, 115))	('methylation', 'MPA', (71, 82))	('HW8822', 'Var', (86, 92))
41266	20053729	This suggests that demethylation in cancer does not equally affect all the components of the genome.	('demethylation', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (36, 42))
41272	20053729	Taken together, these observations suggest a multifactor process modulating methylation of HERVs in cancer, including preferably sequence (family), then chromosomal environment and possibly locus domestication/function.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('modulating', 'Reg', (65, 75))	('HERVs', 'Species', '206037', (91, 96))	('methylation', 'Var', (76, 87))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('HERVs', 'Protein', (91, 96))
41275	20053729	Moreover, modifications of ERVWE1 splicing strategy in testicular tumor suggest that the implication of Syncytin-1 envelope has to be further investigated.	('testicular tumor', 'Disease', 'MESH:D013736', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Syncytin-1', 'Gene', (104, 114))	('testicular tumor', 'Phenotype', 'HP:0010788', (55, 71))	('testicular tumor', 'Disease', (55, 71))	('ERVWE1', 'Gene', '30816', (27, 33))	('ERVWE1', 'Gene', (27, 33))	('Syncytin-1', 'Gene', '30816', (104, 114))	('modifications', 'Var', (10, 23))
41277	20053729	Finally, the tumor-associated hypomethylation of the U3 LTR part of various HERV loci, whether reactivated or not, implies that alteration in methylation is a critical step toward HERV activation in cancers, and that the involvement of DNA methyltransferases in HERV targeting and regulation alterations in cancers should be addressed precisely.	('tumor', 'Disease', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('cancers', 'Disease', (307, 314))	('hypomethylation', 'Var', (30, 45))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('alteration', 'Var', (128, 138))	('cancers', 'Disease', (199, 206))
41331	19053130	In preliminary work, we prepared a site-specifically platinated duplex containing a single 1,2-d(G*pG*) Pt-BP6 adduct, exposed it to HeLa nuclear extracts, and irradiated the solution to activate the benzophenone moiety.	('1,2-d', 'Chemical', '-', (91, 96))	('BP6', 'Gene', (107, 110))	('adduct', 'Var', (111, 117))	('benzophenone', 'Chemical', 'MESH:C047723', (200, 212))	('Pt', 'Chemical', 'MESH:D010984', (104, 106))	('HeLa', 'CellLine', 'CVCL:0030', (133, 137))	('BP6', 'Gene', '474302', (107, 110))
41345	19053130	A 25-bp duplex probe containing a Pt-BP6 1,2-d(G*pG*)-d(CpT) mismatch was also prepared and used in analytical-scale photo-cross-linking experiments.	('CpT', 'Gene', (56, 59))	('Pt', 'Chemical', 'MESH:D010984', (34, 36))	('mismatch', 'Var', (61, 69))	('BP6', 'Gene', '474302', (37, 40))	('1,2-d', 'Chemical', '-', (41, 46))	('BP6', 'Gene', (37, 40))	('CpT', 'Gene', '56994', (56, 59))
41377	19053130	The desthiobiotin-tethered duplex has comparable affinity for streptavidin-coated magnetic beads as the biotin-tethered duplex originally employed (data not shown).	('affinity', 'MPA', (49, 57))	('biotin', 'Chemical', 'MESH:D001710', (11, 17))	('biotin', 'Chemical', 'MESH:D001710', (104, 110))	('desthiobiotin-tethered', 'Var', (4, 26))
41381	19053130	Cells expressing the shRNA (lane 3) had a lower level of PARP-1 than the control HeLa cells (lane 1).	('shRNA', 'Var', (21, 26))	('lower', 'NegReg', (42, 47))	('PARP-1', 'Gene', (57, 63))	('PARP-1', 'Gene', '142', (57, 63))	('HeLa', 'CellLine', 'CVCL:0030', (81, 85))
41388	19053130	The duplex was constructed such that the platinated guanine on the 3'-side of the top strand was mismatched against a thymine residue on the bottom strand.	('mismatched', 'Var', (97, 107))	('thymine', 'Chemical', 'MESH:D013941', (118, 125))	('guanine', 'Chemical', 'MESH:D006147', (52, 59))	('platinated', 'Var', (41, 51))
41391	19053130	The increased affinity of Msh2 for the compound lesion diminishes the binding of other proteins that would otherwise recognize the platinated duplex.	('Msh2', 'Gene', (26, 30))	('proteins', 'Protein', (87, 95))	('binding', 'Interaction', (70, 77))	('compound lesion', 'Var', (39, 54))	('Msh2', 'Gene', '4436', (26, 30))	('diminishes', 'NegReg', (55, 65))	('affinity', 'Interaction', (14, 22))	('increased', 'PosReg', (4, 13))
41444	19053130	Nucleotide excision repair of cisplatin adducts results in excised DNA fragments of approximately 28-32 base pairs, which is longer than the 25-bp probe.	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('excised', 'MPA', (59, 66))	('Nucleotide excision repair', 'Var', (0, 26))	('adducts', 'Var', (40, 47))
41450	19053130	Previous work using EMSAs indicates that the mismatch repair protein, Msh2, has a greater affinity for a 1,2-d(G*pG*) cisplatin cross-link in which the unplatinated DNA strand contains a mismatched thymine opposite the 3'-guanosine.	('1,2-d', 'Chemical', '-', (105, 110))	('thymine', 'Chemical', 'MESH:D013941', (198, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('mismatched', 'Var', (187, 197))	('Msh2', 'Gene', (70, 74))	("3'-guanosine", 'Chemical', '-', (219, 231))	('Msh2', 'Gene', '4436', (70, 74))
41451	19053130	The increased affinity of Msh2 for DNA containing the mismatched platinum cross-link is accompanied by diminished photo-cross-linking to the other proteins.	('platinum', 'Chemical', 'MESH:D010984', (65, 73))	('Msh2', 'Gene', (26, 30))	('mismatched platinum cross-link', 'Var', (54, 84))	('Msh2', 'Gene', '4436', (26, 30))	('photo-cross-linking', 'MPA', (114, 133))	('diminished', 'NegReg', (103, 113))	('affinity', 'Interaction', (14, 22))	('increased', 'PosReg', (4, 13))
41458	19053130	The probe containing a compound lesion of a 1,2-d(G*pG*) adduct of Pt-BP6 and a C T mismatch photo-cross-linked more strongly to the mismatch repair protein Msh2 (Figure 2C).	('Msh2', 'Gene', (157, 161))	('strongly', 'PosReg', (117, 125))	('BP6', 'Gene', '474302', (70, 73))	('1,2-d', 'Chemical', '-', (44, 49))	('BP6', 'Gene', (70, 73))	('Msh2', 'Gene', '4436', (157, 161))	('mismatch', 'Var', (84, 92))	('Pt', 'Chemical', 'MESH:D010984', (67, 69))
41470	19053130	Fewer proteins are present in BxPC3 nuclear extracts that bind to platinated DNA than in similar extracts from the other cells.	('bind', 'Interaction', (58, 62))	('platinated', 'Var', (66, 76))	('BxPC3', 'CellLine', 'CVCL:0186', (30, 35))	('proteins', 'Protein', (6, 14))
41471	19053130	Unlike experiments using the 25-bp probe (Figure 2B), photo-cross-linking studies with the 90-base probe using nuclear extracts in which PARP-1 is silenced did not reveal a resolved band containing this protein (Figure 8).	('PARP-1', 'Gene', (137, 143))	('silenced', 'Var', (147, 155))	('PARP-1', 'Gene', '142', (137, 143))
41486	19053130	PARP-1 is commonly mutated in germ cells, specific variants being Val762Ala and Lys940Arg, two residues in the catalytic domain of the protein.	('PARP-1', 'Gene', '142', (0, 6))	('Val762Ala', 'SUBSTITUTION', 'None', (66, 75))	('Lys940Arg', 'SUBSTITUTION', 'None', (80, 89))	('Val762Ala', 'Var', (66, 75))	('Lys940Arg', 'Var', (80, 89))	('PARP-1', 'Gene', (0, 6))
41487	19053130	Compromised activity of PARP-1 by these mutations may be the reason that such high levels of the protein are present in this cell line.	('Compromised', 'NegReg', (0, 11))	('activity', 'MPA', (12, 20))	('mutations', 'Var', (40, 49))	('PARP-1', 'Gene', (24, 30))	('PARP-1', 'Gene', '142', (24, 30))
41500	19053130	The cisplatin-modified DNA-binding ability of this protein has been demonstrated by using EMSAs with extracts from XPE cells, which contain mutated DDB-1.	('DDB-1', 'Gene', '1642', (148, 153))	('rat', 'Species', '10116', (75, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('DDB-1', 'Gene', (148, 153))	('mutated', 'Var', (140, 147))
41519	19053130	The stalling of topo I at DNA damage sites can interfere with repair, an effect blocked by poly(ADP-ribosyl)ation of topo I by PARP-1 and PARP-2, which dissociates the protein from DNA.	('PARP-2', 'Gene', (138, 144))	('poly', 'Var', (91, 95))	('interfere', 'NegReg', (47, 56))	('PARP-2', 'Gene', '10038', (138, 144))	('stalling', 'MPA', (4, 12))	('PARP-1', 'Gene', (127, 133))	('repair', 'MPA', (62, 68))	('PARP-1', 'Gene', '142', (127, 133))
41528	19053130	Although such poorly expressed proteins would have to compete for binding with other more abundant ones, photo-cross-linking will create an irreversible covalent bond between any protein having an affinity for the platinum-modified DNA and the probe.	('create', 'Reg', (130, 136))	('platinum', 'Chemical', 'MESH:D010984', (214, 222))	('photo-cross-linking', 'Var', (105, 124))	('covalent bond', 'MPA', (153, 166))
41537	19053130	Similarly, a duplex containing the 1,2-d(G*pG*) adduct of Pt-BP6 carrying a mismatched base opposite the platination site has a greater affinity for the mismatch repair protein, Msh2.	('Pt', 'Chemical', 'MESH:D010984', (58, 60))	('affinity', 'MPA', (136, 144))	('Msh2', 'Gene', (178, 182))	('mismatched', 'Var', (76, 86))	('greater', 'PosReg', (128, 135))	('Msh2', 'Gene', '4436', (178, 182))	('BP6', 'Gene', '474302', (61, 64))	('1,2-d', 'Chemical', '-', (35, 40))	('BP6', 'Gene', (61, 64))
41651	12189554	A significant positive association was found between high birth weight and seminoma cases.	('high birth weight', 'Phenotype', 'HP:0001520', (53, 70))	('seminoma', 'Disease', 'MESH:D018239', (75, 83))	('high birth weight', 'Var', (53, 70))	('seminoma', 'Disease', (75, 83))
41653	12189554	As compared with those born normal-for-gestational-age at term, infants born both preterm (before gestational week 37th) and large-for-gestational-age had a three-fold risk for testicular seminomas (OR of 3.29, 95% CI: 1.23-8.80; based on eight exposed cases).	('testicular seminomas', 'Disease', (177, 197))	('testicular seminomas', 'Phenotype', 'HP:0100617', (177, 197))	('infants', 'Species', '9606', (64, 71))	('large-for-gestational-age', 'Var', (125, 150))	('large-for-gestational-age', 'Phenotype', 'HP:0001520', (125, 150))	('testicular seminomas', 'Disease', 'MESH:D018239', (177, 197))	('large-for-gestational-', 'Phenotype', 'HP:0001520', (125, 147))
41655	12189554	High maternal age was associated with an increased risk for seminomas both among firstborn and non-firstborn infants and the effect of maternal age and birth order appeared to be additive (column 12).	('seminomas', 'Disease', (60, 69))	('infants', 'Species', '9606', (109, 116))	('High maternal age', 'Var', (0, 17))	('seminomas', 'Disease', 'MESH:D018239', (60, 69))
41659	12189554	In the previous study the risk for seminomas was associated with high birth and placental weight, while an increased risk for non-seminomas was found for high maternal socio-economic status, short gestational duration, neonatal jaundice and low birth weight.	('short gestational duration', 'Phenotype', 'HP:0001622', (191, 217))	('low birth weight', 'Phenotype', 'HP:0001518', (241, 257))	('neonatal jaundice', 'Phenotype', 'HP:0006579', (219, 236))	('neonatal jaundice', 'Disease', 'MESH:D007567', (219, 236))	('seminomas', 'Disease', 'MESH:D018239', (35, 44))	('seminomas', 'Disease', (35, 44))	('low birth weight', 'Disease', 'MESH:C537577', (241, 257))	('placental weight', 'CPA', (80, 96))	('non-seminomas', 'Disease', 'MESH:D018239', (126, 139))	('low birth weight', 'Disease', (241, 257))	('jaundice', 'Phenotype', 'HP:0000952', (228, 236))	('high birth', 'Var', (65, 75))	('seminomas', 'Disease', 'MESH:D018239', (130, 139))	('neonatal jaundice', 'Disease', (219, 236))	('seminomas', 'Disease', (130, 139))	('non-seminomas', 'Disease', (126, 139))
41712	30004908	Targeted analysis of multiplex TGCT families has identified rare gene mutations, such as DNAAF1 and related ciliary-microtubule genes, as likely culprits of TGCT in certain cases, however these high-impact mutations are rare.	('DNAAF1', 'Gene', (89, 95))	('mutations', 'Var', (70, 79))	('DNAAF1', 'Gene', '123872', (89, 95))
41781	26577765	Metastases showed higher HS than primary invasive UCA (P <= 0.0001), and high HS was associated with a lower pT stage (P <= 0.0001) and a trend toward the absence of lymphovascular invasion (LVI, P = 0.09), but not pN stage (P = 0.35) and surgical margin status (P = 0.81).	('high HS', 'Var', (73, 80))	('lymphovascular invasion', 'CPA', (166, 189))	('pT stage', 'CPA', (109, 117))	('lower', 'NegReg', (103, 108))	('lower pT', 'Phenotype', 'HP:0032198', (103, 111))	('Metastases', 'Disease', (0, 10))	('higher', 'PosReg', (18, 24))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
41793	26577765	A strong association has been found between RBM3 overexpression and early biochemical prostate cancer recurrence in a large series.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('overexpression', 'Var', (49, 63))	('RBM3', 'Gene', '5935', (44, 48))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('RBM3', 'Gene', (44, 48))
41796	26577765	However, conflicting results emerged from many clinical studies which have found high RBM3 expression to be associated with a better prognosis in various cancers including colorectal cancer, melanoma, estrogen-positive breast cancers as well as esophageal and gastric adenocarcinomas.	('breast cancers', 'Disease', 'MESH:D001943', (219, 233))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('breast cancers', 'Disease', (219, 233))	('melanoma', 'Disease', (191, 199))	('high', 'Var', (81, 85))	('RBM3', 'Gene', (86, 90))	('breast cancers', 'Phenotype', 'HP:0003002', (219, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('gastric adenocarcinomas', 'Disease', (260, 283))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (260, 283))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('associated', 'Reg', (108, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('RBM3', 'Gene', '5935', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('colorectal cancer', 'Disease', (172, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('cancers', 'Disease', (226, 233))	('esophageal', 'Disease', (245, 255))	('cancers', 'Disease', (154, 161))	('carcinomas', 'Phenotype', 'HP:0030731', (273, 283))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
41827	26577765	Down-regulation of RBM3 mRNA and protein by small-interfering RNA (siRNA) reduces cell proliferation and viability in human embryonic kidney cells.	('embryonic kidney', 'Disease', (124, 140))	('small-interfering', 'Var', (44, 61))	('RBM3', 'Gene', '5935', (19, 23))	('mRNA and', 'MPA', (24, 32))	('Down-regulation', 'NegReg', (0, 15))	('embryonic kidney', 'Disease', 'MESH:D007674', (124, 140))	('human', 'Species', '9606', (118, 123))	('reduces', 'NegReg', (74, 81))	('protein', 'Protein', (33, 40))	('RBM3', 'Gene', (19, 23))
41834	26577765	It is possible that CIS lesions with a high RBM3 might be more aggressive and become invasive in a shorter time frame for example; however, the testing of this hypothesis would require matched cases of chronologically evolutive lesions:benign, CIS, invasive urothelial carcinoma, and eventually metastasis:which could not be achieved in the current study.	('CIS', 'Disease', (244, 247))	('high', 'Var', (39, 43))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (249, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('benign', 'Disease', (236, 242))	('RBM3', 'Gene', '5935', (44, 48))	('invasive urothelial carcinoma', 'Disease', (249, 278))	('RBM3', 'Gene', (44, 48))
41836	26577765	Other studies that associate high RBM3 expression with a good prognosis in colon, breast, and urothelial cancer purposely highlighted the in vitro data by Sureban et al.	('high', 'Var', (29, 33))	('colon', 'Disease', (75, 80))	('urothelial cancer', 'Disease', 'MESH:D014523', (94, 111))	('RBM3', 'Gene', (34, 38))	('colon', 'Disease', 'MESH:D015179', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('urothelial cancer', 'Disease', (94, 111))	('RBM3', 'Gene', '5935', (34, 38))	('breast', 'Disease', (82, 88))
41845	26577765	Specifically concerning urothelial bladder cancer, the only study currently published on this topic reported loss of RBM3 expression to be associated with clinically more aggressive tumors and to be an independent factor of poor prognosis.	('expression', 'MPA', (122, 132))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('RBM3', 'Gene', '5935', (117, 121))	('aggressive tumors', 'Disease', 'MESH:D001523', (171, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('loss', 'Var', (109, 113))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (24, 49))	('RBM3', 'Gene', (117, 121))	('urothelial bladder cancer', 'Disease', (24, 49))	('associated', 'Reg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('aggressive tumors', 'Disease', (171, 188))	('more', 'PosReg', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
42112	29177237	There are many studies indicating the elevation of spermatozoa with abnormal chromatin in infertile patientswhen are compared with fertile men.	('abnormal', 'Var', (68, 76))	('patients', 'Species', '9606', (100, 108))	('elevation', 'PosReg', (38, 47))	('men', 'Species', '9606', (139, 142))
42114	29177237	Medical dysfunctions like diabetes mellitus (DM) may have detrimental effects on sperm fertility potential and DNA integrity, also varicocele samples contain a higher proportion of spermatozoa with abnormal DNA and immature chromatin than those from fertile men as well as infertile men without varicocele.	('men', 'Species', '9606', (258, 261))	('men', 'Species', '9606', (63, 66))	('varicocele', 'Phenotype', 'HP:0012871', (131, 141))	('sperm fertility potential', 'CPA', (81, 106))	('DM', 'Phenotype', 'HP:0000819', (45, 47))	('DM', 'Disease', 'MESH:D009223', (45, 47))	('varicocele', 'Phenotype', 'HP:0012871', (295, 305))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (26, 43))	('men', 'Species', '9606', (283, 286))	('varicocele', 'Var', (131, 141))	('abnormal', 'Var', (198, 206))	('dysfunctions like diabetes mellitus', 'Disease', (8, 43))	('dysfunctions like diabetes mellitus', 'Disease', 'MESH:D003920', (8, 43))
42121	29177237	Defects in insulin secretion may change testicular and accessory sexual glands function.	('insulin secretion', 'Disease', (11, 28))	('change', 'Reg', (33, 39))	('Defects', 'Var', (0, 7))	('insulin secretion', 'Disease', 'MESH:D007333', (11, 28))
42125	29177237	also, Talebi et al showed that although, the DM may have detrimental effects on the sperm fertility potential and DNA integrity, but, vitamin C, as a potent antioxidant, has positive effects on sperm parameters, sperm function and also prevents sperm chromatin abnormalities and apoptosis in experimentally-induced diabetic mice.	('men', 'Species', '9606', (62, 65))	('diabetic', 'Disease', 'MESH:D003920', (315, 323))	('sperm parameters', 'CPA', (194, 210))	('positive effects', 'PosReg', (174, 190))	('prevents', 'NegReg', (236, 244))	('sperm function', 'CPA', (212, 226))	('vitamin', 'Var', (134, 141))	('DM', 'Phenotype', 'HP:0000819', (45, 47))	('DM', 'Disease', 'MESH:D009223', (45, 47))	('sperm chromatin abnormalities', 'CPA', (245, 274))	('diabetic', 'Disease', (315, 323))	('apoptosis', 'CPA', (279, 288))	('mice', 'Species', '10090', (324, 328))	('vitamin C', 'Chemical', 'MESH:D001205', (134, 143))	('men', 'Species', '9606', (298, 301))
42131	29177237	Additional, variation in mitochondrial DNA seen in DM is reliable for the bad changes observed in motility of spermatozoa (Table I).	('DM', 'Phenotype', 'HP:0000819', (51, 53))	('DM', 'Disease', 'MESH:D009223', (51, 53))	('variation', 'Var', (12, 21))	('motility', 'CPA', (98, 106))	('mitochondrial DNA', 'MPA', (25, 42))
42170	29177237	Tanrikut et al also demonstrated that, paroxetine can induce unusual sperm DNA fragmentation in men with normal semen parameters, but they didn't identify a quantifiable effect of paroxetine on semen parameters.	('men', 'Species', '9606', (196, 199))	('men', 'Species', '9606', (96, 99))	('paroxetine', 'Chemical', 'MESH:D017374', (180, 190))	('paroxetine', 'Var', (39, 49))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (114, 117))	('sperm DNA fragmentation', 'CPA', (69, 92))	('paroxetine', 'Chemical', 'MESH:D017374', (39, 49))	('rat', 'Species', '10116', (27, 30))
42207	29177237	Also, Song et al expressed that ecstasy induces the generation of ROS and reactive nitrogen species and leads to OS.	('generation', 'MPA', (52, 62))	('reactive nitrogen species', 'MPA', (74, 99))	('rat', 'Species', '10116', (56, 59))	('leads to', 'Reg', (104, 112))	('ROS', 'Chemical', 'MESH:D017382', (66, 69))	('OS', 'Chemical', 'MESH:D009992', (67, 69))	('reactive nitrogen species', 'Chemical', 'MESH:D026361', (74, 99))	('OS', 'Chemical', 'MESH:D009992', (113, 115))	('ecstasy', 'Var', (32, 39))	('ROS', 'MPA', (66, 69))
42210	29177237	Another study revealed that, amphetamines lead to a dose-dependent decrease of testosterone and DNA damage.	('decrease', 'NegReg', (67, 75))	('amphetamines', 'Chemical', 'MESH:D000662', (29, 41))	('testosterone', 'MPA', (79, 91))	('decrease of testosterone', 'Phenotype', 'HP:0040171', (67, 91))	('testosterone', 'Chemical', 'MESH:D013739', (79, 91))	('DNA', 'CPA', (96, 99))	('amphetamines', 'Var', (29, 41))
42213	29177237	Age  There are some studies which have demonstrated that, increased paternal age is associated with a decrease in sperm morphology, motility and semen volume.	('sperm morphology', 'CPA', (114, 130))	('rat', 'Species', '10116', (46, 49))	('semen volume', 'CPA', (145, 157))	('paternal age', 'Var', (68, 80))	('decrease', 'NegReg', (102, 110))	('decrease in sperm morphology', 'Phenotype', 'HP:0012207', (102, 130))	('motility', 'CPA', (132, 140))	('men', 'Species', '9606', (147, 150))
42221	29177237	Moreover, it has been revealed that increasing paternal age is along with increasing in chromosomal aneuploidies, autosomal dominant disorders and other diseases.	('autosomal dominant disorders', 'Disease', 'MESH:D030342', (114, 142))	('chromosomal aneuploidies', 'Disease', (88, 112))	('paternal age', 'Var', (47, 59))	('chromosomal aneuploidies', 'Disease', 'MESH:D000782', (88, 112))	('autosomal dominant disorders', 'Disease', (114, 142))
42233	29177237	A study has shown that polychlorinated biphenyls (PCBs) can decrease the sperm parameters and pregnancy outcome.	('decrease', 'NegReg', (60, 68))	('polychlorinated', 'Var', (23, 38))	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (23, 48))	('decrease the sperm parameters', 'Phenotype', 'HP:0012207', (60, 89))	('PCBs', 'Chemical', 'MESH:D011078', (50, 54))	('pregnancy outcome', 'CPA', (94, 111))	('sperm parameters', 'CPA', (73, 89))
42253	29177237	XRCC1 Polymorphisms may alter sperm polycyclic aromatic hydrocarbon-DNA (PAH DNA) levels and could be considered as the useful biomarkers to detect individual susceptibility to DNA damage resulting from exposure to PAHs (192).	('XRCC1', 'Gene', (0, 5))	('XRCC1', 'Gene', '7515', (0, 5))	('Polymorphisms', 'Var', (6, 19))	('alter', 'Reg', (24, 29))
42254	29177237	Polymorphisms of the DNA repair genes XPD6 and XPD23 and a polymorphism CYP1A1MspI as a metabolic gene were associated with high levels of sperm DNA fragmentation in men with a high exposure level of air pollution (193).	('CYP1A1', 'Gene', (72, 78))	('XPD23', 'Gene', (47, 52))	('XPD6', 'Gene', (38, 42))	('Polymorphisms', 'Var', (0, 13))	('CYP1A1', 'Gene', '1543', (72, 78))	('men', 'Species', '9606', (166, 169))	('sperm', 'CPA', (139, 144))	('associated with', 'Reg', (108, 123))	('men', 'Species', '9606', (153, 156))
42344	26347114	In a multivariate model including age and BMI at follow-up and renal function after 1 year, a higher Pt AUC1-3 years was associated with an increased risk for persisting paraesthesia [odds ratio (OR) = 1.07 (95% CI 1.00-1.13), P = 0.043; supplementary Table S5, available at Annals of Oncology online].	('Oncology', 'Phenotype', 'HP:0002664', (285, 293))	('Pt', 'Chemical', 'MESH:D010984', (101, 103))	('Pt AUC1-3 years', 'Var', (101, 116))	('persisting', 'Disease', (159, 169))
42431	25927057	Alkylating agents including cisplatin and cyclophosphamide pose a high risk of azoospermia, particularly when coupled with ifosfamide, and the risk of permanent azoospermia seems to be dose- and agent-dependent.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('ifosfamide', 'Chemical', 'MESH:D007069', (123, 133))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (42, 58))	('azoospermia', 'Disease', 'MESH:D053713', (79, 90))	('cyclophosphamide', 'Var', (42, 58))	('azoospermia', 'Disease', (161, 172))	('azoospermia', 'Phenotype', 'HP:0000027', (161, 172))	('azoospermia', 'Disease', (79, 90))	('cisplatin', 'Var', (28, 37))	('azoospermia', 'Phenotype', 'HP:0000027', (79, 90))	('azoospermia', 'Disease', 'MESH:D053713', (161, 172))
42566	19493328	Immunodetection was carried out using anti-ERalpha (1:50), anti-ERbeta1 and anti-ERbeta2 (1:100) primary antibodies at 4 C overnight.	('ERalpha', 'Gene', '2099', (43, 50))	('ERalpha', 'Gene', (43, 50))	('anti-ERbeta1', 'Var', (59, 71))	('anti-ERbeta2', 'Var', (76, 88))
42634	19050263	Deficiencies in the MMR proteins Msh2, Msh6, Mlh1, Pms2, and Exo1 reduce CSR by 2- to 5-fold.	('Msh6', 'Gene', '17688', (39, 43))	('Msh2', 'Gene', '17685', (33, 37))	('CSR', 'Disease', (73, 76))	('Deficiencies', 'Var', (0, 12))	('Pms2', 'Gene', (51, 55))	('Msh6', 'Gene', (39, 43))	('Mlh1', 'Gene', (45, 49))	('Exo1', 'Gene', '26909', (61, 65))	('Mlh1', 'Gene', '17350', (45, 49))	('Exo1', 'Gene', (61, 65))	('Pms2', 'Gene', '18861', (51, 55))	('reduce', 'NegReg', (66, 72))	('Msh2', 'Gene', (33, 37))
42641	19050263	Deletion of either the msh4 or msh5 gene results in increased aberrant pairing between nonhomologous chromosomes and greatly decreased pairing between homologs during meiosis in both spermatocytes and oocytes.	('msh5', 'Gene', (31, 35))	('msh4', 'Gene', (23, 27))	('increased', 'PosReg', (52, 61))	('decreased', 'NegReg', (125, 134))	('aberrant pairing', 'CPA', (62, 78))	('msh4', 'Gene', '55993', (23, 27))	('pairing', 'MPA', (135, 142))	('Deletion', 'Var', (0, 8))
42648	19050263	From additional analyses of patients with various single-nucleotide mutations within the msh5 gene, they concluded that Msh5 has a role in CSR, although the role was not defined.	('msh5', 'Gene', (89, 93))	('patients', 'Species', '9606', (28, 36))	('single-nucleotide mutations', 'Var', (50, 77))	('CSR', 'Disease', (139, 142))
42682	19050263	These splice variants would result in deletion of at least 124 aa from the C terminus of the 833-residue protein, which are required for binding to Msh4.	('binding', 'Interaction', (137, 144))	('Msh4', 'Gene', '55993', (148, 152))	('Msh4', 'Gene', (148, 152))	('result in', 'Reg', (28, 37))	('deletion', 'Var', (38, 46))
42684	19050263	However, it is unknown whether these Msh4 RNA variants encode proteins, or whether B cells contain these splice variants.	('encode', 'Reg', (55, 61))	('proteins', 'Protein', (62, 70))	('variants', 'Var', (46, 54))	('Msh4', 'Gene', '55993', (37, 41))	('Msh4', 'Gene', (37, 41))
42685	19050263	It is likely that the observed mutations and splicing events perturb normal protein expression, resulting in either no Msh5 protein or an aberrant form of Msh5 that is unable to interact with Msh4.	('mutations', 'Var', (31, 40))	('perturb', 'NegReg', (61, 68))	('Msh4', 'Gene', (192, 196))	('Msh5', 'Gene', (119, 123))	('protein expression', 'MPA', (76, 94))	('Msh5', 'Gene', (155, 159))	('Msh4', 'Gene', '55993', (192, 196))
42687	19050263	To determine whether splenic B cell subsets are altered in Msh5-deficient mice, we characterized splenocytes by flow cytometry after staining with anti-B220, anti-CD24 (Fig.	('anti-B220', 'Var', (147, 156))	('CD24', 'Gene', (163, 167))	('Msh5-deficient', 'Disease', (59, 73))	('CD24', 'Gene', '12484', (163, 167))	('Msh5-deficient', 'Disease', 'MESH:D007153', (59, 73))	('mice', 'Species', '10090', (74, 78))
42695	19050263	4, CSR in the double-KO B cells is not further reduced relative to msh2-/- B cells, suggesting that Msh2 deficiency does not increase the dependence of CSR on Msh5.	('msh2', 'Gene', '17685', (67, 71))	('msh2', 'Gene', (67, 71))	('Msh2', 'Gene', (100, 104))	('Msh2', 'Gene', '17685', (100, 104))	('deficiency', 'Var', (105, 115))
42703	19050263	The Smu DSBs are also reduced in mismatch repair-deficient B cells and in B cells lacking the SmuTR.	('DSBs', 'Chemical', '-', (8, 12))	('Smu DSBs', 'Disease', (4, 12))	('mismatch', 'Var', (33, 41))	('reduced', 'NegReg', (22, 29))
42711	19050263	There was no difference in mutation frequency in the 5' portion of the germline Smu segments in WT and msh5-/- B cells induced to switch to IgG3 with LPS plus anti-delta-dextran, WT: 30.9 x 10-4 mutations per nt (19,417 nt sequenced) and msh5-/-: 28.3 x 10-4 (42,160 nt sequenced).	('IgG3', 'Gene', '380795', (140, 144))	('mutations', 'Var', (195, 204))	('LPS', 'Chemical', 'MESH:D008070', (150, 153))	('IgG3', 'Gene', (140, 144))	('delta-dextran', 'Chemical', '-', (164, 177))
42720	19050263	The frequency of trans-CSR to IgG3 was 8.3% in 108 junctions from WT and 12.7% in 110 junctions from msh5-/- B cells.	('IgG3', 'Gene', (30, 34))	('IgG3', 'Gene', '380795', (30, 34))	('trans-CSR', 'Var', (17, 26))
42730	19050263	Similar to our results, they found no significant reduction in CSR to IgG1, IgG3, or IgA in B cells deficient for Msh5, nor in B cells deficient for Msh4.	('IgA', 'Gene', (85, 88))	('reduction', 'NegReg', (50, 59))	('IgG3', 'Gene', (76, 80))	('IgG1', 'Gene', (70, 74))	('IgG1', 'Gene', '105243590', (70, 74))	('IgG3', 'Gene', '380795', (76, 80))	('Msh4', 'Gene', '55993', (149, 153))	('deficient', 'Var', (100, 109))	('Msh4', 'Gene', (149, 153))	('Msh5', 'Gene', (114, 118))	('CSR', 'MPA', (63, 66))
42734	19050263	Msh5 deficiency results in sterility and diminution in testicular size and a complete loss of ovarian structures.	('testicular size', 'CPA', (55, 70))	('deficiency', 'Var', (5, 15))	('complete loss of ovarian structures', 'Disease', 'MESH:D010051', (77, 112))	('complete loss of ovarian structures', 'Disease', (77, 112))	('Msh5', 'Gene', (0, 4))	('sterility', 'Disease', (27, 36))	('diminution', 'NegReg', (41, 51))
42743	32485873	Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('non-epithelial ovarian tumors', 'Disease', 'MESH:D010051', (110, 139))	('ovarian tumors', 'Phenotype', 'HP:0100615', (125, 139))	('ovarian tumor', 'Phenotype', 'HP:0100615', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epithelial ovarian tumors', 'Phenotype', 'HP:0025318', (114, 139))	('non-epithelial ovarian tumors', 'Disease', (110, 139))	('epithelial ovarian tumor', 'Phenotype', 'HP:0025318', (114, 138))	('germline mutations', 'Var', (76, 94))
42778	32485873	MOGCTs can lead to elevations of tumor markers in the peripheral blood, including alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH).	('hCG', 'Gene', (142, 145))	('AFP', 'Gene', '174', (101, 104))	('alpha-fetoprotein', 'Gene', (82, 99))	('lactate dehydrogenase', 'MPA', (151, 172))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('elevations', 'PosReg', (19, 29))	('MOGCTs', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('MOGCTs', 'Phenotype', 'HP:0031920', (0, 6))	('alpha-fetoprotein', 'Gene', '174', (82, 99))	('tumor', 'Disease', (33, 38))	('AFP', 'Gene', (101, 104))	('MOGCT', 'Phenotype', 'HP:0031920', (0, 5))	('hCG', 'Gene', '93659', (142, 145))	('beta-human', 'MPA', (107, 117))
42779	32485873	MOGCTs represent approximately 3% of all ovarian tumors in the United States, with 4 cases per 1,000,000 women.	('ovarian tumors', 'Phenotype', 'HP:0100615', (41, 55))	('ovarian tumors', 'Disease', 'MESH:D010051', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MOGCTs', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('women', 'Species', '9606', (105, 110))	('MOGCTs', 'Phenotype', 'HP:0031920', (0, 6))	('ovarian tumor', 'Phenotype', 'HP:0100615', (41, 54))	('MOGCT', 'Phenotype', 'HP:0031920', (0, 5))	('ovarian tumors', 'Disease', (41, 55))
42799	32485873	A whole exome sequencing study of 24 MOGCTs found a median of 2.5 (range 0-8) non-synonymous mutations per tumor; an average of 35% of the genome was affected by copy number alterations in 87 patients.	('MOGCTs', 'Phenotype', 'HP:0031920', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('affected', 'Reg', (150, 158))	('MOGCT', 'Phenotype', 'HP:0031920', (37, 42))	('patients', 'Species', '9606', (192, 200))	('copy number alterations', 'Var', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
42802	32485873	In contrast to epithelial ovarian cancer, TP53 mutations were not detected in MOGCTs; the most common mutations were in the genes KIT and KRAS, akin to testicular germ cell tumors.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TP53', 'Gene', '7157', (42, 46))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (15, 40))	('KRAS', 'Gene', '3845', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('KRAS', 'Gene', (138, 142))	('epithelial ovarian cancer', 'Disease', (15, 40))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutations', 'Var', (102, 111))	('KIT', 'Gene', (130, 133))	('cell tumors', 'Disease', (168, 179))	('MOGCTs', 'Phenotype', 'HP:0031920', (78, 84))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (15, 40))	('TP53', 'Gene', (42, 46))	('cell tumors', 'Disease', 'MESH:D005935', (168, 179))	('germ cell tumors', 'Phenotype', 'HP:0100728', (163, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (26, 40))	('KIT', 'Gene', '3815', (130, 133))	('MOGCT', 'Phenotype', 'HP:0031920', (78, 83))	('germ cell tumor', 'Phenotype', 'HP:0100728', (163, 178))
42803	32485873	Similar differences in mutations between epithelial and non-epithelial ovarian tumors can be seen in the Genomics Evidence Neoplasia Information Exchange of the American Association for Cancer Research (GENIE/AACR, version 7.0) database (Figure 2).	('non-epithelial ovarian tumors', 'Disease', 'MESH:D010051', (56, 85))	('epithelial ovarian tumor', 'Phenotype', 'HP:0025318', (60, 84))	('ovarian tumor', 'Phenotype', 'HP:0100615', (71, 84))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('ovarian tumors', 'Phenotype', 'HP:0100615', (71, 85))	('mutations', 'Var', (23, 32))	('Neoplasia', 'Disease', 'MESH:D009369', (123, 132))	('Neoplasia', 'Phenotype', 'HP:0002664', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Neoplasia', 'Disease', (123, 132))	('epithelial ovarian tumors', 'Phenotype', 'HP:0025318', (60, 85))	('non-epithelial ovarian tumors', 'Disease', (56, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
42815	32485873	However, the karyotypic abnormalities involved in gonadal dysgenesis, including the presence of Y chromosome material, are a significant risk factor for the development of dysgerminoma and concurrent gonadoblastoma (a rare neoplasm containing both germ cell and sex cord-stromal cells).	('gonadoblastoma', 'Disease', 'MESH:D018238', (200, 214))	('neoplasm', 'Disease', (223, 231))	('dysgerminoma', 'Phenotype', 'HP:0100621', (172, 184))	('neoplasm', 'Disease', 'MESH:D009369', (223, 231))	('gonadoblastoma', 'Phenotype', 'HP:0000150', (200, 214))	('neoplasm', 'Phenotype', 'HP:0002664', (223, 231))	('presence', 'Var', (84, 92))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (50, 68))	('dysgerminoma', 'Disease', (172, 184))	('gonadoblastoma', 'Disease', (200, 214))	('dysgerminoma', 'Disease', 'MESH:D004407', (172, 184))
42817	32485873	KIT mutations and amplifications have been described in 30-50% of dysgerminomas.	('dysgerminoma', 'Phenotype', 'HP:0100621', (66, 78))	('KIT', 'Gene', '3815', (0, 3))	('amplifications', 'Var', (18, 32))	('dysgerminomas', 'Disease', 'MESH:D004407', (66, 79))	('dysgerminomas', 'Disease', (66, 79))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
42819	32485873	KIT mutations are common in gastrointestinal stromal tumors (GIST), where they are also predictive of response to the tyrosine kinase inhibitor, imatinib.	('common', 'Reg', (18, 24))	('imatinib', 'Chemical', 'MESH:D000068877', (145, 153))	('GIST', 'Phenotype', 'HP:0100723', (61, 65))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (28, 59))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (28, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('KIT', 'Gene', '3815', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Disease', (28, 59))
42829	32485873	Yolk sac tumors are aneuploid with characteristic copy number alterations, including chromosome 12p gain in approximately 60% of the tumors, but are not associated with specific recurrent mutations.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('chromosome 12p', 'Gene', (85, 99))	('gain', 'PosReg', (100, 104))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('aneuploid', 'Disease', (20, 29))	('copy number alterations', 'Var', (50, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('aneuploid', 'Disease', 'MESH:D000782', (20, 29))
42830	32485873	Alterations in the PI3K/AKT/mTOR signaling pathway (Figure 3B), which occur frequently in certain subtypes of epithelial ovarian cancers, seem to be enriched in tumors with a yolk sac component (72%).	('mTOR', 'Gene', '2475', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('epithelial ovarian cancers', 'Disease', (110, 136))	('AKT', 'Gene', (24, 27))	('mTOR', 'Gene', (28, 32))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('Alterations', 'Var', (0, 11))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (110, 136))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (110, 135))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('ovarian cancers', 'Phenotype', 'HP:0100615', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('AKT', 'Gene', '207', (24, 27))
42839	32485873	Unlike other MOGCTs, immature teratoma is typically diploid, and chromosome 12p gain and KIT/KRAS mutations are uncommon.	('immature teratoma', 'Disease', 'MESH:D013724', (21, 38))	('chromosome', 'Var', (65, 75))	('KRAS', 'Gene', (93, 97))	('MOGCTs', 'Phenotype', 'HP:0031920', (13, 19))	('KIT', 'Gene', '3815', (89, 92))	('KRAS', 'Gene', '3845', (93, 97))	('gain', 'PosReg', (80, 84))	('immature teratoma', 'Disease', (21, 38))	('KIT', 'Gene', (89, 92))	('teratoma', 'Phenotype', 'HP:0009792', (30, 38))	('MOGCT', 'Phenotype', 'HP:0031920', (13, 18))
42841	32485873	Variants without known functional significance were detected in TP53, NF1, CTNBB1, and NOTCH2 (once each).	('NF1', 'Gene', '4763', (70, 73))	('Variants', 'Var', (0, 8))	('NOTCH2', 'Gene', (87, 93))	('CTNBB1', 'Gene', (75, 81))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('NOTCH2', 'Gene', '4853', (87, 93))	('NF1', 'Gene', (70, 73))
42844	32485873	While recurrent mutations were not common, variants of unknown significance in POLE, BRCA2 and ATM (one each) were detected.	('ATM', 'Gene', (95, 98))	('BRCA2', 'Gene', (85, 90))	('ATM', 'Gene', '472', (95, 98))	('variants', 'Var', (43, 51))	('BRCA2', 'Gene', '675', (85, 90))
42867	32485873	Genomic studies of SCSTs demonstrate that a single somatic mutation in FOXL2 (C134W) is almost ubiquitous in adult granulosa cell tumors, occurring in up to 97% of cases.	('FOXL2', 'Gene', '668', (71, 76))	('C134W', 'Var', (78, 83))	('SCST', 'Phenotype', 'HP:0031918', (19, 23))	('adult granulosa cell tumors', 'Disease', (109, 136))	('adult granulosa cell tumors', 'Disease', 'MESH:D006106', (109, 136))	('C134W', 'SUBSTITUTION', 'None', (78, 83))	('FOXL2', 'Gene', (71, 76))	('SCSTs', 'Phenotype', 'HP:0031918', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('adult granulosa cell tumors', 'Phenotype', 'HP:0031919', (109, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (115, 136))	('adult granulosa cell tumor', 'Phenotype', 'HP:0031919', (109, 135))
42869	32485873	The presence of the FOXL2 mutation in tumors with equivocal histological diagnosis may aid in the classification of the tumor as an adult granulosa cell one.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumors', 'Disease', (38, 44))	('mutation', 'Var', (26, 34))	('aid', 'Reg', (87, 90))	('presence', 'Reg', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('FOXL2', 'Gene', '668', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('FOXL2', 'Gene', (20, 25))	('tumor', 'Disease', (120, 125))
42872	32485873	The precise mechanism by which this mutation promotes tumor formation is unclear; FOXL2 possibly serves as a tumor suppressor, but others have postulated that it acts as an oncogene.	('FOXL2', 'Gene', '668', (82, 87))	('mutation', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('FOXL2', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('promotes', 'PosReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (109, 114))
42874	32485873	In addition, the mutated FOXL2 increases expression of CYP19/aromatase.	('expression', 'MPA', (41, 51))	('aromatase', 'Gene', (61, 70))	('increases', 'PosReg', (31, 40))	('FOXL2', 'Gene', '668', (25, 30))	('aromatase', 'Gene', '1588', (61, 70))	('CYP19', 'Gene', '1588', (55, 60))	('CYP19', 'Gene', (55, 60))	('FOXL2', 'Gene', (25, 30))	('mutated', 'Var', (17, 24))
42875	32485873	The FOXL2 mutation was also detected in 50% of granulosa theca cell tumors, but it is uncommon in juvenile granulosa cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('detected', 'Reg', (28, 36))	('FOXL2', 'Gene', '668', (4, 9))	('cell tumors', 'Disease', (63, 74))	('mutation', 'Var', (10, 18))	('juvenile granulosa cell tumors', 'Disease', (98, 128))	('cell tumors', 'Disease', 'MESH:D005935', (117, 128))	('FOXL2', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cell tumors', 'Disease', 'MESH:D005935', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('juvenile granulosa cell tumors', 'Disease', 'MESH:D006106', (98, 128))	('juvenile granulosa cell tumors', 'Phenotype', 'HP:0031919', (98, 128))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (107, 128))
42876	32485873	FOXL2 is rarely mutated in other cancers, with mutations occurring in approximately 1% of all cancers profiled by the GENIE/AACR project and less than 5% of any individual tumor type apart from SCSTs.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('occurring', 'Reg', (57, 66))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('tumor', 'Disease', (172, 177))	('FOXL2', 'Gene', '668', (0, 5))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('mutations', 'Var', (47, 56))	('SCSTs', 'Phenotype', 'HP:0031918', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('FOXL2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancers', 'Disease', (94, 101))	('SCST', 'Phenotype', 'HP:0031918', (194, 198))
42877	32485873	Fewer than 10% of these FOXL2 mutations (33/408) are the recurrent C134W mutation, and of the 33 C134W mutations, 31 (94%) were found in SCSTs.	('C134W', 'Var', (67, 72))	('C134W', 'SUBSTITUTION', 'None', (97, 102))	('SCST', 'Phenotype', 'HP:0031918', (137, 141))	('C134W', 'SUBSTITUTION', 'None', (67, 72))	('FOXL2', 'Gene', '668', (24, 29))	('C134W', 'Var', (97, 102))	('mutations', 'Var', (30, 39))	('FOXL2', 'Gene', (24, 29))	('SCSTs', 'Phenotype', 'HP:0031918', (137, 142))
42878	32485873	The functional significance of FOXL2 mutations in other cancers is outside the scope of this review.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (37, 46))	('FOXL2', 'Gene', '668', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('FOXL2', 'Gene', (31, 36))
42881	32485873	Whole genome sequencing of ten granulosa cell tumors revealed no mutations in BRCA1/2 and only a few mutations (10%) in the following genes: TP53, PIK3CA, CTNNB1, and PIK3R1.	('CTNNB1', 'Gene', '1499', (155, 161))	('granulosa cell tumors', 'Disease', (31, 52))	('BRCA1/2', 'Gene', '672;675', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('granulosa cell tumors', 'Disease', 'MESH:D006106', (31, 52))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('PIK3CA', 'Gene', (147, 153))	('CTNNB1', 'Gene', (155, 161))	('PIK3CA', 'Gene', '5290', (147, 153))	('BRCA1/2', 'Gene', (78, 85))	('PIK3R1', 'Gene', '5295', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('PIK3R1', 'Gene', (167, 173))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (31, 52))	('mutations', 'Var', (65, 74))
42883	32485873	Recurrent alterations in KMT2D can be found in over 20% of patients in this database.	('KMT2D', 'Gene', (25, 30))	('KMT2D', 'Gene', '8085', (25, 30))	('alterations', 'Var', (10, 21))	('patients', 'Species', '9606', (59, 67))
42887	32485873	In juvenile granulosa cell tumors, approximately 30% harbored a mutation in GNAS in a cohort of thirty patients.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('juvenile granulosa cell tumors', 'Phenotype', 'HP:0031919', (3, 33))	('mutation', 'Var', (64, 72))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (12, 33))	('GNAS', 'Gene', '2778', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('patients', 'Species', '9606', (103, 111))	('juvenile granulosa cell tumors', 'Disease', (3, 33))	('GNAS', 'Gene', (76, 80))	('harbored', 'Reg', (53, 61))	('juvenile granulosa cell tumors', 'Disease', 'MESH:D006106', (3, 33))
42888	32485873	In a small study of 16 patients, over 60% harbored a duplication of AKT1 (Figure 4B).	('AKT1', 'Gene', (68, 72))	('patients', 'Species', '9606', (23, 31))	('harbored', 'Reg', (42, 50))	('AKT1', 'Gene', '207', (68, 72))	('duplication', 'Var', (53, 64))
42895	32485873	DICER1 mutations have been described in approximately 60% of Sertoli-Leydig tumors (Figure 4C).	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))	('Sertoli-Leydig tumors', 'Disease', 'MESH:D018310', (61, 82))	('described', 'Reg', (27, 36))	('Sertoli-Leydig tumors', 'Disease', (61, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Leydig tumors', 'Phenotype', 'HP:0100618', (69, 82))	('Sertoli-Leydig tumors', 'Phenotype', 'HP:0100619', (61, 82))	('mutations', 'Var', (7, 16))
42896	32485873	The prevalence of DICER1 mutations in Sertoli-Leydig cell tumors may be even higher when accounting for potential histological misclassification.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (25, 34))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (46, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('Sertoli-Leydig cell tumors', 'Disease', (38, 64))	('DICER1', 'Gene', (18, 24))	('DICER1', 'Gene', '23405', (18, 24))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (38, 64))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (38, 64))
42899	32485873	Some cases with somatic DICER1 mutations were also found to harbor a germline mutation in DICER1, predisposing to additional tumors including pleuropulmonary blastoma.	('DICER1', 'Gene', '23405', (24, 30))	('mutations', 'Var', (31, 40))	('DICER1', 'Gene', (90, 96))	('pleuropulmonary blastoma', 'Disease', (142, 166))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DICER1', 'Gene', '23405', (90, 96))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('predisposing', 'Reg', (98, 110))	('germline mutation', 'Var', (69, 86))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (142, 166))	('DICER1', 'Gene', (24, 30))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (142, 166))
42901	32485873	DICER1 is rarely mutated in cancers that are not associated with germline DICER1 mutations.	('cancers', 'Disease', (28, 35))	('DICER1', 'Gene', (0, 6))	('DICER1', 'Gene', '23405', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DICER1', 'Gene', '23405', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('mutations', 'Var', (81, 90))	('DICER1', 'Gene', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
42902	32485873	FOXL2 mutations have been described in 10-20% of Sertoli-Leydig tumors.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Sertoli-Leydig tumors', 'Phenotype', 'HP:0100619', (49, 70))	('Leydig tumors', 'Phenotype', 'HP:0100618', (57, 70))	('Sertoli-Leydig tumors', 'Disease', 'MESH:D018310', (49, 70))	('FOXL2', 'Gene', '668', (0, 5))	('Sertoli-Leydig tumors', 'Disease', (49, 70))	('FOXL2', 'Gene', (0, 5))	('described', 'Reg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (6, 15))
42903	32485873	One study found that DICER1 and FOXL2 mutations are mutually exclusive in Sertoli-Leydig tumors and that each mutation was associated with distinct clinicopathological features.	('DICER1', 'Gene', (21, 27))	('FOXL2', 'Gene', '668', (32, 37))	('associated', 'Reg', (123, 133))	('Sertoli-Leydig tumors', 'Disease', 'MESH:D018310', (74, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('Sertoli-Leydig tumors', 'Disease', (74, 95))	('DICER1', 'Gene', '23405', (21, 27))	('Leydig tumors', 'Phenotype', 'HP:0100618', (82, 95))	('FOXL2', 'Gene', (32, 37))	('Sertoli-Leydig tumors', 'Phenotype', 'HP:0100619', (74, 95))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
42905	32485873	Peutz-Jeghers syndrome caused by mutations in the serine-threonine kinase 11 gene (STK11) can predispose to a specific subtype of SCSTs.	('serine-threonine kinase 11', 'Gene', '6794', (50, 76))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (0, 22))	('SCST', 'Phenotype', 'HP:0031918', (130, 134))	('predispose', 'Reg', (94, 104))	('serine-threonine kinase 11', 'Gene', (50, 76))	('caused by', 'Reg', (23, 32))	('mutations', 'Var', (33, 42))	('STK11', 'Gene', (83, 88))	('Peutz-Jeghers syndrome', 'Disease', (0, 22))	('STK11', 'Gene', '6794', (83, 88))	('SCSTs', 'Phenotype', 'HP:0031918', (130, 135))
42912	32485873	The alterations in signaling pathways discussed above and pan-cancer observations of kinase alterations provide the rationale for using kinase inhibitors for the treatment of non-epithelial ovarian cancers.	('non-epithelial ovarian cancers', 'Disease', (175, 205))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('ovarian cancers', 'Phenotype', 'HP:0100615', (190, 205))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('alterations', 'Var', (92, 103))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (179, 204))	('non-epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (175, 205))
42934	32485873	Recent discoveries about the hormonal effects of mutated FOXL2 (Figure 4), which functions as a transcription factor that plays a role in granulosa cell development and in expression of hypophyseal gonadotropin-releasing hormone (GnRH) receptor expression, and the physiologic presence of follicle-stimulating hormone (FSH) receptors on granulosa cells provide the rationale for this approach.	('FOXL2', 'Gene', '668', (57, 62))	('mutated', 'Var', (49, 56))	('presence of follicle', 'Phenotype', 'HP:0100874', (277, 297))	('GnRH', 'Gene', (230, 234))	('GnRH', 'Gene', '2796', (230, 234))	('FOXL2', 'Gene', (57, 62))	('gonadotropin-releasing hormone', 'Gene', '2796', (198, 228))	('gonadotropin-releasing hormone', 'Gene', (198, 228))	('hypophyseal gonadotropin', 'Phenotype', 'HP:0008213', (186, 210))
42948	32485873	Mutations in FOXL2 as noted in granulosa cell tumors, therefore, may result in increased androstenedione levels.	('androstenedione', 'Chemical', 'MESH:D000735', (89, 104))	('increased', 'PosReg', (79, 88))	('granulosa cell tumors', 'Disease', (31, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('FOXL2', 'Gene', '668', (13, 18))	('increased androstenedione', 'Phenotype', 'HP:0025380', (79, 104))	('granulosa cell tumors', 'Disease', 'MESH:D006106', (31, 52))	('Mutations', 'Var', (0, 9))	('FOXL2', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('androstenedione levels', 'MPA', (89, 111))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (31, 52))
42951	32485873	Based on this single-arm trial of ketoconazole in six patients with adult granulosa cell tumor, only three of whom were confirmed to have the somatic FOXL2 mutation, ketoconazole achieved stable disease in five patients and was granted an orphan designation for this indication by the European Medicines Agency.	('adult granulosa cell tumor', 'Phenotype', 'HP:0031919', (68, 94))	('adult granulosa cell tumor', 'Disease', (68, 94))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (54, 62))	('FOXL2', 'Gene', '668', (150, 155))	('adult granulosa cell tumor', 'Disease', 'MESH:D006106', (68, 94))	('ketoconazole', 'Chemical', 'MESH:D007654', (34, 46))	('FOXL2', 'Gene', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('ketoconazole', 'Chemical', 'MESH:D007654', (166, 178))	('mutation', 'Var', (156, 164))
42954	32485873	Non-epithelial ovarian tumors are not considered to harbor homologous recombination deficiency (HRD); mutations in BRCA1/2 and other HRD-associated genes are uncommon (Figure 2).	('Non-epithelial ovarian tumors', 'Disease', 'MESH:D010051', (0, 29))	('Non-epithelial ovarian tumors', 'Disease', (0, 29))	('epithelial ovarian tumors', 'Phenotype', 'HP:0025318', (4, 29))	('ovarian tumors', 'Phenotype', 'HP:0100615', (15, 29))	('ovarian tumor', 'Phenotype', 'HP:0100615', (15, 28))	('HRD', 'Disease', 'None', (96, 99))	('BRCA1/2', 'Gene', (115, 122))	('deficiency', 'Disease', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HRD', 'Disease', (133, 136))	('mutations', 'Var', (102, 111))	('deficiency', 'Disease', 'MESH:D007153', (84, 94))	('BRCA1/2', 'Gene', '672;675', (115, 122))	('epithelial ovarian tumor', 'Phenotype', 'HP:0025318', (4, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('HRD', 'Disease', (96, 99))	('HRD', 'Disease', 'None', (133, 136))
42981	32485873	Other alterations are fairly specific to subtypes of non-epithelial ovarian tumors, including the recurrent FOXL2 and common DICER1 mutations in adult granulosa cell tumors and Sertoli-Leydig cell tumors, respectively.	('DICER1', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('epithelial ovarian tumor', 'Phenotype', 'HP:0025318', (57, 81))	('FOXL2', 'Gene', '668', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Sertoli-Leydig cell tumors', 'Disease', (177, 203))	('FOXL2', 'Gene', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('adult granulosa cell tumors', 'Disease', 'MESH:D006106', (145, 172))	('non-epithelial ovarian tumors', 'Disease', (53, 82))	('Sertoli-Leydig cell tumors', 'Disease', 'MESH:D018310', (177, 203))	('Sertoli-Leydig cell tumors', 'Phenotype', 'HP:0100619', (177, 203))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ovarian tumors', 'Phenotype', 'HP:0100615', (68, 82))	('ovarian tumor', 'Phenotype', 'HP:0100615', (68, 81))	('granulosa cell tumors', 'Phenotype', 'HP:0031919', (151, 172))	('DICER1', 'Gene', '23405', (125, 131))	('mutations', 'Var', (132, 141))	('adult granulosa cell tumor', 'Phenotype', 'HP:0031919', (145, 171))	('adult granulosa cell tumors', 'Phenotype', 'HP:0031919', (145, 172))	('Leydig cell tumors', 'Phenotype', 'HP:0100618', (185, 203))	('non-epithelial ovarian tumors', 'Disease', 'MESH:D010051', (53, 82))	('adult granulosa cell tumors', 'Disease', (145, 172))	('epithelial ovarian tumors', 'Phenotype', 'HP:0025318', (57, 82))
43019	32252689	The ICD-O-3 site codes C620, C621, and C629 represent the tumor sites undescended testis, descended testis, and NOS, respectively.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('undescended testis', 'Phenotype', 'HP:0000028', (70, 88))	('descended testis', 'Disease', (90, 106))	('C620', 'Var', (23, 27))	('C629', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('C621', 'Var', (29, 33))	('undescended testis', 'Disease', (70, 88))
43020	32252689	Histologic types are also grouped using the ICD-O-3 code, with patients with GCT, teratoma, and EC identified by the histology codes 9060-9065, 9080-9085, and 9070-9072, respectively.	('teratoma', 'Disease', (82, 90))	('patients', 'Species', '9606', (63, 71))	('teratoma', 'Phenotype', 'HP:0009792', (82, 90))	('9060-9065', 'Var', (133, 142))	('9080-9085', 'Var', (144, 153))	('teratoma', 'Disease', 'MESH:D013724', (82, 90))	('EC', 'Phenotype', 'HP:0002898', (96, 98))	('GCT', 'Disease', (77, 80))	('9070-9072', 'Var', (159, 168))
43087	32252689	For patients receiving chemotherapy alone or combined chemotherapy and radiation, the treatment efficacy among NHWs is obviously superior to that observed among APIs and blacks.	('NHWs', 'Var', (111, 115))	('superior', 'PosReg', (129, 137))	('men', 'Species', '9606', (91, 94))	('patients', 'Species', '9606', (4, 12))	('treatment efficacy', 'CPA', (86, 104))
43121	28783265	The likely result of SDF is infertility, but it has been suggested that offspring generated from such defective sperm are at an increased risk of imprinting disorders and cancer.	('infertility', 'Disease', 'MESH:D007247', (28, 39))	('SDF', 'Chemical', '-', (21, 24))	('infertility', 'Phenotype', 'HP:0000789', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('infertility', 'Disease', (28, 39))	('cancer', 'Disease', (171, 177))	('imprinting disorders', 'Disease', (146, 166))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('defective', 'Var', (102, 111))
43144	27033539	Social constraints moderated the relationship, such that high restrictive emotionality was associated with higher depressive symptoms in those with high constraints.	('depressive symptoms', 'Disease', (114, 133))	('depressive symptoms', 'Phenotype', 'HP:0000716', (114, 133))	('higher', 'PosReg', (107, 113))	('high restrictive', 'Var', (57, 73))	('depressive symptoms', 'Disease', 'MESH:D000275', (114, 133))
43210	27033539	Simple slope analyses revealed that among young adult men with medium (beta = .07, p < .05) or high (beta = .15, p < .001) social constraints, high restrictive emotionality was associated with greater depressive symptoms.	('depressive symptoms', 'Disease', 'MESH:D000275', (201, 220))	('high restrictive', 'Var', (143, 159))	('men', 'Species', '9606', (54, 57))	('greater', 'PosReg', (193, 200))	('depressive symptoms', 'Disease', (201, 220))	('depressive symptoms', 'Phenotype', 'HP:0000716', (201, 220))
43293	21383689	Three micro-RNAs and three small nucleolar RNAs were differentially methylated; one, miR-199a, was associated with the progression and prognosis of gastric and ovarian cancers.	('gastric and ovarian cancers', 'Disease', 'MESH:D013274', (148, 175))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('associated with', 'Reg', (99, 114))	('ovarian cancers', 'Phenotype', 'HP:0100615', (160, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('miR-199a', 'Var', (85, 93))	('miR-199a', 'Chemical', '-', (85, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (160, 174))
43294	21383689	In this report we document, by epigenomic profiling of testicular tissue, that miR-199a is transcribed as antisense of dynamin 3 (chromosome 1q24.3), and hypermethylation of this region is correlated with miR-199a-5p/3p repression and tumor malignancy.	('correlated', 'Reg', (189, 199))	('tumor malignancy', 'Disease', 'MESH:D018198', (235, 251))	('miR-199a', 'Gene', (79, 87))	('miR-199a', 'Chemical', '-', (205, 213))	('dynamin 3', 'Gene', '26052', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor malignancy', 'Disease', (235, 251))	('miR-199a', 'Chemical', '-', (79, 87))	('dynamin 3', 'Gene', (119, 128))	('miR-199a-5p/3p repression', 'Var', (205, 230))	('hypermethylation', 'Var', (154, 170))
43296	21383689	The miR-199a-5p, one of two mature miRNA species derived from miR-199a, is associated with tumor malignancy.	('tumor malignancy', 'Disease', 'MESH:D018198', (91, 107))	('miR-199a', 'Chemical', '-', (62, 70))	('miR-199a-5p', 'Var', (4, 15))	('miR-199a', 'Gene', (62, 70))	('tumor malignancy', 'Disease', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (75, 85))	('miR-199a', 'Chemical', '-', (4, 12))
43297	21383689	We further identified the embryonal carcinoma antigen podocalyxin-like protein 1 (PODXL), an anti-adhesive protein expressed in aggressive tumors, as a target of miR-199a-5p.	('PODXL', 'Gene', (82, 87))	('aggressive tumors', 'Disease', (128, 145))	('miR-199a', 'Chemical', '-', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (26, 45))	('miR-199a-5p', 'Var', (162, 173))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (26, 45))	('embryonal carcinoma', 'Disease', (26, 45))	('podocalyxin-like protein 1', 'Gene', '5420', (54, 80))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('aggressive tumors', 'Disease', 'MESH:D001523', (128, 145))	('PODXL', 'Gene', '5420', (82, 87))	('podocalyxin-like protein 1', 'Gene', (54, 80))
43299	21383689	The inverse relationship between PODXL and miR-199a-5p expression suggests PODXL is a downstream effector mediating the action of miR199a-5p.	('miR-199a-5p', 'Gene', (43, 54))	('PODXL', 'Gene', (75, 80))	('199a', 'Chemical', '-', (133, 137))	('199a', 'Chemical', '-', (47, 51))	('miR-199a', 'Chemical', '-', (43, 51))	('PODXL', 'Gene', '5420', (33, 38))	('PODXL', 'Gene', '5420', (75, 80))	('miR199a-5p', 'Var', (130, 140))	('PODXL', 'Gene', (33, 38))
43300	21383689	This report identifies DNA methylation, miR-199a dysregulation and PODXL as critical factors in tumor malignancy.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor malignancy', 'Disease', 'MESH:D018198', (96, 112))	('miR-199a', 'Chemical', '-', (40, 48))	('PODXL', 'Gene', '5420', (67, 72))	('dysregulation', 'Var', (49, 62))	('miR-199a', 'Gene', (40, 48))	('tumor malignancy', 'Disease', (96, 112))	('PODXL', 'Gene', (67, 72))
43301	21383689	Altered gene and/or non-coding RNA expression are key features of cancer.	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (66, 72))	('Altered gene', 'Var', (0, 12))
43302	21383689	Genetic and epigenetic modulation is an essential phenomenon of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('carcinogenesis', 'Disease', (64, 78))	('Genetic', 'Var', (0, 7))	('epigenetic modulation', 'Var', (12, 33))
43303	21383689	In cancer cells, hypermethylation of tumor suppressor genes, and/or hypomethylation of oncogenes or heterochromatin results in aberrant expression of genes leading to tumorigenesis, genomic instability or the promotion of cell proliferation.	('hypomethylation', 'Var', (68, 83))	('genomic instability', 'CPA', (182, 201))	('expression', 'MPA', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('aberrant', 'Var', (127, 135))	('leading to', 'Reg', (156, 166))	('genes', 'Gene', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('promotion', 'PosReg', (209, 218))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('hypermethylation', 'Var', (17, 33))	('cell proliferation', 'CPA', (222, 240))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
43304	21383689	Recent reports suggested methylation may have a role in the regulation of tumor malignancy.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor malignancy', 'Disease', (74, 90))	('methylation', 'Var', (25, 36))	('role', 'Reg', (48, 52))	('tumor malignancy', 'Disease', 'MESH:D018198', (74, 90))
43307	21383689	We hypothesize that aberrant DNA methylation is a factor for development of testicular malignancy.	('factor', 'Reg', (50, 56))	('testicular malignancy', 'Phenotype', 'HP:0010788', (76, 97))	('aberrant', 'Var', (20, 28))	('testicular malignancy', 'Disease', (76, 97))	('testicular malignancy', 'Disease', 'MESH:D013733', (76, 97))	('DNA', 'Protein', (29, 32))
43310	21383689	In this study we document that miR-199a was generally hypermethylated in malignant testicular tumor, which correlated with its downregulation.	('testicular tumor', 'Phenotype', 'HP:0010788', (83, 99))	('miR-199a', 'Gene', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('hypermethylated', 'Var', (54, 69))	('downregulation', 'NegReg', (127, 141))	('malignant testicular tumor', 'Disease', 'MESH:D013736', (73, 99))	('miR-199a', 'Chemical', '-', (31, 39))	('malignant testicular tumor', 'Disease', (73, 99))
43312	21383689	We identified podocalyxin-like protein 1 (PODXL) as a target of miR-199a-5p.	('podocalyxin-like protein 1', 'Gene', '5420', (14, 40))	('PODXL', 'Gene', '5420', (42, 47))	('podocalyxin-like protein 1', 'Gene', (14, 40))	('PODXL', 'Gene', (42, 47))	('miR-199a', 'Chemical', '-', (64, 72))	('miR-199a-5p', 'Var', (64, 75))
43315	21383689	Our data imply that an epigenetic change in a previously unrecognized intronic region contributes to the aggressive behavior of testicular tumors via dysregulation of miR-199a and its corresponding target, PODXL.	('aggressive behavior', 'CPA', (105, 124))	('testicular tumor', 'Phenotype', 'HP:0010788', (128, 144))	('miR-199a', 'Gene', (167, 175))	('PODXL', 'Gene', '5420', (206, 211))	('aggressive behavior', 'Phenotype', 'HP:0000718', (105, 124))	('testicular tumors', 'Disease', (128, 145))	('dysregulation', 'MPA', (150, 163))	('PODXL', 'Gene', (206, 211))	('miR-199a', 'Chemical', '-', (167, 175))	('contributes', 'Reg', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('testicular tumors', 'Disease', 'MESH:D013736', (128, 145))	('testicular tumors', 'Phenotype', 'HP:0010788', (128, 145))	('epigenetic change', 'Var', (23, 40))
43317	21383689	The miR-199a is transcribed as antisense of the host gene DNM3.	('miR-199a', 'Var', (4, 12))	('DNM3', 'Gene', '26052', (58, 62))	('DNM3', 'Gene', (58, 62))	('miR-199a', 'Chemical', '-', (4, 12))
43318	21383689	Luciferase assay indicated that the upstream region of miR-199a (+9:-471) has promoter activity (Supplementary Figure 1a).	('promoter activity', 'MPA', (78, 95))	('miR-199a', 'Var', (55, 63))	('miR-199a', 'Chemical', '-', (55, 63))
43321	21383689	To investigate whether aberrant methylation of miR-199a is related to tumor malignancy, we obtained tumor DNA from patients with testicular cancer with different degrees of metastasis and with three normal specimens as controls.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (115, 123))	('aberrant', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('testicular cancer', 'Phenotype', 'HP:0010788', (129, 146))	('tumor malignancy', 'Disease', (70, 86))	('testicular cancer', 'Disease', 'MESH:D013736', (129, 146))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (70, 75))	('miR-199a', 'Chemical', '-', (47, 55))	('tumor malignancy', 'Disease', 'MESH:D018198', (70, 86))	('testicular cancer', 'Disease', (129, 146))	('related', 'Reg', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('miR-199a', 'Gene', (47, 55))
43327	21383689	Comparison of the non-cancerous and malignant groups indicated miR-199a-5p was significantly downregulated in malignant tumors (P = 0.000007).	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('miR-199a-5p', 'Var', (63, 74))	('malignant tumors', 'Disease', (110, 126))	('non-cancerous', 'Disease', (18, 31))	('downregulated', 'NegReg', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('miR-199a', 'Chemical', '-', (63, 71))	('non-cancerous', 'Disease', 'MESH:D009369', (18, 31))	('malignant tumors', 'Disease', 'MESH:D018198', (110, 126))
43336	21383689	In addition, in vitro methylation of the cloned miR-199a promoter ligated to a luciferase gene suppressed the luciferase activity by 80%, as compared with the unmethylated promoter control (Supplementary Figure 1b).	('miR-199a', 'Chemical', '-', (48, 56))	('luciferase', 'Enzyme', (110, 120))	('suppressed', 'NegReg', (95, 105))	('activity', 'MPA', (121, 129))	('miR-199a', 'Gene', (48, 56))	('methylation', 'Var', (22, 33))	('luciferase', 'Gene', (79, 89))
43342	21383689	Matrigel invasion assay indicated that expression of miR-199a significantly suppressed the ability of NT2 cells to invade the matrigel basement (P < 0.005) (Figure 3c).	('suppressed', 'NegReg', (76, 86))	('miR-199a', 'Chemical', '-', (53, 61))	('miR-199a', 'Var', (53, 61))
43344	21383689	Two months after subcutaneous implantation of transfected cells in athymic nude mice, the average size of the tumors in the NT2-199a group was ~33% smaller than that in the control group (P = 0.145) (Figure 3d).	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('nude mice', 'Species', '10090', (75, 84))	('tumors', 'Disease', (110, 116))	('smaller', 'NegReg', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('199a', 'Chemical', '-', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('NT2-199a', 'Var', (124, 132))
43346	21383689	To confirm the anti-metastastic property of miR-199a, we used a xenograft animal model to study its function in vivo.	('anti-metastastic', 'MPA', (15, 31))	('miR-199a', 'Chemical', '-', (44, 52))	('miR-199a', 'Var', (44, 52))
43355	21383689	At later stage (day 82), miR-199a appeared to be less effective in suppressing metastasis.	('miR-199a', 'Chemical', '-', (25, 33))	('metastasis', 'CPA', (79, 89))	('suppressing', 'NegReg', (67, 78))	('miR-199a', 'Var', (25, 33))
43356	21383689	The lung and liver metastases from NT2-199a group at day 82 expressed miR-199a-5p/3p at a comparable level to those of cultured NT2-199a cells (Supplementary Figure 5).	('199a', 'Chemical', '-', (74, 78))	('199a', 'Chemical', '-', (39, 43))	('miR-199a-5p/3p', 'Var', (70, 84))	('metastases', 'Disease', (19, 29))	('metastases', 'Disease', 'MESH:D009362', (19, 29))	('199a', 'Chemical', '-', (132, 136))	('NT2-199a', 'Var', (35, 43))	('miR-199a', 'Chemical', '-', (70, 78))
43357	21383689	As only miR-199a-5p was related to tumor malignancy, we sought to identify targets of miR-199a-5p compatible with its function (Figure 2b).	('miR-199a', 'Chemical', '-', (8, 16))	('miR-199a', 'Chemical', '-', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-199a-5p', 'Var', (86, 97))	('tumor malignancy', 'Disease', 'MESH:D018198', (35, 51))	('tumor malignancy', 'Disease', (35, 51))
43362	21383689	Furthermore, demethylation of NT2 cells by 5-aza restored the miR-199a-5p level and suppressed PODXL expression, suggesting a link between methylation, miR-199a-5p expression and PODXL level (Figure 5b).	('miR-199a', 'Chemical', '-', (62, 70))	('miR-199a', 'Chemical', '-', (152, 160))	('PODXL', 'Gene', (95, 100))	('PODXL', 'Gene', (179, 184))	('restored', 'PosReg', (49, 57))	('demethylation', 'Var', (13, 26))	('5-aza', 'Chemical', 'MESH:D001374', (43, 48))	('miR-199a-5p level', 'MPA', (62, 79))	('suppressed', 'NegReg', (84, 94))	('PODXL', 'Gene', '5420', (95, 100))	('PODXL', 'Gene', '5420', (179, 184))
43364	21383689	Seventy-two hours after transfection, the PODXL protein was significantly decreased following miR-199a-5p, but not miR-199a-3p treatment.	('PODXL', 'Gene', '5420', (42, 47))	('miR-199a', 'Chemical', '-', (115, 123))	('miR-199a', 'Chemical', '-', (94, 102))	('PODXL', 'Gene', (42, 47))	('miR-199a-5p', 'Var', (94, 105))	('decreased', 'NegReg', (74, 83))	('miR-199a-3p', 'Gene', (115, 126))	('miR-199a-3p', 'Gene', '406977', (115, 126))
43366	21383689	When NT2-199a cells were transfected with miR-199a-5p inhibitor (5pi), the PODXL level was restored.	('PODXL', 'Gene', (75, 80))	('miR-199a', 'Chemical', '-', (42, 50))	('miR-199a-5p', 'Var', (42, 53))	('5pi', 'Chemical', '-', (65, 68))	('PODXL', 'Gene', '5420', (75, 80))	('restored', 'PosReg', (91, 99))	('199a', 'Chemical', '-', (9, 13))	('199a', 'Chemical', '-', (46, 50))
43368	21383689	Regulation of PODXL by miR-199a-5p probably occurs through binding of miRNA at its 3'-UTR.	('miR-199a-5p', 'Var', (23, 34))	('miRNA', 'Protein', (70, 75))	('PODXL', 'Gene', '5420', (14, 19))	('binding', 'Interaction', (59, 66))	('PODXL', 'Gene', (14, 19))	('miR-199a', 'Chemical', '-', (23, 31))
43373	21383689	These data show that miR-199a-5p regulates PODXL through a conserved binding site in its 3'-UTR.	('regulates', 'Reg', (33, 42))	('PODXL', 'Gene', (43, 48))	('miR-199a-5p', 'Var', (21, 32))	('binding', 'Interaction', (69, 76))	('miR-199a', 'Chemical', '-', (21, 29))	('PODXL', 'Gene', '5420', (43, 48))
43374	21383689	Given that PODXL is a target of miR-199a-5p, the expression and its correlation with miR-199a-5p in primary tissue remains unclear.	('PODXL', 'Gene', '5420', (11, 16))	('miR-199a', 'Chemical', '-', (32, 40))	('PODXL', 'Gene', (11, 16))	('miR-199a', 'Chemical', '-', (85, 93))	('miR-199a-5p', 'Var', (32, 43))
43379	21383689	An inverse relationship between miR-199a-5p and PODXL was observed in cultured cells (Figures 5a-d).	('miR-199a', 'Chemical', '-', (32, 40))	('miR-199a-5p', 'Var', (32, 43))	('PODXL', 'Gene', (48, 53))	('PODXL', 'Gene', '5420', (48, 53))
43385	21383689	The difference of the correlation coefficient agrees with the finding that PODXL is a target of miR-199a-5p, but not miR-199a-3p.	('PODXL', 'Gene', (75, 80))	('miR-199a-3p', 'Gene', (117, 128))	('miR-199a-5p', 'Var', (96, 107))	('PODXL', 'Gene', '5420', (75, 80))	('miR-199a-3p', 'Gene', '406977', (117, 128))	('miR-199a', 'Chemical', '-', (96, 104))	('miR-199a', 'Chemical', '-', (117, 125))
43386	21383689	As a target of miR-199a-5p, PODXL might participate in the anti-metastatic function of this miRNA.	('PODXL', 'Gene', '5420', (28, 33))	('miR-199a', 'Chemical', '-', (15, 23))	('participate', 'Reg', (40, 51))	('PODXL', 'Gene', (28, 33))	('anti-metastatic', 'CPA', (59, 74))	('miR-199a-5p', 'Var', (15, 26))
43387	21383689	To validate this hypothesis, we stably knocked down PODXL in NT2 cells with RNAi.	('PODXL', 'Gene', '5420', (52, 57))	('knocked', 'Var', (39, 46))	('PODXL', 'Gene', (52, 57))
43391	21383689	However, in NT2-PODXLi cells the level of miR-199a was invariable relative to the parent NT2 cells (Supplementary Figure 3b).	('miR-199a', 'Var', (42, 50))	('PODXL', 'Gene', (16, 21))	('PODXL', 'Gene', '5420', (16, 21))	('miR-199a', 'Chemical', '-', (42, 50))
43392	21383689	Thus, we demonstrated that knockdown of PODXL alone without changing the level of its riboregulator miR-199a-5p would suppress cancer invasion in a manner similar to the effect of overexpression of miR-199a, implying that PODXL is a downstream target of miR-199a-5p.	('suppress', 'NegReg', (118, 126))	('knockdown', 'Var', (27, 36))	('PODXL', 'Gene', (222, 227))	('miR-199a', 'Chemical', '-', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('PODXL', 'Gene', (40, 45))	('miR-199a', 'Chemical', '-', (254, 262))	('miR-199a', 'Chemical', '-', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('PODXL', 'Gene', '5420', (222, 227))	('cancer', 'Disease', (127, 133))	('PODXL', 'Gene', '5420', (40, 45))
43397	21383689	Epigenetic alteration is a mechanism for carcinogenesis.	('carcinogenesis', 'Disease', (41, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('Epigenetic alteration', 'Var', (0, 21))
43399	21383689	Here we describe DNA methylation linked dysregulation of a conserved miR-199a caused by aberrant methylation in an intronic region of DNM3 at 1q24.3.	('DNM3', 'Gene', (134, 138))	('miR-199a', 'Gene', (69, 77))	('aberrant methylation', 'Var', (88, 108))	('caused by', 'Reg', (78, 87))	('dysregulation', 'MPA', (40, 53))	('DNM3', 'Gene', '26052', (134, 138))	('miR-199a', 'Chemical', '-', (69, 77))	('methylation', 'Var', (97, 108))
43400	21383689	We found that hypermethylation in the DNM3 intron leads to miR-199a depression.	('hypermethylation', 'Var', (14, 30))	('DNM3', 'Gene', (38, 42))	('miR-199a depression', 'Disease', 'MESH:D000275', (59, 78))	('DNM3', 'Gene', '26052', (38, 42))	('depression', 'Phenotype', 'HP:0000716', (68, 78))	('leads to', 'Reg', (50, 58))	('miR-199a depression', 'Disease', (59, 78))
43401	21383689	Both miR-199a methylation and expression are associated with testicular tumor malignancy.	('testicular tumor malignancy', 'Disease', (61, 88))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('expression', 'MPA', (30, 40))	('miR-199a', 'Chemical', '-', (5, 13))	('associated', 'Reg', (45, 55))	('testicular tumor malignancy', 'Disease', 'MESH:D013736', (61, 88))	('methylation', 'Var', (14, 25))	('testicular tumor', 'Phenotype', 'HP:0010788', (61, 77))	('miR-199a', 'Gene', (5, 13))
43403	21383689	Subsequently we identified an embryonal carcinoma tumor antigen, PODXL, as a target of miR-199a-5p.	('miR-199a', 'Chemical', '-', (87, 95))	('carcinoma tumor', 'Disease', 'MESH:D009369', (40, 55))	('PODXL', 'Gene', '5420', (65, 70))	('embryonal carcinoma tumor', 'Phenotype', 'HP:0002898', (30, 55))	('PODXL', 'Gene', (65, 70))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (30, 49))	('miR-199a-5p', 'Var', (87, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (30, 49))	('embryonal carcinoma', 'Disease', (30, 49))	('carcinoma tumor', 'Disease', (40, 55))
43405	21383689	We showed that miR-199a-5p is a negative regulator of PODXL.	('PODXL', 'Gene', (54, 59))	('PODXL', 'Gene', '5420', (54, 59))	('miR-199a-5p', 'Var', (15, 26))	('miR-199a', 'Chemical', '-', (15, 23))
43406	21383689	Based on our data we propose that epigenetic alteration in an intron of DNM3 leads to dysregulation of miR-199a and PODXL, and that this is one mechanism for development of testicular cancer.	('DNM3', 'Gene', '26052', (72, 76))	('PODXL', 'Gene', (116, 121))	('miR-199a', 'MPA', (103, 111))	('testicular cancer', 'Phenotype', 'HP:0010788', (173, 190))	('testicular cancer', 'Disease', 'MESH:D013736', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('testicular cancer', 'Disease', (173, 190))	('epigenetic alteration', 'Var', (34, 55))	('DNM3', 'Gene', (72, 76))	('PODXL', 'Gene', '5420', (116, 121))	('dysregulation', 'MPA', (86, 99))	('miR-199a', 'Chemical', '-', (103, 111))
43409	21383689	Specifically, some miRNA such as miR-122, miR-148a, miR-34b/c, miR-21, miR-373 and miR-520 have been shown to be important in cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('miR-373', 'Gene', (71, 78))	('miR-373', 'Gene', '442918', (71, 78))	('cancer metastasis', 'Disease', 'MESH:D009362', (126, 143))	('miR-520', 'Var', (83, 90))	('miR-148a', 'Gene', '406940', (42, 50))	('miR-21', 'Gene', '406991', (63, 69))	('miR-21', 'Gene', (63, 69))	('miR-148a', 'Gene', (42, 50))	('miR-122', 'Gene', (33, 40))	('miR-122', 'Gene', '406906', (33, 40))	('important', 'Reg', (113, 122))	('cancer metastasis', 'Disease', (126, 143))	('miR-34b', 'Gene', (52, 59))	('miR-34b', 'Gene', '407041', (52, 59))
43414	21383689	Although both miR-199a-5p and miR-199a-3p are derived from the same precursor RNA, only miR-199a- 5p was identified to be downregulated in testicular tumor malignancy.	('downregulated', 'NegReg', (122, 135))	('miR-199a- 5p', 'Var', (88, 100))	('miR-199a-3p', 'Gene', '406977', (30, 41))	('testicular tumor malignancy', 'Disease', 'MESH:D013736', (139, 166))	('testicular tumor', 'Phenotype', 'HP:0010788', (139, 155))	('miR-199a', 'Chemical', '-', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('miR-199a', 'Chemical', '-', (30, 38))	('miR-199a-3p', 'Gene', (30, 41))	('testicular tumor malignancy', 'Disease', (139, 166))	('miR-199a', 'Chemical', '-', (14, 22))
43423	21383689	By using luciferase assay, we showed miR-199a-5p could suppress PODXL through binding to a conserved site (Figure 5e).	('miR-199a-5p', 'Var', (37, 48))	('binding', 'Interaction', (78, 85))	('PODXL', 'Gene', (64, 69))	('miR-199a', 'Chemical', '-', (37, 45))	('PODXL', 'Gene', '5420', (64, 69))	('suppress', 'NegReg', (55, 63))
43424	21383689	For the scramble miRNA control groups, the constructs carrying a conserved (pGL-C) or a poorly conserved (pGL-P) miR-199a-5p-binding site showed a lower luciferase activity than the no 3'-UTR control, probably due to the presence of other background miRNA-binding sites that interact with endogenous miRNAs (for example miR-145 and miR-181 are found in the flanking miR-199a-5p conserved site based on TargetScan and PicTar).	('miR-145', 'Gene', '406937', (320, 327))	('luciferase', 'Enzyme', (153, 163))	('activity', 'MPA', (164, 172))	('lower', 'NegReg', (147, 152))	('miR-199a', 'Chemical', '-', (113, 121))	('miR-199a', 'Chemical', '-', (366, 374))	('miR-199a-5p-binding', 'Var', (113, 132))	('miR-145', 'Gene', (320, 327))
43425	21383689	Although we have shown that PODXL is a target of miR-199a-5p, we cannot rule out other targets that might modulate tumor invasion.	('PODXL', 'Gene', '5420', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PODXL', 'Gene', (28, 33))	('tumor', 'Disease', (115, 120))	('miR-199a-5p', 'Var', (49, 60))	('miR-199a', 'Chemical', '-', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
43426	21383689	In the other report, miR-199a-5p targets IKKbeta in ovarian cancer.	('ovarian cancer', 'Disease', (52, 66))	('IKKbeta', 'Gene', (41, 48))	('miR-199a-5p', 'Var', (21, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('IKKbeta', 'Gene', '3551', (41, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('miR-199a', 'Chemical', '-', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
43429	21383689	In our xenografted animal model, expression of miR-199a in NT2 cells suppressed metastasis at day 49 and 64.	('miR-199a', 'Chemical', '-', (47, 55))	('suppressed', 'NegReg', (69, 79))	('miR-199a', 'Var', (47, 55))
43431	21383689	Lung and liver metastases expressing miR-199a-5p and miR-199a-3p in the NT2-199a group at day 82 were comparable to those of cultured NT2-199a cells (Supplementary Figure 5).	('miR-199a-5p', 'Var', (37, 48))	('miR-199a-3p', 'Gene', '406977', (53, 64))	('metastases', 'Disease', (15, 25))	('199a', 'Chemical', '-', (57, 61))	('miR-199a', 'Chemical', '-', (53, 61))	('199a', 'Chemical', '-', (41, 45))	('miR-199a', 'Chemical', '-', (37, 45))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('miR-199a-3p', 'Gene', (53, 64))	('199a', 'Chemical', '-', (138, 142))	('199a', 'Chemical', '-', (76, 80))
43438	21383689	Similar to the observation for methylation, the P-values of 'cancerous vs non-cancerous' comparisons for miR-199a-5p/3p expressions are smaller (P < 0.00001) than those of 'seminoma vs non-seminoma' (P < 0.05).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	("'seminoma vs non-seminoma", 'Disease', 'MESH:D018239', (172, 197))	('miR-199a', 'Chemical', '-', (105, 113))	('cancerous', 'Disease', (78, 87))	('non-cancerous', 'Disease', 'MESH:D009369', (74, 87))	('cancerous', 'Disease', (61, 70))	("'seminoma vs non-seminoma", 'Disease', (172, 197))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('miR-199a-5p/3p', 'Var', (105, 119))	('cancerous', 'Disease', 'MESH:D009369', (61, 70))	('cancerous', 'Disease', 'MESH:D009369', (78, 87))	('smaller', 'NegReg', (136, 143))	('non-cancerous', 'Disease', (74, 87))
43440	21383689	Collectively, we report that aberrant DNA methylation in an intron of a host gene DNM3 as a critical factor for testicular tumor malignancy by modulating the level of anti-metastatic miR-199a and its corresponding target PODXL.	('DNM3', 'Gene', (82, 86))	('miR-199a', 'Chemical', '-', (183, 191))	('anti-metastatic miR-199a', 'MPA', (167, 191))	('modulating', 'Reg', (143, 153))	('level', 'MPA', (158, 163))	('PODXL', 'Gene', '5420', (221, 226))	('DNM3', 'Gene', '26052', (82, 86))	('testicular tumor malignancy', 'Disease', 'MESH:D013736', (112, 139))	('testicular tumor', 'Phenotype', 'HP:0010788', (112, 128))	('aberrant', 'Var', (29, 37))	('PODXL', 'Gene', (221, 226))	('testicular tumor malignancy', 'Disease', (112, 139))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
43470	21383689	Primary antibodies used were as follows: PODXL (clone 3D3, 3 microg/ml, Santa Cruz Biotechnology, Santa Cruz, CA, USA); GAPDH (1:8000, Genway, San Diego, CA, USA).	('1:8000', 'Var', (127, 133))	('PODXL', 'Gene', (41, 46))	('PODXL', 'Gene', '5420', (41, 46))
43476	21383689	For in vivo tumor growth study, 5-week-old male athymic nude mice (Charles River, Wilmington, MA, USA) were injected subcutaneously with 1 x 107 NT2-GFP or NT2-199a (n = 10 for each group) in each flank of each mouse.	('NT2-199a', 'Var', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mouse', 'Species', '10090', (211, 216))	('tumor', 'Disease', (12, 17))	('nude mice', 'Species', '10090', (56, 65))	('199a', 'Chemical', '-', (160, 164))
43665	31588363	treatment for infertility (DN46-DN469W [excluding DN469E]), vasectomy (KKFD46), cryptorchidism (DQ53-DQ539), varicocele (DN43-DN434), testicular torsion (DN44-DN449), or orchitis (DN450-DN450C).	('cryptorchidism', 'Disease', (80, 94))	('orchitis', 'Disease', 'MESH:D009920', (170, 178))	('infertility', 'Phenotype', 'HP:0000789', (14, 25))	('testicular torsion', 'Phenotype', 'HP:0100813', (134, 152))	('varicocele', 'Phenotype', 'HP:0012871', (109, 119))	('orchitis', 'Disease', (170, 178))	('cryptorchidism', 'Phenotype', 'HP:0000028', (80, 94))	('orchitis', 'Phenotype', 'HP:0100796', (170, 178))	('varicocele', 'Disease', (109, 119))	('DN44-DN449', 'Var', (154, 164))	('testicular torsion', 'Disease', (134, 152))	('infertility', 'Disease', (14, 25))	('DN46-DN469W', 'Var', (27, 38))	('infertility', 'Disease', 'MESH:D007246', (14, 25))	('DQ53-DQ539', 'Var', (96, 106))	('cryptorchidism', 'Disease', 'MESH:D003456', (80, 94))	('DN43-DN434', 'Var', (121, 131))	('vasectomy', 'Disease', (60, 69))	('men', 'Species', '9606', (5, 8))
43723	30611645	Genetic dysregulation in the setting of malignancy often impacts core cellular functions that lead to dysfunctional cell differentiation and growth.	('growth', 'CPA', (141, 147))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('dysfunctional', 'Disease', 'MESH:D009461', (102, 115))	('impacts', 'Reg', (57, 64))	('core cellular functions', 'MPA', (65, 88))	('Genetic dysregulation', 'Var', (0, 21))	('lead', 'Reg', (94, 98))	('dysfunctional', 'Disease', (102, 115))	('malignancy', 'Disease', (40, 50))
43733	30611645	Disruptions in the functions of these genes can result in benign disease such as infertility, as well as dysregulated cell growth and possibly consequent malignancy.	('Disruptions', 'Var', (0, 11))	('result in', 'Reg', (48, 57))	('functions', 'MPA', (19, 28))	('benign disease', 'Disease', (58, 72))	('infertility', 'Phenotype', 'HP:0000789', (81, 92))	('benign disease', 'Disease', 'MESH:D009369', (58, 72))	('infertility', 'Disease', 'MESH:D007247', (81, 92))	('dysregulated', 'MPA', (105, 117))	('infertility', 'Disease', (81, 92))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('malignancy', 'Disease', (154, 164))
43741	30611645	Inclusion criteria additionally included the requirement of addressing male or female infertility, benign urologic conditions, or genetics and epigenetics in the context of urology.	('epigenetics', 'Var', (143, 154))	('infertility', 'Phenotype', 'HP:0000789', (86, 97))	('male infertility', 'Phenotype', 'HP:0003251', (81, 97))	('male infertility', 'Disease', 'MESH:D007248', (81, 97))	('men', 'Species', '9606', (52, 55))	('male infertility', 'Disease', (81, 97))	('female infertility', 'Phenotype', 'HP:0008222', (79, 97))
43745	30611645	The authors found significant medical pathology - cystic fibrosis mutations, testis cancer, prostate cancer, diabetes mellitus, and hypothyroidism - in 33 out of their 536 patients (6%).	('mutations', 'Var', (66, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('testis cancer', 'Disease', 'MESH:D013736', (77, 90))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (109, 126))	('hypothyroidism', 'Disease', 'MESH:D007037', (132, 146))	('testis cancer', 'Phenotype', 'HP:0010788', (77, 90))	('hypothyroidism', 'Phenotype', 'HP:0000821', (132, 146))	('prostate cancer', 'Disease', (92, 107))	('hypothyroidism', 'Disease', (132, 146))	('diabetes mellitus', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('patients', 'Species', '9606', (172, 180))	('testis cancer', 'Disease', (77, 90))	('diabetes mellitus', 'Disease', 'MESH:D003920', (109, 126))	('fibrosis', 'Disease', 'MESH:D005355', (57, 65))	('fibrosis', 'Disease', (57, 65))
43758	30611645	Proposed mechanisms that could potentially explain the link between male infertility and the development of testicular cancer include genetic alterations in the sex-determining region of the Y chromosome (SRY) gene, which is essential for testicular development (Figure 1) (Table 2).	('men', 'Species', '9606', (257, 260))	('male infertility', 'Phenotype', 'HP:0003251', (68, 84))	('testicular cancer', 'Disease', 'MESH:D013736', (108, 125))	('men', 'Species', '9606', (100, 103))	('male infertility', 'Disease', 'MESH:D007248', (68, 84))	('infertility', 'Phenotype', 'HP:0000789', (73, 84))	('male infertility', 'Disease', (68, 84))	('SRY', 'Gene', '6736', (205, 208))	('testicular cancer', 'Disease', (108, 125))	('genetic alterations', 'Var', (134, 153))	('SRY', 'Gene', (205, 208))	('testicular cancer', 'Phenotype', 'HP:0010788', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
43761	30611645	Consequently, mutations in SRY are thought to cause both gonadal dysgenesis and tumor development.	('SRY', 'Gene', '6736', (27, 30))	('SRY', 'Gene', (27, 30))	('men', 'Species', '9606', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('gonadal dysgenesis and tumor', 'Disease', 'None', (57, 85))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (57, 75))	('cause', 'Reg', (46, 51))	('mutations', 'Var', (14, 23))
43764	30611645	Mutations may lead to chromosomal and genetic instability that increase the probability of cancer cell development.	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lead to', 'Reg', (14, 21))
43765	30611645	Structural chromosomal defects such as amplification of the 12p region, specifically isochromosome (i(12p)) formation, have been linked to invasive testicular germ cell cancer (TGCC) and impaired spermatogenesis.	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (187, 211))	('cancer', 'Disease', (169, 175))	('germ cell cancer', 'Phenotype', 'HP:0100728', (159, 175))	('amplification', 'Var', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('impaired spermatogenesis', 'CPA', (187, 211))	('linked', 'Reg', (129, 135))	('Structural chromosomal defects', 'Disease', 'MESH:D025063', (0, 30))	('Structural chromosomal defects', 'Disease', (0, 30))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
43766	30611645	Copy number increases in the 17q region have also been associated with TGCCs: gain of the proximal region 17q11-q21 with nonseminomas and gain of the distal region 17q24-qter common to all TGCCs.	('TGCCs', 'Disease', (71, 76))	('gain', 'PosReg', (138, 142))	('nonseminomas', 'Disease', (121, 133))	('nonseminomas', 'Disease', 'None', (121, 133))	('gain', 'PosReg', (78, 82))	('Copy number', 'Var', (0, 11))
43780	30611645	found an increased prostate cancer risk in subjects with shorter CAG repeat lengths, hypothesizing that the shorter CAG repeat lengths are associated with higher transcriptional activity and consequently are linked with higher prostate cancer risk.	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('prostate cancer', 'Disease', (19, 34))	('shorter CAG repeat lengths', 'Var', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('transcriptional activity', 'MPA', (162, 186))	('prostate cancer', 'Disease', (227, 242))	('shorter', 'Var', (57, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (19, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (19, 34))	('higher', 'PosReg', (155, 161))
43783	30611645	Impaired mismatch repair function allows mutations to accumulate that disrupt normal cellular processes and lead to genomic instability and consequent spermatogenic failure and cancer development.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('disrupt', 'NegReg', (70, 77))	('spermatogenic failure', 'Disease', (151, 172))	('genomic instability', 'CPA', (116, 135))	('men', 'Species', '9606', (191, 194))	('lead to', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('mismatch repair', 'Protein', (9, 24))	('normal', 'CPA', (78, 84))	('spermatogenic failure', 'Disease', 'OMIM:108420', (151, 172))
43795	30611645	While no molecular mechanisms have causally linked male infertility to any associated malignancies, it is likely that there are numerous genes that regulate male fertility that, when altered, could result in increased risk for one or more malignancies.	('malignancies', 'Disease', (239, 251))	('altered', 'Var', (183, 190))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('infertility', 'Phenotype', 'HP:0000789', (56, 67))	('male infertility', 'Disease', (51, 67))	('male infertility', 'Disease', 'MESH:D007248', (51, 67))	('male infertility', 'Phenotype', 'HP:0003251', (51, 67))	('malignancies', 'Disease', (86, 98))	('malignancies', 'Disease', 'MESH:D009369', (239, 251))	('result', 'Reg', (198, 204))
43796	30611645	More than 1,500 genes are thought to contribute to spermatogenesis, and defects in one or more of these may facilitate the cellular growth and proliferation that results in malignancy.	('defects', 'Var', (72, 79))	('cellular growth', 'CPA', (123, 138))	('facilitate', 'PosReg', (108, 118))	('malignancy', 'Disease', 'MESH:D009369', (173, 183))	('malignancy', 'Disease', (173, 183))	('results in', 'Reg', (162, 172))
43797	30611645	For example, mutational defects in DNA repair affect meiosis and mitosis and consequently the processes of both spermatogenesis and carcinogenesis, especially as oxidative stress-related DNA fragmentation is more frequent in subfertile men and can lead to decreased sperm motility and fertilization ability.	('sperm motility', 'CPA', (266, 280))	('decreased sperm motility', 'Phenotype', 'HP:0012207', (256, 280))	('carcinogenesis', 'Disease', (132, 146))	('DNA repair', 'Gene', (35, 45))	('affect', 'Reg', (46, 52))	('men', 'Species', '9606', (236, 239))	('oxidative stress', 'Phenotype', 'HP:0025464', (162, 178))	('fertilization ability', 'CPA', (285, 306))	('meiosis and mitosis', 'Disease', 'MESH:C536875', (53, 72))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('mutational defects', 'Var', (13, 31))	('men', 'Species', '9606', (195, 198))	('decreased', 'NegReg', (256, 265))
43798	30611645	Epigenetic modifications - DNA hypermethylation, imprinting, and histone modification - may also modify the relationship between infertility and cancer.	('cancer', 'Disease', (145, 151))	('infertility', 'Disease', (129, 140))	('histone modification -', 'Var', (65, 87))	('modify', 'Reg', (97, 103))	('relationship', 'Interaction', (108, 120))	('imprinting', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('infertility', 'Disease', 'MESH:D007247', (129, 140))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('infertility', 'Phenotype', 'HP:0000789', (129, 140))
43800	30611645	The histone methyltransferase EHMT2, which results in male infertility when ablated, can also function to epigenetically silence tumor suppressor genes via methylation of H3K9.	('infertility', 'Phenotype', 'HP:0000789', (59, 70))	('male infertility', 'Disease', (54, 70))	('results in', 'Reg', (43, 53))	('EHMT2', 'Gene', (30, 35))	('epigenetically', 'Var', (106, 120))	('H3K9', 'Protein', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('EHMT2', 'Gene', '10919', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('male infertility', 'Phenotype', 'HP:0003251', (54, 70))	('male infertility', 'Disease', 'MESH:D007248', (54, 70))	('methylation', 'Var', (156, 167))
43805	30611645	One study found that infants born to mothers taking exogenous hormones during pregnancy were more likely to develop testicular cancer (OR 4.9, 95% CI 1.7-13.9), suggesting an influence of hormone exposure.	('testicular cancer', 'Disease', (116, 133))	('exogenous hormones', 'Var', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('develop', 'PosReg', (108, 115))	('infants', 'Species', '9606', (21, 28))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))
43824	30611645	Genetic abnormalities contributory to PD such as duplication of chromosomes 7 and 8, Y chromosome deletions, and structural alterations such as reciprocal translocations of 46XY,t(11;12)(q11,p11), 46XY,t(1;5)(q25;q11), and inversion of 46XY,inv(7)(p22q36) may overlap with the Y chromosome abnormalities associated with cancer.	('cancer', 'Disease', (320, 326))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('duplication', 'Var', (49, 60))	('Genetic abnormalities', 'Disease', (0, 21))	('t(1;5)(q25;q11', 'Var', (202, 216))	('PD', 'Disease', 'MESH:D010300', (38, 40))	('inversion', 'Var', (223, 232))	('t(11;12)(q11', 'Var', (178, 190))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('inv(7)(p22q36', 'Var', (241, 254))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (279, 303))	('p11', 'Gene', '6281', (191, 194))	('Genetic abnormalities', 'Disease', 'MESH:D030342', (0, 21))	('p11', 'Gene', (191, 194))	('chromosome abnormalities', 'Disease', (279, 303))	('46XY,t(1;5)(q25;q11)', 'STRUCTURAL_ABNORMALITY', 'None', (197, 217))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (279, 303))	('46XY', 'Var', (173, 177))	('46XY', 'Var', (197, 201))
43846	28267895	However, men with TML did consume more crisp than men without.	('TML', 'Var', (18, 21))	('TML', 'Phenotype', 'HP:0012215', (18, 21))	('more', 'PosReg', (34, 38))	('men', 'Species', '9606', (9, 12))	('men', 'Species', '9606', (50, 53))
43856	28267895	A recent meta-analysis including more than 35 000 men concluded that TML was significantly associated with risk of testicular cancer (Wang et al., 2015).	('testicular cancer', 'Phenotype', 'HP:0010788', (115, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TML', 'Phenotype', 'HP:0012215', (69, 72))	('TML', 'Var', (69, 72))	('testicular cancer', 'Disease', (115, 132))	('men', 'Species', '9606', (50, 53))	('associated', 'Reg', (91, 101))
43882	28267895	Trauma to the testicles was reported more often in men with TML than in men without TML (8.6% vs. 5.3%, p = 0.065).	('men', 'Species', '9606', (51, 54))	('men', 'Species', '9606', (72, 75))	('TML', 'Phenotype', 'HP:0012215', (60, 63))	('TML', 'Phenotype', 'HP:0012215', (84, 87))	('Trauma', 'Disease', 'MESH:D014947', (0, 6))	('TML', 'Var', (60, 63))	('Trauma', 'Disease', (0, 6))
43884	28267895	Pain was most common in both groups of men (32.2% in men with TML vs. 27.1% in men without, p = 0.151).	('men', 'Species', '9606', (79, 82))	('TML', 'Var', (62, 65))	('TML', 'Phenotype', 'HP:0012215', (62, 65))	('Pain', 'Phenotype', 'HP:0012531', (0, 4))	('Pain', 'Disease', 'MESH:D010146', (0, 4))	('men', 'Species', '9606', (53, 56))	('men', 'Species', '9606', (39, 42))	('Pain', 'Disease', (0, 4))
43895	28267895	Men with TML reported less physical exercise than men without TML, had a higher consumption of crisp and experienced more testicular discomfort.	('TML', 'Phenotype', 'HP:0012215', (62, 65))	('testicular discomfort', 'CPA', (122, 143))	('less', 'NegReg', (22, 26))	('Men', 'Species', '9606', (0, 3))	('men', 'Species', '9606', (50, 53))	('TML', 'Var', (9, 12))	('physical exercise', 'CPA', (27, 44))	('TML', 'Phenotype', 'HP:0012215', (9, 12))	('consumption of crisp', 'MPA', (80, 100))	('higher', 'PosReg', (73, 79))
43897	28267895	Secondarily, a total of 43 men were diagnosed with cancer (2.8%), and the presence of TML was significantly associated with cancer compared to no TML (5.6% vs. 2.4%) (p = 0.011).	('cancer', 'Disease', (124, 130))	('TML', 'Var', (86, 89))	('TML', 'Phenotype', 'HP:0012215', (86, 89))	('presence', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TML', 'Phenotype', 'HP:0012215', (146, 149))	('associated', 'Reg', (108, 118))	('men', 'Species', '9606', (27, 30))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
43916	28267895	However, men with TML consumed more crisp and popcorn than men without TML.	('TML', 'Var', (18, 21))	('TML', 'Phenotype', 'HP:0012215', (18, 21))	('men', 'Species', '9606', (9, 12))	('TML', 'Phenotype', 'HP:0012215', (71, 74))	('more', 'PosReg', (31, 35))	('men', 'Species', '9606', (59, 62))
43919	28267895	In some studies, rodent acrylamide has been shown to generate tumours in multiple organs, including mesotheliomas of the testicles (Johnson et al., 1986; Friedman et al., 1995; Klaunig, 2008).	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('acrylamide', 'Chemical', 'MESH:D020106', (24, 34))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('acrylamide', 'Var', (24, 34))	('mesotheliomas of', 'Disease', (100, 116))	('tumours', 'Disease', (62, 69))
43923	28267895	Testicular pain was the most frequent referral reason to US investigation, and men with TML tended more often to have testicular pain than men without.	('men', 'Species', '9606', (79, 82))	('testicular pain', 'Disease', 'MESH:D010146', (118, 133))	('Testicular pain', 'Disease', 'MESH:D010146', (0, 15))	('Testicular pain', 'Disease', (0, 15))	('pain', 'Phenotype', 'HP:0012531', (129, 133))	('men', 'Species', '9606', (139, 142))	('testicular pain', 'Disease', (118, 133))	('TML', 'Var', (88, 91))	('TML', 'Phenotype', 'HP:0012215', (88, 91))	('pain', 'Phenotype', 'HP:0012531', (11, 15))
43941	26625006	Hypermethylation of genes in testicular embryonal carcinomas Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males.	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (72, 91))	('testicular embryonal carcinomas', 'Disease', (29, 60))	('non-seminomatous germ cell tumours', 'Disease', (119, 153))	('EC', 'Phenotype', 'HP:0002898', (93, 95))	('testicular embryonal carcinomas', 'Disease', 'MESH:D013736', (29, 60))	('Hypermethylation', 'Var', (0, 16))	('non-seminomatous germ cell tumours', 'Disease', 'MESH:C537844', (119, 153))	('germ cell tumour', 'Phenotype', 'HP:0100728', (136, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('Testicular embryonal carcinoma', 'Disease', (61, 91))	('Testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (61, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (40, 59))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))
43962	26625006	It is critical to use relatively pure form of EC for methylation analysis, as the epigenetic variation among heterogeneous NSGCTs complicates the interpretation of experimental data.	('EC', 'Phenotype', 'HP:0002898', (46, 48))	('men', 'Species', '9606', (170, 173))	('epigenetic', 'Var', (82, 92))	('complicates', 'Reg', (130, 141))
43966	26625006	Recent methylation studies indicated that epigenetic factors may have an essential role in the genesis of germ cell neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (116, 125))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (106, 125))	('neoplasia', 'Disease', (116, 125))	('epigenetic factors', 'Var', (42, 60))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))
43998	26625006	A total of 1167 hypermethylated DMRs were enriched in the ECs.	('EC', 'Phenotype', 'HP:0002898', (58, 60))	('DMRs', 'Chemical', '-', (32, 36))	('ECs', 'Disease', (58, 61))	('hypermethylated', 'Var', (16, 31))
44006	26625006	To investigate whether the identified hypermethylated genes/ncRNAs are associated with reduced transcription, the relative mRNA expression of nine randomly selected genes/ncRNAs (AGPAT3, MIR1184, SUCLG2, RBMY1, SPANXD, RNF168, USP13, FAM197Y2P and STAG2) was examined by RT-qPCR.	('STAG2', 'Gene', (248, 253))	('RNF168', 'Gene', (219, 225))	('ncRNA', 'Gene', (171, 176))	('USP13', 'Gene', (227, 232))	('MIR1184', 'Gene', (187, 194))	('ncRNA', 'Gene', '220202', (171, 176))	('transcription', 'MPA', (95, 108))	('SPANXD', 'Gene', (211, 217))	('ncRNA', 'Gene', (60, 65))	('RNF168', 'Gene', '165918', (219, 225))	('MIR1184', 'Gene', '100302111', (187, 194))	('ncRNA', 'Gene', '220202', (60, 65))	('SUCLG2', 'Gene', (196, 202))	('SPANXD', 'Gene', '64648', (211, 217))	('reduced', 'NegReg', (87, 94))	('SUCLG2', 'Gene', '8801', (196, 202))	('FAM197Y2P', 'Gene', (234, 243))	('AGPAT3', 'Gene', '56894', (179, 185))	('hypermethylated', 'Var', (38, 53))	('STAG2', 'Gene', '10735', (248, 253))	('FAM197Y2P', 'Gene', '252946', (234, 243))	('USP13', 'Gene', '8975', (227, 232))	('AGPAT3', 'Gene', (179, 185))
44007	26625006	Although we had limited sample size, 8 out of 9 genes (except STAG2) showed reduced expression in tumours of both metastatic and non-metastatic ECs (Figure 2), suggesting promoter methylation may hinder transcription of these genes.	('STAG2', 'Gene', (62, 67))	('STAG2', 'Gene', '10735', (62, 67))	('hinder', 'NegReg', (196, 202))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('transcription', 'MPA', (203, 216))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('reduced', 'NegReg', (76, 83))	('EC', 'Phenotype', 'HP:0002898', (144, 146))	('expression', 'MPA', (84, 94))	('promoter methylation', 'Var', (171, 191))
44018	26625006	As the majority of type-2 TGCTs originate from germ cells, it suggests that epigenetic silencing of sex-linked genes might have a crucial role in suppressing tumour initiation or its progression.	('tumour initiation', 'Disease', 'MESH:D009369', (158, 175))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour initiation', 'Disease', (158, 175))	('epigenetic silencing', 'Var', (76, 96))	('suppressing', 'NegReg', (146, 157))	('progression', 'CPA', (183, 194))
44019	26625006	The identification of DNA methylation of these sex-linked genes suggests that epigenetic alterations associated with testicular transformation may involve genes critical for germ cell development.	('men', 'Species', '9606', (191, 194))	('methylation', 'Var', (26, 37))	('testicular transformation', 'Disease', (117, 142))	('epigenetic alterations', 'Var', (78, 100))
44033	26625006	Mutation of this gene gives rise to Riddle syndrome.	('Riddle syndrome', 'Disease', 'MESH:C567453', (36, 51))	('Mutation', 'Var', (0, 8))	('gives rise to', 'Reg', (22, 35))	('Riddle syndrome', 'Disease', (36, 51))
44037	26625006	Genes that govern tumour suppression could be regulated by epigenetic changes.	('regulated', 'Reg', (46, 55))	('govern tumour', 'Disease', (11, 24))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour suppression', 'Disease', (18, 36))	('epigenetic changes', 'Var', (59, 77))	('govern tumour', 'Disease', 'MESH:D009369', (11, 24))	('tumour suppression', 'Disease', 'OMIM:146850', (18, 36))
44068	25424124	Of particular interest, 12p gains were detected exclusively in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('12p gains', 'Var', (24, 33))
44069	25424124	In peripheral blood samples, loss of 9p13.1-p12 was the unique novel CNV shared by the twins, confirming the involvement of CNTNAP3 gene in TGCTs development.	('CNTNAP3', 'Gene', '79937', (124, 131))	('men', 'Species', '9606', (153, 156))	('loss of 9p13.1-p12', 'Var', (29, 47))	('men', 'Species', '9606', (116, 119))	('CNTNAP3', 'Gene', (124, 131))
44082	25424124	Gains at Xq27, XRCC1 polymorphisms and deletions of the Y chromosome have been described as associated with susceptibility to testicular germ cell tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('Gains', 'Var', (0, 5))	('deletions', 'Var', (39, 48))	('germ cell tumor', 'Phenotype', 'HP:0100728', (137, 152))	('XRCC1', 'Gene', '7515', (15, 20))	('susceptibility', 'Reg', (108, 122))	('Xq27', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('polymorphisms', 'Var', (21, 34))	('associated', 'Reg', (92, 102))	('XRCC1', 'Gene', (15, 20))
44120	25424124	The differences in genetic profiles of MZ twins has been previously characterized according to alterations involving the number or morphology of chromosomes, chromosomal mosaicism, single nucleotide polymorphisms and epigenetic modifications.	('epigenetic modifications', 'Var', (217, 241))	('alterations', 'Reg', (95, 106))	('MZ', 'Chemical', '-', (39, 41))	('single nucleotide polymorphisms', 'Var', (181, 212))
44149	25424124	A high incidence of 13q deletion has been reported in primary TGCTs and in non-seminomatous germ cell tumours with acquired treatment resistance.	('non-seminomatous germ cell tumours', 'Disease', (75, 109))	('non-seminomatous germ cell tumours', 'Disease', 'MESH:C537844', (75, 109))	('primary TGCTs', 'Disease', (54, 67))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('men', 'Species', '9606', (129, 132))	('13q deletion', 'Var', (20, 32))
44159	25424124	Instead, the authors described one potential deletion of PTPN1 gene (mapped at 20q13) as rare CNVs.	('PTPN1', 'Gene', '5770', (57, 62))	('deletion', 'Var', (45, 53))	('PTPN1', 'Gene', (57, 62))
44160	25424124	described three de novo CNV events involving amplification of 7q11.22 and 12q24.1, and loss of 6p21.2 in 3/43 familial testicular germ cell tumor trios evaluated.	('6p21.2', 'Gene', (95, 101))	('loss', 'Var', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('germ cell tumor', 'Phenotype', 'HP:0100728', (130, 145))	('amplification', 'Var', (45, 58))	('tumor', 'Disease', (140, 145))
44358	15999104	Hypogonadism was common in this group with 38% of patients having either subnormal testosterone or testosterone replacement.	('Hypogonadism', 'Phenotype', 'HP:0000135', (0, 12))	('patients', 'Species', '9606', (50, 58))	('subnormal testosterone', 'Phenotype', 'HP:0030087', (73, 95))	('testosterone', 'Chemical', 'MESH:D013739', (83, 95))	('subnormal', 'Var', (73, 82))	('men', 'Species', '9606', (119, 122))	('Hypogonadism', 'Disease', (0, 12))	('testosterone', 'Chemical', 'MESH:D013739', (99, 111))
44372	15999104	Additionally, radiotherapy treatment was associated with reduced sexual enjoyment (RT vs S P=0.05).	('radiotherapy treatment', 'Var', (14, 36))	('men', 'Species', '9606', (32, 35))	('men', 'Species', '9606', (77, 80))	('sexual enjoyment', 'CPA', (65, 81))	('reduced', 'NegReg', (57, 64))
44374	15999104	Although 72% of patients with low testosterone continued to report that sex was satisfying, there was evidence of significant morbidity in all six domains of the testicular quality of life module that relate to sexual activity.	('patients', 'Species', '9606', (16, 24))	('low testosterone', 'Phenotype', 'HP:0040171', (30, 46))	('low', 'Var', (30, 33))	('testosterone', 'Chemical', 'MESH:D013739', (34, 46))	('testosterone', 'Gene', (34, 46))	('sexual activity', 'Phenotype', 'HP:0030214', (211, 226))
44375	15999104	In addition to effects on sexuality, men with a low testosterone had evidence of more general impairment in quality of life.	('men', 'Species', '9606', (100, 103))	('testosterone', 'Chemical', 'MESH:D013739', (52, 64))	('men', 'Species', '9606', (37, 40))	('low testosterone', 'Phenotype', 'HP:0040171', (48, 64))	('low', 'Var', (48, 51))	('quality of life', 'CPA', (108, 123))
44377	15999104	Low testosterone was also associated with a marked increase in dyspnoea (mean score 14.3 (95% CI 9.4-19.3) compared to 6.4 (CI 5.0-7.8) P<0.001) and lesser increases in the complaint of pain (P=0.048), sleep disturbance (P=0.039), constipation (P=0.03) and nausea (P=0.031).	('increase in dyspnoea', 'Disease', (51, 71))	('sleep disturbance', 'Phenotype', 'HP:0002360', (202, 219))	('increase in dyspnoea', 'Disease', 'MESH:D009122', (51, 71))	('constipation', 'Phenotype', 'HP:0002019', (231, 243))	('nausea', 'Disease', (257, 263))	('testosterone', 'Chemical', 'MESH:D013739', (4, 16))	('pain', 'Phenotype', 'HP:0012531', (186, 190))	('Low testosterone', 'Var', (0, 16))	('constipation', 'Disease', 'MESH:D003248', (231, 243))	('nausea', 'Phenotype', 'HP:0002018', (257, 263))	('pain', 'Disease', 'MESH:D010146', (186, 190))	('sleep disturbance', 'Disease', (202, 219))	('pain', 'Disease', (186, 190))	('increases', 'PosReg', (156, 165))	('nausea', 'Disease', 'MESH:D009325', (257, 263))	('constipation', 'Disease', (231, 243))	('Low testosterone', 'Phenotype', 'HP:0040171', (0, 16))	('sleep disturbance', 'Disease', 'MESH:D012893', (202, 219))
44379	15999104	As well as quality of life effects, we have previously recognised that low testosterone is associated with a higher body mass Index compared to those with normal testosterone levels (median BMI of 28.6 compared to 25.7 kg m-2; P<0.001) (Huddart and Norman, 2003).	('testosterone', 'MPA', (75, 87))	('man', 'Species', '9606', (252, 255))	('low testosterone', 'Phenotype', 'HP:0040171', (71, 87))	('low', 'Var', (71, 74))	('testosterone', 'Chemical', 'MESH:D013739', (75, 87))	('higher', 'PosReg', (109, 115))	('testosterone', 'Chemical', 'MESH:D013739', (162, 174))	('body mass Index', 'MPA', (116, 131))
44380	15999104	Low testosterone is also associated with higher systolic (median 140 compared to 130 P<0.004) and diastolic blood pressure (median 90 compared to mean 85 P<0.016) (Figure 3).	('diastolic blood pressure', 'MPA', (98, 122))	('testosterone', 'Chemical', 'MESH:D013739', (4, 16))	('higher', 'PosReg', (41, 47))	('Low testosterone', 'Phenotype', 'HP:0040171', (0, 16))	('Low', 'Var', (0, 3))
44387	15999104	The deleterious effects of low testosterone are well recognised in a number of patient groups including patients receiving hormone therapy for prostate cancer (Bates et al, 1996; Simon et al, 1997; Smith et al, 2001).	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('testosterone', 'Chemical', 'MESH:D013739', (31, 43))	('low', 'Var', (27, 30))	('patient', 'Species', '9606', (104, 111))	('prostate cancer', 'Disease', (143, 158))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('low testosterone', 'Phenotype', 'HP:0040171', (27, 43))	('patients', 'Species', '9606', (104, 112))
44390	15999104	Additionally, in this study we have shown that patients with low testosterone have higher average systolic and diastolic blood pressure.	('low testosterone', 'Phenotype', 'HP:0040171', (61, 77))	('patients', 'Species', '9606', (47, 55))	('low', 'Var', (61, 64))	('testosterone', 'Chemical', 'MESH:D013739', (65, 77))	('testosterone', 'Gene', (65, 77))	('higher', 'PosReg', (83, 89))
44391	15999104	As would be anticipated, we have shown that a low testosterone has a significant effect on the quality of sexual experience, although it is interesting to observe that up to three quarters of men with low testosterone report satisfaction with their sexual life.	('low', 'Var', (201, 204))	('quality of sexual experience', 'CPA', (95, 123))	('testosterone', 'Chemical', 'MESH:D013739', (205, 217))	('sexual experience', 'Phenotype', 'HP:0030214', (106, 123))	('men', 'Species', '9606', (192, 195))	('testosterone', 'Chemical', 'MESH:D013739', (50, 62))	('low testosterone', 'Phenotype', 'HP:0040171', (201, 217))	('low testosterone', 'Phenotype', 'HP:0040171', (46, 62))
44392	15999104	A similar effect on sexual activity of mild leydig cell insufficiency has also been reported in men after treatment for haematological malignancy (Howell et al, 2000).	('men', 'Species', '9606', (96, 99))	('men', 'Species', '9606', (111, 114))	('mild leydig', 'Var', (39, 50))	('haematological malignancy', 'Disease', (120, 145))	('haematological malignancy', 'Disease', 'MESH:D019337', (120, 145))	('insufficiency', 'Disease', 'MESH:D000309', (56, 69))	('insufficiency', 'Disease', (56, 69))	('sexual activity', 'Phenotype', 'HP:0030214', (20, 35))
44428	15999104	This is in keeping with the observations in the MRC-randomised trial of dogleg vs para-aortic radiotherapy that by 3 years 92% of patients treated by dogleg radiotherapy have re-attained sperm counts of 10 million ml-1 or greater.	('patients', 'Species', '9606', (130, 138))	('sperm counts', 'CPA', (187, 199))	('dogleg', 'Var', (150, 156))	('MRC', 'CellLine', 'CVCL:0440', (48, 51))
44446	31327741	Both cis-acting inherited genetic variation and somatically acquired mutations in trans-acting repressors contribute to DUX4 re-expression in cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('genetic variation', 'Var', (26, 43))	('DUX4', 'Gene', (120, 124))	('cancer', 'Disease', (142, 148))
44447	31327741	Although many DUX4 target genes encode self-antigens, DUX4-expressing cancers were paradoxically characterized by reduced markers of anti-tumor cytolytic activity and lower MHC Class I gene expression.	('lower', 'NegReg', (167, 172))	('MHC', 'Gene', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (138, 143))	('reduced', 'NegReg', (114, 121))	('DUX4-expressing', 'Var', (54, 69))	('markers', 'MPA', (122, 129))	('MHC', 'Gene', '3107', (173, 176))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cancers', 'Disease', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
44449	31327741	Clinical data in metastatic melanoma confirmed that DUX4 expression was associated with significantly reduced progression-free and overall survival in response to anti-CTLA-4.	('melanoma', 'Disease', (28, 36))	('CTLA-4', 'Gene', (168, 174))	('expression', 'Var', (57, 67))	('overall survival', 'CPA', (131, 147))	('DUX4', 'Gene', (52, 56))	('CTLA-4', 'Gene', '1493', (168, 174))	('progression-free', 'CPA', (110, 126))	('reduced', 'NegReg', (102, 109))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
44452	31327741	DUX4 suppresses anti-cancer immune activity by blocking interferon-gamma-mediated induction of MHC Class I and is associated with reduced efficacy of immune checkpoint blockade therapy.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('DUX4', 'Var', (0, 4))	('interferon-gamma', 'Gene', (56, 72))	('suppresses', 'NegReg', (5, 15))	('MHC', 'Gene', (95, 98))	('reduced', 'NegReg', (130, 137))	('cancer', 'Disease', (21, 27))	('blocking', 'NegReg', (47, 55))	('MHC', 'Gene', '3107', (95, 98))	('interferon-gamma', 'Gene', '3458', (56, 72))
44456	31327741	As a consequence, genetic lesions that suppress antigen presentation or blunt tumor-immune interactions can permit malignant cells to evade cytotoxic T cells.	('genetic lesions', 'Var', (18, 33))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('permit', 'Reg', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('suppress', 'NegReg', (39, 47))	('antigen presentation', 'MPA', (48, 68))	('tumor', 'Disease', (78, 83))	('evade', 'NegReg', (134, 139))	('blunt', 'NegReg', (72, 77))
44457	31327741	For example, loss-of-function mutations in B2M, JAK1, and JAK2, resulting in loss of MHC Class I expression (B2M) or response to interferon-gamma (JAK1 and JAK2), have been identified in patients who relapsed following an initial response to checkpoint blockade.	('B2M', 'Gene', (43, 46))	('loss', 'NegReg', (77, 81))	('JAK1', 'Gene', '3716', (147, 151))	('JAK2', 'Gene', (58, 62))	('JAK1', 'Gene', (48, 52))	('patients', 'Species', '9606', (187, 195))	('B2M', 'Gene', '567', (43, 46))	('MHC', 'Gene', (85, 88))	('JAK2', 'Gene', '3717', (156, 160))	('B2M', 'Gene', (109, 112))	('interferon-gamma', 'Gene', (129, 145))	('mutations', 'Var', (30, 39))	('JAK1', 'Gene', (147, 151))	('MHC', 'Gene', '3107', (85, 88))	('JAK1', 'Gene', '3716', (48, 52))	('JAK2', 'Gene', (156, 160))	('B2M', 'Gene', '567', (109, 112))	('loss-of-function', 'NegReg', (13, 29))	('interferon-gamma', 'Gene', '3458', (129, 145))	('JAK2', 'Gene', '3717', (58, 62))
44458	31327741	Copy number alterations affecting MHC Class I and interferon-gamma response genes are likewise enriched in cancers that never respond to these therapies.	('interferon-gamma', 'Gene', '3458', (50, 66))	('cancers', 'Disease', (107, 114))	('MHC', 'Gene', '3107', (34, 37))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('interferon-gamma', 'Gene', (50, 66))	('Copy number alterations', 'Var', (0, 23))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('MHC', 'Gene', (34, 37))
44460	31327741	For example, activation of WNT/beta-catenin signaling promotes T cell exclusion from the melanoma microenvironment, while depletion of LSD1 promotes anti-tumor immune activity.	('beta-catenin', 'Gene', (31, 43))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('depletion', 'Var', (122, 131))	('beta-catenin', 'Gene', '1499', (31, 43))	('promotes', 'PosReg', (140, 148))	('LSD1', 'Gene', (135, 139))	('T cell exclusion', 'CPA', (63, 79))	('LSD1', 'Gene', '23028', (135, 139))	('activation', 'PosReg', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('promotes', 'PosReg', (54, 62))
44491	31327741	We aligned reads from each DUX4+ solid cancer, preimplantation embryos, and B-ALL with DUX4 translocations to the full-length DUX4 mRNA sequence.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('translocations', 'Var', (92, 106))	('DUX4', 'Gene', (87, 91))	('DUX4+', 'Gene', (27, 32))	('preimplantation embryos', 'Phenotype', 'HP:0032479', (47, 70))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
44506	31327741	We identified all cancer samples with or without predicted loss-of-function mutations in 23 genes encoding validated or likely repressors of DUX4, including proteins encoded by Modifier of murine metastable epiallele (Momme) genes, components of the Nucleosome Remodeling Deacetylase and Chromatin Assembly Factor 1 complexes, and other epigenetic factors (Table S2).	('mutations', 'Var', (76, 85))	('loss-of-function', 'NegReg', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('murine', 'Species', '10090', (189, 195))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
44507	31327741	We tested whether samples with loss-of-function mutations in each gene exhibited elevated DUX4 expression relative to wild-type samples for each cancer type.	('cancer', 'Disease', (145, 151))	('DUX4', 'Protein', (90, 94))	('loss-of-function', 'NegReg', (31, 47))	('elevated', 'PosReg', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('mutations', 'Var', (48, 57))	('expression', 'MPA', (95, 105))
44508	31327741	Mutations in 12 tested genes were significantly associated with increased DUX4 expression in one or more cancer types (Fig.	('expression', 'MPA', (79, 89))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increased', 'PosReg', (64, 73))	('DUX4', 'Gene', (74, 78))
44509	31327741	2G, S2D), suggesting that loss of epigenetic repressors of the DUX4 locus contributes to DUX4 re-expression in cancer.	('DUX4', 'Gene', (89, 93))	('DUX4', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('epigenetic', 'Var', (34, 44))	('loss', 'NegReg', (26, 30))	('re-expression', 'MPA', (94, 107))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
44513	31327741	We knocked down (KD) PRPF8 in myoblasts isolated from a healthy individual and an individual whose FSHD was caused by cis-acting genetic variation that potentiated DUX4 de-repression.	('caused by', 'Reg', (108, 117))	('FSHD', 'Phenotype', 'HP:0008970', (99, 103))	('FSHD', 'Gene', '2489', (99, 103))	('de-repression', 'MPA', (169, 182))	('knocked', 'Var', (3, 10))	('PRPF8', 'Gene', '10594', (21, 26))	('PRPF8', 'Gene', (21, 26))	('FSHD', 'Gene', (99, 103))	('variation', 'Var', (137, 146))
44516	31327741	In addition to identifying PRPF8 as a repressor of DUX4 expression, our results demonstrate that both cis-acting genetic variation and somatic mutations in trans-acting repressors contribute to DUX4 expression in cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'MPA', (199, 209))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('PRPF8', 'Gene', '10594', (27, 32))	('cancer', 'Disease', (213, 219))	('PRPF8', 'Gene', (27, 32))	('DUX4', 'Gene', (194, 198))	('contribute', 'Reg', (180, 190))	('mutations', 'Var', (143, 152))
44519	31327741	First, while DUX4+ cancers exhibited increased expression of many DUX4-induced genes irrespective of cancer type, one or more specific target genes were particularly highly expressed in each cancer type.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('DUX4+', 'Var', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Disease', (101, 107))	('cancers', 'Disease', (19, 26))	('cancer', 'Disease', (19, 25))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('DUX4-induced genes', 'Gene', (66, 84))	('highly expressed', 'PosReg', (166, 182))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('increased', 'PosReg', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('expression', 'MPA', (47, 57))
44527	31327741	Nonetheless, as DUXB expression is promoted by DUX4 (Fig.	('DUXB', 'Gene', (16, 20))	('expression', 'MPA', (21, 31))	('DUXB', 'Gene', '100033411', (16, 20))	('promoted', 'PosReg', (35, 43))	('DUX4', 'Var', (47, 51))
44529	31327741	We established a myoblast cell line with a doxycycline-inducible DUXB transgene and performed RNA-seq on cells with or without doxycycline treatment.	('doxycycline', 'Chemical', 'MESH:D004318', (43, 54))	('transgene', 'Var', (70, 79))	('DUXB', 'Gene', (65, 69))	('doxycycline', 'Chemical', 'MESH:D004318', (127, 138))	('DUXB', 'Gene', '100033411', (65, 69))
44536	31327741	First, we identified genes that were consistently differentially expressed in multiple cancer types in DUX4+ versus DUX4- samples and performed a Gene Ontology (GO)-based analysis of enriched functional categories (Fig.	('cancer', 'Disease', (87, 93))	('differentially', 'Reg', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('DUX4+', 'Var', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
44538	31327741	However, contrary to our hypothesis that DUX4 expression might trigger immune surveillance, the immune-related GO terms were uniformly associated with decreased gene expression in DUX4+ versus DUX4- cancers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('decreased', 'NegReg', (151, 160))	('gene expression', 'MPA', (161, 176))	('DUX4+', 'Var', (180, 185))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('cancers', 'Disease', (199, 206))
44541	31327741	DUX4 expression was associated with reduced infiltration of diverse immune cells, most notably cytotoxic CD8+ T cells, in many cancers (Fig.	('CD8', 'Gene', (105, 108))	('DUX4', 'Gene', (0, 4))	('CD8', 'Gene', '925', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('infiltration of', 'CPA', (44, 59))	('expression', 'Var', (5, 15))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('reduced', 'NegReg', (36, 43))	('cancers', 'Disease', (127, 134))
44545	31327741	The Treg marker gene FOXP3 was significantly down-regulated in DUX4+ samples in a few, although not most, cancer types (Fig.	('FOXP3', 'Gene', (21, 26))	('DUX4+', 'Var', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('Treg', 'Chemical', '-', (4, 8))	('down-regulated', 'NegReg', (45, 59))	('cancer', 'Disease', (106, 112))	('FOXP3', 'Gene', '50943', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
44548	31327741	As DUX4 promotes CT antigen expression yet DUX4+ cancers exhibited low anti-tumor immune activity, we wondered whether antigen presentation might be suppressed in DUX4-expressing cells.	('low', 'NegReg', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DUX4', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CT antigen expression', 'MPA', (17, 38))	('promotes', 'PosReg', (8, 16))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('DUX4+', 'Var', (43, 48))
44550	31327741	We therefore compared the expression levels of MHC Class I genes in DUX4+ and DUX4- cancers to find that DUX4 expression was associated with reduced expression of B2M, HLA-A, HLA-B, and HLA-C in most cancer types (Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('HLA-A', 'Gene', '3105', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('MHC', 'Gene', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('HLA-B', 'Gene', '3106', (175, 180))	('cancer', 'Disease', (84, 90))	('reduced', 'NegReg', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('expression', 'MPA', (149, 159))	('HLA-A', 'Gene', (168, 173))	('B2M', 'Gene', (163, 166))	('MHC', 'Gene', '3107', (47, 50))	('DUX4', 'Var', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('B2M', 'Gene', '567', (163, 166))	('HLA-B', 'Gene', (175, 180))	('cancer', 'Disease', (200, 206))
44551	31327741	Decreased expression of MHC Class I genes could be a direct consequence of DUX4 expression, or alternatively might be an independent event that enhances the survival of DUX4-expressing cancers.	('MHC', 'Gene', (24, 27))	('DUX4', 'Gene', (75, 79))	('survival', 'CPA', (157, 165))	('MHC', 'Gene', '3107', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('enhances', 'PosReg', (144, 152))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Disease', (185, 192))	('expression', 'Var', (80, 90))
44553	31327741	We found that DUX4-expressing cells exhibited reduced levels of MHC Class I genes relative to DUX4- control cells in all three datasets (Fig.	('DUX4-expressing', 'Var', (14, 29))	('reduced', 'NegReg', (46, 53))	('levels', 'MPA', (54, 60))	('MHC', 'Gene', (64, 67))	('MHC', 'Gene', '3107', (64, 67))
44556	31327741	JAK1, JAK2, and STAT1 exhibited similarly reduced expression following acute DUX4 expression in cultured myoblasts (Fig.	('reduced', 'NegReg', (42, 49))	('JAK1', 'Gene', '3716', (0, 4))	('JAK2', 'Gene', '3717', (6, 10))	('expression', 'Var', (82, 92))	('JAK2', 'Gene', (6, 10))	('JAK1', 'Gene', (0, 4))	('STAT1', 'Gene', (16, 21))	('STAT1', 'Gene', '6772', (16, 21))	('DUX4', 'Gene', (77, 81))	('expression', 'MPA', (50, 60))
44572	31327741	DUX4-mediated suppression of MHC Class I was particularly notable in HeLa cells, where DUX4 suppressed cell surface levels of MHC Class I beyond the basal state even in the presence of interferon-gamma.	('suppressed', 'NegReg', (92, 102))	('MHC', 'Gene', '3107', (126, 129))	('DUX4', 'Var', (87, 91))	('interferon-gamma', 'Gene', '3458', (185, 201))	('MHC', 'Gene', (29, 32))	('MHC', 'Gene', (126, 129))	('MHC', 'Gene', '3107', (29, 32))	('interferon-gamma', 'Gene', (185, 201))	('HeLa', 'CellLine', 'CVCL:0030', (69, 73))
44573	31327741	Together, these data demonstrate that DUX4 blocks interferon-gamma-mediated induction of MHC Class I and antigen presentation in untransformed and cancer cells.	('interferon-gamma', 'Gene', '3458', (50, 66))	('blocks', 'NegReg', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MHC', 'Gene', '3107', (89, 92))	('DUX4', 'Var', (38, 42))	('interferon-gamma', 'Gene', (50, 66))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('MHC', 'Gene', (89, 92))	('cancer', 'Disease', (147, 153))	('antigen presentation', 'MPA', (105, 125))
44581	31327741	We conclude that DUX4-mediated suppression of MHC Class I-dependent antigen presentation is a clinically relevant biomarker for response to immune checkpoint blockade.	('suppression', 'NegReg', (31, 42))	('MHC', 'Gene', '3107', (46, 49))	('DUX4-mediated', 'Var', (17, 30))	('MHC', 'Gene', (46, 49))
44584	31327741	Second, prior to the recent discovery of DUX4's embryonic role, DUX4 was best known for causing FSHD when aberrantly expressed in skeletal muscle due to genetic variation that causes loss of its normal epigenetic repression in somatic tissues.	('FSHD', 'Gene', (96, 100))	('epigenetic repression', 'MPA', (202, 223))	('loss', 'NegReg', (183, 187))	('aberrantly', 'Var', (106, 116))	('FSHD', 'Gene', '2489', (96, 100))	('genetic variation', 'Var', (153, 170))	('causing', 'Reg', (88, 95))	('DUX4', 'Gene', (64, 68))	('FSHD', 'Phenotype', 'HP:0008970', (96, 100))
44585	31327741	Third, while DUX4's normal transcription factor activity has not been previously reported to play a role in cancer, the presence of recurrent translocations involving the DUX4 locus in round-cell sarcoma and B-ALL strongly suggests that DUX4 has pro-oncogenic capacity, at least when expressed as part of the CIC-DUX4 or DUX4-IGH fusion proteins.	('CIC', 'Gene', (309, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('pro-oncogenic capacity', 'CPA', (246, 268))	('IGH', 'Gene', '3492', (326, 329))	('DUX4', 'Gene', (237, 241))	('translocations', 'Var', (142, 156))	('cancer', 'Disease', (108, 114))	('sarcoma', 'Disease', 'MESH:D012509', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('IGH', 'Gene', (326, 329))	('CIC', 'Gene', '23152', (309, 312))	('sarcoma', 'Disease', (196, 203))	('DUX4', 'Gene', (171, 175))
44592	31327741	5D-I, S5B-D), further work is required to determine why DUX4 expression results in immune attack in FSHD muscle but immune evasion in cancers.	('FSHD', 'Phenotype', 'HP:0008970', (100, 104))	('FSHD', 'Gene', (100, 104))	('immune evasion', 'MPA', (116, 130))	('S5B', 'Gene', '5711', (6, 9))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('expression', 'Var', (61, 71))	('cancers', 'Disease', (134, 141))	('FSHD', 'Gene', '2489', (100, 104))	('S5B', 'Gene', (6, 9))	('DUX4', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('results in', 'Reg', (72, 82))	('immune attack', 'MPA', (83, 96))
44608	31327741	Further work is required to confirm that DUX4 influences CXCL9 and CXCL10 levels in cancer cells and identify all of the potentially diverse means by which DUX4 contributes to immune evasion.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('CXCL10', 'Gene', '3627', (67, 73))	('CXCL10', 'Gene', (67, 73))	('cancer', 'Disease', (84, 90))	('DUX4', 'Var', (41, 45))	('contributes', 'Reg', (161, 172))	('CXCL9', 'Gene', '4283', (57, 62))	('immune evasion', 'MPA', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('CXCL9', 'Gene', (57, 62))	('influences', 'Reg', (46, 56))
44613	31327741	Ectopic expression of CCNA1 in the murine hematopoietic lineage caused abnormal myelopoiesis and sporadic progression to acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (121, 143))	('abnormal myelopoiesis', 'Disease', (71, 92))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (127, 143))	('Ectopic expression', 'Var', (0, 18))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (121, 143))	('abnormal myelopoiesis', 'Disease', 'MESH:C563551', (71, 92))	('CCNA1', 'Gene', (22, 27))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('acute myeloid leukemia', 'Disease', (121, 143))	('caused', 'Reg', (64, 70))	('murine', 'Species', '10090', (35, 41))
44628	31327741	MB2401, MB073, MB135, MB135iDUX4, and MB135iDUXB myoblasts were maintained in Ham's F-10 Nutrient Mix (Gibco) supplemented with 20% HyClone Fetal Bovine Serum, 100 U/100 mug penicillin/streptomycin (Gibco), 10 ng/ml recombinant human basic fibroblast growth factor (Promega Corporation), 1 muM dexamethasone (Sigma-Aldrich), and, for MB135iDUX4 and MB135iDUXB, 3 mug/ml or 2 mug/ml puromycin (Sigma-Aldrich), respectively.	('DUXB', 'Gene', '100033411', (355, 359))	('DUXB', 'Gene', (44, 48))	('puromycin', 'Chemical', 'MESH:D011691', (382, 391))	('DUXB', 'Gene', '100033411', (44, 48))	('MB135iDUX4', 'Var', (334, 344))	('penicillin', 'Chemical', 'MESH:D010406', (174, 184))	('MB2401', 'CellLine', 'CVCL:5M21', (0, 6))	('human', 'Species', '9606', (228, 233))	('streptomycin', 'Chemical', 'MESH:D013307', (185, 197))	('DUXB', 'Gene', (355, 359))
44636	31327741	In each cancer cohort, for each gene tested, samples with deleterious mutations were compared to samples with low impact or no mutations.	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
44642	31327741	A one-sided Mann-Whitney U test was used to test for a statistically significant difference in immune cell infiltration between DUX4- and DUX4+ cancer samples.	('DUX4-', 'Var', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('DUX4+', 'Var', (138, 143))	('immune cell infiltration', 'CPA', (95, 119))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
44657	31327741	The early embryonic transcription factor DUX4 is active in many human cancers DUX4-expressing cancers are characterized by low anti-tumor immune activity DUX4 blocks interferon-g-mediated induction of MHC Class I and antigen presentation DUX4 is significantly associated with failure to respond to anti-CTLA-4 therapy	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('antigen presentation', 'MPA', (217, 237))	('MHC', 'Gene', '3107', (201, 204))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('interferon-g-mediated induction', 'MPA', (166, 197))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (70, 77))	('CTLA-4', 'Gene', '1493', (303, 309))	('cancers', 'Disease', (94, 101))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CTLA-4', 'Gene', (303, 309))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('blocks', 'NegReg', (159, 165))	('MHC', 'Gene', (201, 204))	('DUX4', 'Var', (154, 158))	('cancers', 'Disease', 'MESH:D009369', (70, 77))
44662	31085753	We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population.	('SHBG', 'Gene', '6462', (123, 127))	('rs6258', 'Var', (63, 69))	('sex hormone-binding globulin', 'Gene', (93, 121))	('SHBG', 'Gene', (123, 127))	('hypogonadism', 'Phenotype', 'HP:0000135', (159, 171))	('hypogonadism', 'Disease', 'MESH:D007006', (159, 171))	('rs12150660', 'Var', (74, 84))	('rs12150660', 'Mutation', 'rs12150660', (74, 84))	('hypogonadism', 'Disease', (159, 171))	('rs6258', 'Mutation', 'rs6258', (63, 69))	('sex hormone-binding globulin', 'Gene', '6462', (93, 121))
44664	31085753	Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P=.006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P=.011) or >=30 kg/m2 (OR, 2.36; P=.005) compared with <25 kg/m2.	('>=30 kg/m2', 'Var', (239, 249))	('hypogonadism', 'Phenotype', 'HP:0000135', (61, 73))	('hypogonadism', 'Disease', 'MESH:D007006', (61, 73))	('hypogonadism', 'Disease', (61, 73))
44677	31085753	Recent genetic investigations in the general population have identified 2 single nucleotide polymorphisms (SNPs) in the sex hormone-binding globulin gene (SHBG) through genome-wide association studies associated with increased risk for hypogonadism.	('SHBG', 'Gene', (155, 159))	('hypogonadism', 'Phenotype', 'HP:0000135', (236, 248))	('hypogonadism', 'Disease', (236, 248))	('sex hormone-binding globulin', 'Gene', '6462', (120, 148))	('hypogonadism', 'Disease', 'MESH:D007006', (236, 248))	('associated', 'Reg', (201, 211))	('single nucleotide polymorphisms', 'Var', (74, 105))	('SHBG', 'Gene', '6462', (155, 159))	('sex hormone-binding globulin', 'Gene', (120, 148))
44682	31085753	The role of SHBG gene polymorphisms in hypogonadism risk among TCS are also investigated for the first time.	('SHBG', 'Gene', '6462', (12, 16))	('polymorphisms', 'Var', (22, 35))	('hypogonadism', 'Phenotype', 'HP:0000135', (39, 51))	('hypogonadism', 'Disease', (39, 51))	('hypogonadism', 'Disease', 'MESH:D007006', (39, 51))	('TCS', 'Chemical', '-', (63, 66))	('SHBG', 'Gene', (12, 16))
44705	31085753	Although significant in bivariate analysis, vigorous-intensity physical activity was only marginally associated with reduced hypogonadism risk (OR, 0.66; 95% CI, 0.41-1.04; P=.07) after adjusting for other independent variables in the model.	('hypogonadism', 'Disease', (125, 137))	('hypogonadism', 'Disease', 'MESH:D007006', (125, 137))	('reduced', 'NegReg', (117, 124))	('vigorous-intensity', 'Var', (44, 62))	('hypogonadism', 'Phenotype', 'HP:0000135', (125, 137))
44712	31085753	We assessed the association of 2 SNPs (rs6258 and rs12150660) in the SHBG locus previously implicated in increased hypogonadism risk in the general population.	('hypogonadism', 'Disease', 'MESH:D007006', (115, 127))	('hypogonadism', 'Phenotype', 'HP:0000135', (115, 127))	('hypogonadism', 'Disease', (115, 127))	('rs6258', 'Mutation', 'rs6258', (39, 45))	('rs6258', 'Var', (39, 45))	('rs12150660', 'Var', (50, 60))	('increased', 'PosReg', (105, 114))	('SHBG', 'Gene', '6462', (69, 73))	('rs12150660', 'Mutation', 'rs12150660', (50, 60))	('SHBG', 'Gene', (69, 73))
44713	31085753	SNPs rs12150660 and rs6258 showed, respectively, high imputation quality (R2, 0.99 and 0.87), high call rate (>99.7% and >99.8%), and perfect Hardy-Weinberg equilibrium (P=.98 and .97).	('rs6258', 'Var', (20, 26))	('rs12150660', 'Var', (5, 15))	('rs12150660', 'Mutation', 'rs12150660', (5, 15))	('rs6258', 'Mutation', 'rs6258', (20, 26))
44718	31085753	It is also the first series to investigate the influence of genetic variants in the SHBG gene on hypogonadism risk in TCS.	('hypogonadism', 'Disease', (97, 109))	('genetic variants', 'Var', (60, 76))	('hypogonadism', 'Disease', 'MESH:D007006', (97, 109))	('SHBG', 'Gene', '6462', (84, 88))	('SHBG', 'Gene', (84, 88))	('TCS', 'Chemical', '-', (118, 121))	('hypogonadism', 'Phenotype', 'HP:0000135', (97, 109))
44720	31085753	Although vigorous-intensity physical activity appeared protective and genetic variants in SHBG may have influenced hypogonadism risk, results were of borderline significance.	('hypogonadism', 'Disease', 'MESH:D007006', (115, 127))	('hypogonadism', 'Phenotype', 'HP:0000135', (115, 127))	('hypogonadism', 'Disease', (115, 127))	('SHBG', 'Gene', (90, 94))	('genetic variants', 'Var', (70, 86))	('SHBG', 'Gene', '6462', (90, 94))	('influenced', 'Reg', (104, 114))
44732	31085753	Ohlsson et al recently performed a meta-analysis of genome-wide association data in 14,429 men from 7 cohorts in the general population and identified 2 SNPs at the SHBG locus as independently associated with serum testosterone concentration.	('SNPs', 'Var', (153, 157))	('serum testosterone concentration', 'MPA', (209, 241))	('men', 'Species', '9606', (91, 94))	('SHBG', 'Gene', '6462', (165, 169))	('associated with', 'Reg', (193, 208))	('testosterone', 'Chemical', 'MESH:D013739', (215, 227))	('SHBG', 'Gene', (165, 169))
44733	31085753	In our study, these SNPs also appeared to affect testosterone concentration but were of borderline statistical significance.	('affect', 'Reg', (42, 48))	('SNPs', 'Var', (20, 24))	('testosterone', 'Chemical', 'MESH:D013739', (49, 61))	('testosterone concentration', 'MPA', (49, 75))
44734	31085753	In addition, although the magnitude of influence of these genetic variants on serum testosterone concentration (OR, 1.26 per additional risk allele) in TCS was some-what less than reported in the general population (OR, 1.62 per additional risk allele), the 95% CIs overlapped substantially.	('serum testosterone concentration', 'MPA', (78, 110))	('TCS', 'Disease', (152, 155))	('variants', 'Var', (66, 74))	('TCS', 'Chemical', '-', (152, 155))	('testosterone', 'Chemical', 'MESH:D013739', (84, 96))
44735	31085753	In addition, it is possible that other genetic variants, possibly ones that predispose to testicular dysgenesis syndrome (eg, INSL3 and LGR8), may be of higher importance in TCS.	('variants', 'Var', (47, 55))	('INSL3', 'Gene', (126, 131))	('TCS', 'Chemical', '-', (174, 177))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (90, 111))	('testicular dysgenesis syndrome', 'Disease', 'None', (90, 120))	('LGR8', 'Gene', (136, 140))	('testicular dysgenesis syndrome', 'Disease', (90, 120))	('INSL3', 'Gene', '3640', (126, 131))	('LGR8', 'Gene', '122042', (136, 140))
44736	31085753	A critical question is the extent to which these polymorphisms might also influence the eventual development of CVD, and not only mediate low testosterone levels.	('testosterone levels', 'MPA', (142, 161))	('CVD', 'Disease', (112, 115))	('influence', 'Reg', (74, 83))	('men', 'Species', '9606', (104, 107))	('testosterone', 'Chemical', 'MESH:D013739', (142, 154))	('CVD', 'Phenotype', 'HP:0001626', (112, 115))	('polymorphisms', 'Var', (49, 62))	('low testosterone', 'Phenotype', 'HP:0040171', (138, 154))	('CVD', 'Disease', 'MESH:D002318', (112, 115))	('low', 'NegReg', (138, 141))
44748	31085753	Strengths of our study include the large number of patients, detailed medical chart abstraction, and evaluation of several risk factors for hypogonadism, including genetic variants.	('hypogonadism', 'Phenotype', 'HP:0000135', (140, 152))	('hypogonadism', 'Disease', (140, 152))	('genetic variants', 'Var', (164, 180))	('hypogonadism', 'Disease', 'MESH:D007006', (140, 152))	('patients', 'Species', '9606', (51, 59))
44757	31085753	The clinical value of assessing possible genetic variants in the role of hypogonadism requires further study before these are recommended for use in the clinic.	('hypogonadism', 'Disease', 'MESH:D007006', (73, 85))	('men', 'Species', '9606', (131, 134))	('genetic variants', 'Var', (41, 57))	('hypogonadism', 'Phenotype', 'HP:0000135', (73, 85))	('hypogonadism', 'Disease', (73, 85))
44790	30563561	Tumor markers following the completion of treatment were AFP 2.7 mug/L, beta-HCG 2.4 IU/L, and LDH 247 U/L.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LDH 247 U/L', 'Var', (95, 106))	('AFP', 'Gene', (57, 60))	('AFP', 'Gene', '174', (57, 60))	('men', 'Species', '9606', (47, 50))
44854	26060594	Histopathological evaluation of the specimens revealed the following: (a) an embryonal cell carcinoma of the right testis limited to the testis with lymphovascular invasion of pathological stage pT2 (Figure 1): staining with antibodies showed CD30(+) and a-FP(-); (b) a seminoma of the left testis, limited to the testis without invasion of the tunica albuginea or vascular invasion of pathological stage pT1 (Figure 2): staining with antibodies showed CD117(+), CD30(-), and a-FP(-).	('tunica albuginea', 'Disease', (345, 361))	('CD117(+', 'Var', (453, 460))	('CD30(-', 'Var', (463, 469))	('pT1', 'Gene', (405, 408))	('embryonal cell carcinoma', 'Phenotype', 'HP:0002898', (77, 101))	('seminoma of the left testis', 'Disease', (270, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('seminoma of the left testis', 'Disease', 'MESH:D018239', (270, 297))	('tunica albuginea', 'Disease', 'None', (345, 361))	('a-FP(-', 'Var', (476, 482))	('pT1', 'Gene', '58492', (405, 408))	('embryonal cell carcinoma of the right testis', 'Disease', 'MESH:D013736', (77, 121))	('testis limited', 'Phenotype', 'HP:0008734', (115, 129))	('embryonal cell carcinoma of the right testis', 'Disease', (77, 121))	('men', 'Species', '9606', (41, 44))
44940	22048036	Therefore, the focus of this review was on retrieving systematic reviews and randomised controlled trials (RCTs) of interventions for common problems including symptoms of depression, anxiety and fear of recurrence, emotional distress, fatigue and pain and impairments to physical functioning, social functioning (including relationships), work and employment and cognitive functioning.	('cognitive functioning', 'CPA', (364, 385))	('pain', 'Disease', (248, 252))	('depression', 'Disease', (172, 182))	('anxiety', 'Phenotype', 'HP:0000739', (184, 191))	('fatigue', 'Disease', (236, 243))	('fatigue', 'Phenotype', 'HP:0012378', (236, 243))	('physical functioning', 'CPA', (272, 292))	('pain', 'Phenotype', 'HP:0012531', (248, 252))	('impairments', 'Var', (257, 268))	('social functioning', 'CPA', (294, 312))	('men', 'Species', '9606', (263, 266))	('depression', 'Disease', 'MESH:D000275', (172, 182))	('pain', 'Disease', 'MESH:D010146', (248, 252))	('fatigue', 'Disease', 'MESH:D005221', (236, 243))	('anxiety', 'Disease', (184, 191))	('emotional distress', 'Phenotype', 'HP:0000712', (216, 234))	('depression', 'Phenotype', 'HP:0000716', (172, 182))	('anxiety', 'Disease', 'MESH:D001008', (184, 191))	('men', 'Species', '9606', (355, 358))
45117	22048036	J Clin Oncol 27(11): 1794-1799 Petticrew M, Bell R, Hunter D (2002) Influence of psychological coping on survival and recurrence in people with cancer: Systematic review.	('people', 'Species', '9606', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('1794-1799', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
45129	22048036	Cancer Nurs 31(6): E36-E45 Salsman JM, Segerstrom SC, Brechting EH, Carlson CR, Andrykowski MA (2009) Posttraumatic growth and PTSD symptomatology among colorectal cancer survivors: a 3-month longitudinal examination of cognitive processing.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('Posttraumatic growth', 'Disease', 'MESH:D006130', (102, 122))	('PTSD', 'Disease', 'MESH:D013313', (127, 131))	('Posttraumatic growth', 'Disease', (102, 122))	('rectal cancer', 'Phenotype', 'HP:0100743', (157, 170))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('E36-E45', 'Var', (19, 26))	('PTSD', 'Disease', (127, 131))	('colorectal cancer', 'Disease', (153, 170))
45208	21819630	As an example, in a retrospective analysis of prognostic factors for relapse among 638 men with stage I seminoma, there was only a trend towards worse five-year relapse-free survival with anaplastic as compared to classical histology (83 vs 71%, p = 0.056); in multivariate analysis, only tumor size and rete-testis invasion were significant predictors of outcome.	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('men', 'Species', '9606', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('I seminoma', 'Disease', (102, 112))	('I seminoma', 'Disease', 'MESH:D018239', (102, 112))	('tumor', 'Disease', (289, 294))	('anaplastic', 'Var', (188, 198))
45380	18694875	Such 'organizational' differences in germ cells might be a factor that predisposes towards development of CIS cells in the human but not in the rodent.	('human', 'Species', '9606', (123, 128))	('men', 'Species', '9606', (98, 101))	('development of CIS cells', 'CPA', (91, 115))	('differences', 'Var', (22, 33))
45432	18694875	2), NANOG and AP-2gamma (not shown) were detected in most testicular germ cells of first trimester fetuses but the proportion of immunopositive germ cells decreased as gestation progressed.	('NANOG', 'Var', (4, 9))	('AP-2gamma', 'Gene', '7022', (14, 23))	('AP-2gamma', 'Gene', (14, 23))
45453	18694875	Immunoexpression of Ki67 was detected in the marmoset testis at all fetal ages investigated from 11 weeks' gestation until birth, with a reduction in the number of Ki67-positive germ cells during weeks 15-16 (Fig.	('marmoset', 'Species', '9483', (45, 53))	('Ki67', 'Var', (20, 24))	('reduction', 'NegReg', (137, 146))
45458	18694875	Ki67 expression in the rat was high at e15.5 with the majority of germ cells immunopositive, while at e19.5 none of the germ cells expressed this protein (Fig.	('rat', 'Species', '10116', (23, 26))	('Ki67', 'Gene', (0, 4))	('expression', 'MPA', (5, 15))	('e15.5', 'Var', (39, 44))
45486	18694875	This suggests that there is a transition from germ cells expressing AP-2gamma or OCT4 to germ cells expressing VASA.	('AP-2gamma', 'Gene', '7022', (68, 77))	('AP-2gamma', 'Gene', (68, 77))	('VASA', 'Gene', '102188630', (111, 115))	('VASA', 'Gene', (111, 115))	('OCT4', 'Var', (81, 85))
45487	18694875	Similar subpopulations have also been described in the human for combinations of markers including OCT4/VASA, OCT4/MAGE-A4 and AP-2gamma/MAGE-A4 and these subpopulations are associated with morphological changes that occur as gonocytes differentiate into spermatogonia.	('associated', 'Reg', (174, 184))	('VASA', 'Gene', '102188630', (104, 108))	('OCT4/MAGE-A4', 'Var', (110, 122))	('AP-2gamma', 'Gene', (127, 136))	('human', 'Species', '9606', (55, 60))	('VASA', 'Gene', (104, 108))	('AP-2gamma', 'Gene', '7022', (127, 136))
45494	18694875	In the rat, by e19.5 all of the germ cells in every cord no longer expressed OCT4 but remained VASA-positive.	('VASA', 'Gene', (95, 99))	('OCT4', 'Protein', (77, 81))	('rat', 'Species', '10116', (7, 10))	('e19.5', 'Var', (15, 20))	('VASA', 'Gene', '102188630', (95, 99))
45497	18694875	In contrast, the rat exhibits a synchronized pattern of germ cell proliferation in which a high proliferation index occurs at e15.5 followed by a complete cessation of proliferation for the remainder of gestation and until postnatal Days 4-6.	('proliferation', 'CPA', (168, 181))	('rat', 'Species', '10116', (103, 106))	('e15.5', 'Var', (126, 131))	('cessation', 'NegReg', (155, 164))	('rat', 'Species', '10116', (175, 178))	('rat', 'Species', '10116', (17, 20))	('rat', 'Species', '10116', (73, 76))
45522	32966175	Overexpression of PLK4, the kinase necessary for canonical centriole duplication, is sufficient to generate extra centrioles in diploid human cells, a condition known as centriole amplification (CA), without inducing tetraploidy as CA generated through cytokinesis failure does.	('human', 'Species', '9606', (136, 141))	('PLK4', 'Gene', '10733', (18, 22))	('cytokinesis failure', 'Disease', 'MESH:D006333', (253, 272))	('cytokinesis failure', 'Disease', (253, 272))	('tetraploidy', 'Disease', 'MESH:D057891', (217, 228))	('Overexpression', 'Var', (0, 14))	('tetraploidy', 'Disease', (217, 228))	('PLK4', 'Gene', (18, 22))
45523	32966175	Both overexpression of a PLK4 mutant unable to be autophosphorylated:a process which leads to its ubiquitination and destruction:and CA due to induced cytokinesis failure lead to p53-dependent cell cycle arrest.	('PLK4', 'Gene', '10733', (25, 29))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('arrest', 'Disease', 'MESH:D006323', (204, 210))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (193, 210))	('cytokinesis failure', 'Disease', (151, 170))	('arrest', 'Disease', (204, 210))	('cytokinesis failure', 'Disease', 'MESH:D006333', (151, 170))	('mutant', 'Var', (30, 36))	('PLK4', 'Gene', (25, 29))
45562	32966175	To predict cancers to which our observations might apply, we assessed alterations (including mutation, fusion, amplification, deep deletion, or multiple alterations) of the p53 pathway genes TP53, CDKN1A, CDKN2A, MDM2, MDM4, and RB1 across 32 cancer types from the Pan-Cancer project from The Cancer Genome Atlas (TCGA; Supplemental Figure S4A).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TP53', 'Gene', '7157', (191, 195))	('MDM2', 'Gene', '4193', (213, 217))	('RB1', 'Gene', (229, 232))	('CDKN2A', 'Gene', '1029', (205, 211))	('Cancer', 'Disease', 'MESH:D009369', (269, 275))	('Cancer', 'Disease', 'MESH:D009369', (293, 299))	('Pan-Cancer', 'Disease', 'MESH:D009369', (265, 275))	('p53', 'Gene', '7157', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('RB1', 'Gene', '5925', (229, 232))	('p53', 'Gene', (173, 176))	('TP53', 'Gene', (191, 195))	('cancers', 'Disease', (11, 18))	('Cancer', 'Phenotype', 'HP:0002664', (269, 275))	('Cancer', 'Phenotype', 'HP:0002664', (293, 299))	('CDKN1A', 'Gene', (197, 203))	('MDM4', 'Gene', '4194', (219, 223))	('CDKN2A', 'Gene', (205, 211))	('CDKN1A', 'Gene', '1026', (197, 203))	('MDM4', 'Gene', (219, 223))	('cancer', 'Disease', (243, 249))	('MDM2', 'Gene', (213, 217))	('Cancer', 'Disease', (269, 275))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('Cancer', 'Disease', (293, 299))	('cancer', 'Disease', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mutation', 'Var', (93, 101))	('Pan-Cancer', 'Disease', (265, 275))
45564	32966175	The three cancer types with the highest median PLK4 mRNA expression were cervical cancer, testicular germ cell cancer, and AML, which all had less than 20% of cases with genomic alterations in TP53, CDKN1A, CDKN2A, MDM2, MDM4, and RB1 (Figure 5A; Supplemental Figure S4A).	('PLK4', 'Gene', (47, 51))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (111, 117))	('RB1', 'Gene', '5925', (231, 234))	('alterations', 'Var', (178, 189))	('mRNA expression', 'MPA', (52, 67))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MDM4', 'Gene', '4194', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CDKN1A', 'Gene', (199, 205))	('TP53', 'Gene', (193, 197))	('CDKN1A', 'Gene', '1026', (199, 205))	('MDM4', 'Gene', (221, 225))	('MDM2', 'Gene', (215, 219))	('CDKN2A', 'Gene', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('MDM2', 'Gene', '4193', (215, 219))	('CDKN2A', 'Gene', '1029', (207, 213))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('TP53', 'Gene', '7157', (193, 197))	('RB1', 'Gene', (231, 234))	('germ cell cancer', 'Phenotype', 'HP:0100728', (101, 117))	('AML', 'Disease', (123, 126))	('PLK4', 'Gene', '10733', (47, 51))
45572	32966175	Through examination of single cells rather than populations, we found that individual cells with amplified centrioles do not all arrest immediately in the next cell cycle.	('centrioles', 'Gene', (107, 117))	('arrest', 'Disease', (129, 135))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('amplified', 'Var', (97, 106))
45618	33430117	Our results elucidate the role of nuclear PTTG1 in promoting invasiveness and the metastatic process of these cells through its transcriptional target matrix-metalloproteinase-2 (MMP-2).	('matrix-metalloproteinase-2', 'Gene', '4313', (151, 177))	('MMP-2', 'Gene', (179, 184))	('promoting', 'PosReg', (51, 60))	('PTTG1', 'Gene', (42, 47))	('metastatic process of these cells', 'CPA', (82, 115))	('invasiveness', 'CPA', (61, 73))	('matrix-metalloproteinase-2', 'Gene', (151, 177))	('MMP-2', 'Gene', '4313', (179, 184))	('nuclear', 'Var', (34, 41))
45629	33430117	(4) Conclusions: nuclear PTTG1 promotes invasiveness of seminoma cell lines.	('promotes', 'PosReg', (31, 39))	('invasiveness of seminoma', 'Disease', 'MESH:D018239', (40, 64))	('nuclear', 'Var', (17, 24))	('PTTG1', 'Gene', (25, 30))	('invasiveness of seminoma', 'Disease', (40, 64))
45630	33430117	These data lead to the hypothesis that nuclear PTTG1 is an eligible prognostic factor in seminomas.	('nuclear PTTG1', 'Var', (39, 52))	('seminomas', 'Disease', 'MESH:D018239', (89, 98))	('seminomas', 'Disease', (89, 98))
45635	33430117	PTTG1 overexpression is reported to exert its oncogenic function by altering sister chromatid separation during cell division, leading to aneuploidy.	('overexpression', 'Var', (6, 20))	('PTTG1', 'Gene', (0, 5))	('sister chromatid separation during cell division', 'CPA', (77, 125))	('aneuploidy', 'Disease', (138, 148))	('aneuploidy', 'Disease', 'MESH:D000782', (138, 148))	('leading to', 'Reg', (127, 137))	('altering', 'Reg', (68, 76))
45638	33430117	As an oncogene, overexpressed PTTG1 causes aneuploidy and genetic instability and its contribution to tumorigenesis is also accountable to the promotion of invasiveness by its transcriptional activity.	('aneuploidy', 'Disease', 'MESH:D000782', (43, 53))	('genetic instability', 'CPA', (58, 77))	('PTTG1', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('aneuploidy', 'Disease', (43, 53))	('invasiveness', 'CPA', (156, 168))	('overexpressed', 'Var', (16, 29))	('promotion', 'PosReg', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('causes', 'Reg', (36, 42))
45660	33430117	The tM2 was 10% for TCAM2 while it was significantly higher, around 50%, for JKT-1 and SEM-1 (Figure 1F).	('SEM-1', 'Gene', (87, 92))	('TCAM2', 'Var', (20, 25))	('SEM-1', 'Gene', '7979', (87, 92))
45667	33430117	Since it has been reported that PTTG1 enhances MMP-2 expression and activity, we investigated metalloproteinases secretion/activity in the seminoma cell lines by zymography.	('seminoma', 'Disease', (139, 147))	('PTTG1', 'Var', (32, 37))	('MMP-2', 'Gene', '4313', (47, 52))	('seminoma', 'Disease', 'MESH:D018239', (139, 147))	('activity', 'MPA', (68, 76))	('expression', 'MPA', (53, 63))	('enhances', 'PosReg', (38, 46))	('MMP-2', 'Gene', (47, 52))
45681	33430117	Confocal microscopy analysis revealed that in TCAM2, the co-localization index between the two proteins was significantly lower with respect to other cell lines (Figure 4C), with values of tM2 coefficient ranging from approximately 50% in TCAM2 to ~80% in JKT-1 and SEM-1 cells (Figure 4D).	('lower', 'NegReg', (122, 127))	('SEM-1', 'Gene', '7979', (266, 271))	('TCAM2', 'Var', (46, 51))	('co-localization index between', 'MPA', (57, 86))	('SEM-1', 'Gene', (266, 271))
45711	33430117	It has been reported that only nuclear PTTG1 expression is associated with an aggressive phenotype, at least in pituitary tumors.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('PTTG1', 'Gene', (39, 44))	('pituitary tumors', 'Disease', (112, 128))	('associated', 'Reg', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('nuclear', 'Var', (31, 38))	('pituitary tumors', 'Disease', 'MESH:D010911', (112, 128))
45715	33430117	On the contrary, PTTG1 overexpression in TCAM2 was able to increase the MMP-2 protein level, but it was not sufficient to increase MMP-2 activity, due to the very poor nuclear overexpression despite a high transfection efficiency.	('MMP-2', 'Gene', '4313', (72, 77))	('MMP-2', 'Gene', '4313', (131, 136))	('MMP-2', 'Gene', (72, 77))	('MMP-2', 'Gene', (131, 136))	('overexpression', 'Var', (23, 37))	('PTTG1 overexpression', 'Var', (17, 37))	('increase', 'PosReg', (59, 67))
45719	33430117	These results lead to the hypothesis that in TCAM2 cells, PTTG1 is sequestered in the cytoplasm by specific interactors and/or by post-translational modifications (PTMs) that impair PTTG1 interaction with PBF.	('impair', 'NegReg', (175, 181))	('interaction', 'Interaction', (188, 199))	('modifications', 'Var', (149, 162))	('PBF', 'Gene', '754', (205, 208))	('PTTG1', 'Gene', (58, 63))	('PTTG1', 'Gene', (182, 187))	('PBF', 'Gene', (205, 208))
45722	33430117	Of interest, we validated the in vivo role of nuclear PTTG1 in seminoma via interrogation of the Atlas database of human testicular cancer.	('cancer', 'Disease', (132, 138))	('PTTG1', 'Gene', (54, 59))	('nuclear', 'Var', (46, 53))	('seminoma', 'Disease', 'MESH:D018239', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (115, 120))	('seminoma', 'Disease', (63, 71))	('testicular cancer', 'Phenotype', 'HP:0010788', (121, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
45724	33430117	These data support the hypothesis that nuclear PTTG1 was a specific feature of seminoma compared to others testicular tumors.	('nuclear PTTG1', 'Var', (39, 52))	('seminoma', 'Disease', 'MESH:D018239', (79, 87))	('testicular tumors', 'Disease', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('seminoma', 'Disease', (79, 87))	('testicular tumors', 'Disease', 'MESH:D013736', (107, 124))	('testicular tumors', 'Phenotype', 'HP:0010788', (107, 124))
45730	33430117	Plasmids used were: pcDNA3.1, pCMV (as control vectors -CTR), pcDNA3.1-PTTG1, pCMV-FLAG-PTTG1, and pCIneo HA-PBF.	('pcDNA3.1-PTTG1', 'Var', (62, 76))	('CTR', 'Gene', '799', (56, 59))	('CTR', 'Gene', (56, 59))	('pCIneo HA-PBF', 'Disease', (99, 112))	('pCIneo HA-PBF', 'Disease', 'MESH:C537629', (99, 112))
45757	33430117	Overall, these data strongly suggest that nuclear PTTG1 may be a prognostic factor in seminomas.	('seminomas', 'Disease', (86, 95))	('nuclear PTTG1', 'Var', (42, 55))	('seminomas', 'Disease', 'MESH:D018239', (86, 95))
45763	29456685	Consistently, an in vivo xenograft study also demonstrated the suppressive effects of miR-372 knockdown on tumor growth.	('knockdown', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('miR-372', 'Gene', (86, 93))	('miR-372', 'Gene', '442917', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('suppressive', 'NegReg', (63, 74))
45765	29456685	Furthermore, silencing of LATS2 was able to rescue the effect of the miR-372 inhibitor.	('miR-372', 'Gene', '442917', (69, 76))	('LATS2', 'Gene', (26, 31))	('LATS2', 'Gene', '26524', (26, 31))	('miR-372', 'Gene', (69, 76))	('effect', 'MPA', (55, 61))	('silencing', 'Var', (13, 22))
45772	29456685	Dysregulated miR-372 can act as an oncogenic miRNA in testicular germ cell tumors, human embryonic stem cells (hESCs), head and neck squamous cell carcinoma (HNSCC), and colorectal cancer.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('germ cell tumors', 'Phenotype', 'HP:0100728', (65, 81))	('neck squamous cell carcinoma', 'Disease', (128, 156))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (128, 156))	('miR-372', 'Gene', (13, 20))	('germ cell tumor', 'Phenotype', 'HP:0100728', (65, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('Dysregulated', 'Var', (0, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('miR-372', 'Gene', '442917', (13, 20))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (119, 156))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('human', 'Species', '9606', (83, 88))	('colorectal cancer', 'Disease', (170, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
45779	29456685	Additionally, the downregulation of miR-372 by antisense-miR-327 markedly arrested the cell cycle in G1/S phase, and increased apoptosis of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('arrested', 'NegReg', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('increased', 'PosReg', (117, 126))	('breast cancer', 'Disease', (140, 153))	('miR-372', 'Gene', '442917', (36, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('antisense-miR-327', 'Var', (47, 64))	('apoptosis', 'CPA', (127, 136))	('cell cycle in G1/S phase', 'CPA', (87, 111))	('downregulation', 'NegReg', (18, 32))	('miR-372', 'Gene', (36, 43))	('miR-327', 'Chemical', '-', (57, 64))
45801	29456685	The generation of Renilla luciferase constructs containing the wild type (WT) or mutant (MUT) target site of the LATS2 3'-UTR was conducted as described previously.	('LATS2', 'Gene', (113, 118))	('LATS2', 'Gene', '26524', (113, 118))	('Renilla luciferase constructs', 'Disease', 'MESH:D000381', (18, 47))	('mutant', 'Var', (81, 87))	('Renilla luciferase constructs', 'Disease', (18, 47))
45819	29456685	Cell cycle analysis demonstrated that AS-miR-372 transfection increased the percentage of cells in G1 phase vs. the scramble-transfected cell group (Fig.	('increased', 'PosReg', (62, 71))	('miR-372', 'Gene', '442917', (41, 48))	('transfection', 'Var', (49, 61))	('miR-372', 'Gene', (41, 48))
45821	29456685	However, the percentage of annexin V+ MCF-10A cells remained approximately 2% after AS-miR-372 transfection (Fig.	('annexin V', 'Gene', '308', (27, 36))	('transfection', 'Var', (95, 107))	('annexin V', 'Gene', (27, 36))	('MCF-10A', 'CellLine', 'CVCL:0598', (38, 45))	('miR-372', 'Gene', (87, 94))	('miR-372', 'Gene', '442917', (87, 94))
45823	29456685	From week 3, the tumorigenicity of the AS-miR-372 transfection group was markedly slow compared with that of the scramble group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('slow', 'NegReg', (82, 86))	('miR-372', 'Gene', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('miR-372', 'Gene', '442917', (42, 49))	('transfection', 'Var', (50, 62))
45825	29456685	These results indicate that miR-327 stimulates the tumor growth of breast cancer cells in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('stimulates', 'PosReg', (36, 46))	('miR-327', 'Chemical', '-', (28, 35))	('tumor', 'Disease', (51, 56))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('miR-327', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
45829	29456685	LATS2 protein expression was also increased following AS-miR-372 transfection (Fig.	('protein', 'Protein', (6, 13))	('miR-372', 'Gene', (57, 64))	('LATS2', 'Gene', (0, 5))	('LATS2', 'Gene', '26524', (0, 5))	('expression', 'MPA', (14, 24))	('transfection', 'Var', (65, 77))	('miR-372', 'Gene', '442917', (57, 64))	('increased', 'PosReg', (34, 43))
45830	29456685	Furthermore, a dual-luciferase reporter system, with luciferase reporter vectors containing either the WT or the MUT 3'-UTR of LATS2, was used to determine whether LATS2 is a direct target of miR-327 in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('miR-327', 'Var', (192, 199))	('LATS2', 'Gene', (127, 132))	('LATS2', 'Gene', '26524', (127, 132))	('LATS2', 'Gene', (164, 169))	('LATS2', 'Gene', '26524', (164, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('miR-327', 'Chemical', '-', (192, 199))
45836	29456685	We subsequently asked if the inhibitory effect of AS-miR-327 in breast cancer cells is mediated through downregulation of LATS2.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('AS-miR-327', 'Var', (50, 60))	('LATS2', 'Gene', (122, 127))	('LATS2', 'Gene', '26524', (122, 127))	('miR-327', 'Chemical', '-', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('downregulation', 'NegReg', (104, 118))	('breast cancer', 'Disease', (64, 77))
45839	29456685	A reduced cell colony number following AS-miR-327-transfection was also rescued to a colony number similar to that of the scramble transfection group by LATS2-downregulation (Fig.	('miR-327', 'Chemical', '-', (42, 49))	('reduced', 'NegReg', (2, 9))	('AS-miR-327-transfection', 'Var', (39, 62))	('cell colony number', 'CPA', (10, 28))	('LATS2', 'Gene', (153, 158))	('LATS2', 'Gene', '26524', (153, 158))
45859	29456685	Indeed, the silencing of LATS2 by siRNA in the present study successfully rescued the suppresive effect of the AS-miR-372 on cell proliferation and colony formation in MDA-MB-231 cells.	('miR-372', 'Gene', '442917', (114, 121))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (168, 178))	('LATS2', 'Gene', '26524', (25, 30))	('silencing', 'Var', (12, 21))	('cell proliferation', 'CPA', (125, 143))	('LATS2', 'Gene', (25, 30))	('miR-372', 'Gene', (114, 121))	('suppresive effect', 'MPA', (86, 103))	('colony formation', 'CPA', (148, 164))
45942	24799882	This antibiotic is an anti-tumor that plays an important role in the treatment of lymphomas, carcinomas and germ cells and makes its affect through creating single or double stranded DNA in tumor cells and interrupting the cell cycle.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('single or double stranded DNA', 'Var', (157, 186))	('cell cycle', 'CPA', (223, 233))	('tumor', 'Disease', (27, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Disease', (93, 103))	('lymphomas', 'Disease', (82, 91))	('interrupting', 'NegReg', (206, 218))	('tumor', 'Disease', (190, 195))	('carcinomas', 'Disease', 'MESH:D002277', (93, 103))	('lymphomas', 'Disease', 'MESH:D008223', (82, 91))	('lymphomas', 'Phenotype', 'HP:0002665', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
45976	24799882	The RJ contains amino acids such as aspartic acid, cysteine, cystine, tyrosine, glycine, lysine, leucine, valine, and isoleucine that are biologically active.	('lysine', 'MPA', (89, 95))	('leucine', 'Var', (97, 104))	('isoleucine', 'Var', (118, 128))	('aspartic acid', 'Chemical', 'MESH:D001224', (36, 49))	('tyrosine', 'Chemical', 'MESH:D014443', (70, 78))	('glycine', 'MPA', (80, 87))	('cystine', 'MPA', (61, 68))	('isoleucine', 'Chemical', 'MESH:D007532', (118, 128))	('leucine', 'Chemical', 'MESH:D007930', (121, 128))	('valine', 'MPA', (106, 112))	('leucine', 'Chemical', 'MESH:D007930', (97, 104))	('valine', 'Chemical', 'MESH:D014633', (106, 112))	('glycine', 'Chemical', 'MESH:D005998', (80, 87))	('cysteine', 'MPA', (51, 59))	('tyrosine', 'MPA', (70, 78))	('cystine', 'Chemical', 'MESH:D003553', (61, 68))
45977	24799882	Abnormal histone retention or protamines deficiency in sperm is in association with the reduction in fertility and increased risk of embryonic failure after fertilization.	('retention or protamines deficiency', 'Disease', 'MESH:D016055', (17, 51))	('reduction', 'NegReg', (88, 97))	('embryonic failure', 'Disease', 'MESH:D017093', (133, 150))	('retention or protamines deficiency', 'Disease', (17, 51))	('Abnormal', 'Var', (0, 8))	('fertility', 'CPA', (101, 110))	('embryonic failure', 'Disease', (133, 150))
46001	23049638	The pathogenesis of testicular germ cell tumors remains unknown; however, although recently questioned , cryptorchidism is the main risk factor, and molecular studies have shown strong evidence of an association between genetic alterations and testicular germ cell tumors .	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cryptorchidism', 'Phenotype', 'HP:0000028', (105, 119))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('genetic alterations', 'Var', (220, 239))	('cell tumors', 'Disease', 'MESH:D005935', (260, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('association', 'Interaction', (200, 211))	('cryptorchidism', 'Disease', (105, 119))	('cell tumors', 'Disease', (36, 47))	('cell tumors', 'Disease', (260, 271))	('cell tumors', 'Disease', 'MESH:D005935', (36, 47))
46048	33160340	Two tubular components (ETTF2323C70EE, ETCF2525C49EE) of Endurant abdominal stent-grafts were implanted via right common femoral artery and the intervention was performed by specialists at the National Institute of Cardiovascular Diseases in Bratislava.	('ETCF2525C49EE', 'Var', (39, 52))	('Cardiovascular Diseases', 'Disease', (215, 238))	('ETTF2323C70EE', 'Var', (24, 37))	('common femoral artery', 'Phenotype', 'HP:0001660', (114, 135))	('Cardiovascular Diseases', 'Phenotype', 'HP:0001626', (215, 238))	('Cardiovascular Diseases', 'Disease', 'MESH:D002318', (215, 238))
46250	28435402	Two studies detected a point mutation in the c-kit codon 816 in the majority of the bilateral testis cancer.	('c-kit', 'Gene', '3815', (45, 50))	('c-kit', 'Gene', (45, 50))	('detected', 'Reg', (12, 20))	('bilateral testis', 'Phenotype', 'HP:0010470', (84, 100))	('bilateral testis cancer', 'Disease', 'MESH:D013736', (84, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('point mutation', 'Var', (23, 37))	('bilateral testis cancer', 'Disease', (84, 107))	('testis cancer', 'Phenotype', 'HP:0010788', (94, 107))
46282	28435402	Low testosterone levels have also been linked to metabolic syndrome and type II diabetes, with both conditions being associated with cardiovascular disease, and shown to predict elevated overall and cardiovascular-related mortality in middle-aged and older men.	('men', 'Species', '9606', (257, 260))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (133, 155))	('associated', 'Reg', (117, 127))	('type II diabetes', 'Phenotype', 'HP:0005978', (72, 88))	('testosterone', 'Chemical', 'MESH:D013739', (4, 16))	('Low testosterone', 'Phenotype', 'HP:0040171', (0, 16))	('cardiovascular disease', 'Disease', 'MESH:D002318', (133, 155))	('elevated', 'PosReg', (178, 186))	('linked', 'Reg', (39, 45))	('metabolic syndrome and type II diabetes', 'Disease', 'MESH:D003924', (49, 88))	('cardiovascular disease', 'Disease', (133, 155))	('Low', 'Var', (0, 3))
46320	26123546	Down syndrome is the most common and best-known chromosomal disorder in humans; 95 % of cases are due to trisomy of chromosome 21.	('chromosomal disorder', 'Disease', (48, 68))	('due', 'Reg', (98, 101))	('trisomy of chromosome 21', 'Var', (105, 129))	('chromosomal disorder', 'Disease', 'MESH:D025063', (48, 68))	('Down syndrome', 'Disease', (0, 13))	('humans', 'Species', '9606', (72, 78))
46387	26123546	Despite drug modifications, patients are still likely to suffer chemotherapy toxicity.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('toxicity', 'Disease', (77, 85))	('suffer', 'Reg', (57, 63))	('chemotherapy', 'MPA', (64, 76))	('patients', 'Species', '9606', (28, 36))	('modifications', 'Var', (13, 26))
46393	26123546	Therefore, although surveillance following orchiectomy is acceptable in the general population, the individual appropriateness of an intense surveillance protocol should be judged and discussed with the patient and carers in Down syndrome as poor adherence to surveillance could mean potential recurrence at advanced stage disease necessitating more chemotherapy than would have been required in the adjuvant setting.	('mean', 'Reg', (279, 283))	('patient', 'Species', '9606', (203, 210))	('poor adherence', 'Var', (242, 256))
46457	19679044	The histology (ICD) codes used were dysgerminoma/seminoma (9060-9064), teratoma (9080, 9082-9084, 9090-9091), embryonal carcinoma (9070), yolk sac tumor (9071), choriocarcinoma (9100-9103), and mixed GCT (ICD 9072, 9081, 9085).	('ICD', 'Disease', (15, 18))	('ICD', 'Disease', (205, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('teratoma', 'Phenotype', 'HP:0009792', (71, 79))	('choriocarcinoma', 'Disease', 'MESH:D002822', (161, 176))	('tumor', 'Disease', (147, 152))	('choriocarcinoma', 'Disease', (161, 176))	('ICD', 'Disease', 'OMIM:252500', (15, 18))	('ICD', 'Disease', 'OMIM:252500', (205, 208))	('9060-9064', 'Var', (59, 68))	('9071', 'Var', (154, 158))	('9080', 'Var', (81, 85))	('9090-9091', 'Var', (98, 107))	('dysgerminoma/seminoma', 'Disease', (36, 57))	('9100-9103', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('teratoma', 'Disease', 'MESH:D013724', (71, 79))	('dysgerminoma/seminoma', 'Disease', 'MESH:D004407', (36, 57))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (161, 176))	('GCT', 'Gene', '25797', (200, 203))	('9070', 'Var', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('GCT', 'Gene', (200, 203))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (110, 129))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (110, 129))	('embryonal carcinoma', 'Disease', (110, 129))	('teratoma', 'Disease', (71, 79))	('dysgerminoma', 'Phenotype', 'HP:0100621', (36, 48))
46532	19679044	Chromosomal aberrations are frequent in both tumor types; the most common is the presence of isochromosome 12p.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('isochromosome 12p', 'Var', (93, 110))	('tumor', 'Disease', (45, 50))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
46542	32620889	Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('variants', 'Var', (73, 81))	('cancers', 'Disease', (218, 225))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
46543	32620889	Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('variants', 'Var', (143, 151))
46548	32620889	In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size.	('variants', 'Var', (20, 28))	('contribute', 'Reg', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
46550	32620889	Genome-wide association studies (GWASs) have led to the identification of hundreds of independent cancer susceptibility loci containing common, low-risk variants.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('variants', 'Var', (153, 161))
46554	32620889	Across cancer types, polygenic risk scores (PRSs) show varying levels of risk stratification depending on the heritability explained by the identified variants and the disease incidence rates in the population.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('variants', 'Var', (151, 159))	('PRS', 'Chemical', '-', (44, 47))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
46555	32620889	Estimation of heritability due to additive effects of all single-nucleotide polymorphisms (SNPs) included in GWAS arrays, referred to as GWAS heritability in this article, have shown that common variants have substantial potential to identify individuals at different levels of risk for many cancer types.	('variants', 'Var', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('identify', 'Reg', (234, 242))	('cancer', 'Disease', (292, 298))
46557	32620889	Herein we apply our recently published method to estimate the degree of polygenicity and the effect-size distribution associated with common variants (minor allele frequency (MAF) > 0.05) across 14 different cancer types, based on summary-level association statistics from available GWASs from populations of European ancestry (Supplementary Table 1).	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('variants', 'Var', (141, 149))	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
46561	32620889	Estimates of the number of susceptibility variants with independent risk associations vary from ~1000 to 7500 between the 14 cancer sites (Table 1).	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('variants', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))
46562	32620889	For GWASs with <10,000 cancer cases (group 1), CLL and testicular cancer are each associated with 2000-2500 variants and characterized by a much larger proportion of variants with larger estimated effect sizes than for the other group 1 cancers, as reflected by wider effect-size distribution with heavier tails (Fig.	('associated', 'Reg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (237, 243))	('CLL', 'Disease', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (23, 29))	('variants', 'Var', (166, 174))	('2000-2500 variants', 'Var', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('variants', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('CLL', 'Phenotype', 'HP:0005550', (47, 50))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('cancer', 'Disease', (66, 72))
46563	32620889	GWAS heritability estimates indicate that, in aggregate, common variants explain a high degree of variation of risk for these two cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('variants', 'Var', (64, 72))
46564	32620889	In contrast, in group 1, esophageal and oropharyngeal cancers are associated with a larger proportion of variants with substantially smaller effect sizes, compared with CLL and testicular cancers in group 1.	('testicular cancers', 'Disease', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('testicular cancer', 'Phenotype', 'HP:0010788', (177, 194))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('CLL', 'Phenotype', 'HP:0005550', (169, 172))	('esophageal', 'Disease', (25, 35))	('cancers', 'Disease', (188, 195))	('testicular cancers', 'Disease', 'MESH:D013736', (177, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('testicular cancers', 'Phenotype', 'HP:0010788', (177, 195))	('variants', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
46567	32620889	Finally, for the 3 GWAS with >25,000 cases each (group 3), prostate cancer is remarkable for having more variants with large effect sizes, namely, the underlying effect-size distribution has a heavier tail, compared with cancers of the breast and lung (Fig.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('cancers', 'Disease', (221, 228))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('heavier', 'PosReg', (193, 200))	('variants', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('prostate cancer', 'Disease', (59, 74))
46568	32620889	In this group, all three cancer types tend to have large numbers of associated variants (>4500) compared with cancer sites in other groups, but this pattern could partially be due to the very large sample sizes of group 3 GWAS.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('variants', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
46569	32620889	For a large majority of the 14 cancer sites, a two-component normal-mixture model for non-null effects provides a substantially better fit to observed summary statistics than a single normal distribution; this indicates the presence of a fraction of variants with distinctly larger effect sizes than the remaining (Supplementary Figs.	('cancer', 'Disease', (31, 37))	('variants', 'Var', (250, 258))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
46570	32620889	In contrast, a single normal distribution appears to be adequate for esophageal and oropharyngeal cancer, indicating the presence of a large number of variants with a continuum of small effects, similar to our previous findings for traits related to mental health and abilities.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variants', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('presence', 'Reg', (121, 129))	('esophageal', 'Disease', (69, 79))	('cancer', 'Disease', (98, 104))
46574	32620889	Known variants explain more than a quarter of heritability for cancer sites based on very large sample sizes (e.g., breast and prostate cancer) or for cancer sites that have susceptibility variants with relatively large effect sizes (e.g., CLL, melanoma, and testicular cancer).	('CLL', 'Disease', (240, 243))	('testicular cancer', 'Phenotype', 'HP:0010788', (259, 276))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('cancer', 'Disease', (270, 276))	('melanoma', 'Disease', (245, 253))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', (63, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('CLL', 'Phenotype', 'HP:0005550', (240, 243))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('variants', 'Var', (6, 14))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (116, 142))	('variants', 'Var', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
46576	32620889	The sample size needed to identify common variants that could explain approximately 80% of the total GWAS heritability for the cancers evaluated is generally very large, requiring 200,000-1,000,000 cancer cases, with a comparable number of controls (Fig.	('000-1,000,000 cancer', 'Disease', 'MESH:C564120', (184, 204))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('variants', 'Var', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
46577	32620889	However, for three sites, namely, testicular cancer, CLL, and melanoma, the required sample size is smaller, 60,000, 80,000, and 110,000 cases, respectively, due to the large effect sizes of their associated variants.	('melanoma', 'Disease', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('testicular cancer', 'Phenotype', 'HP:0010788', (34, 51))	('CLL', 'Phenotype', 'HP:0005550', (53, 56))	('variants', 'Var', (208, 216))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('CLL', 'Disease', (53, 56))	('cancer', 'Disease', (45, 51))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
46596	32620889	A number of these cancers are known to have rare high-penetrant risk variants, but for this study we have focused on estimating effect-size distribution associated with common variants.	('cancers', 'Disease', (18, 25))	('variants', 'Var', (69, 77))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
46597	32620889	Furthermore, heritability analysis indicate that uncommon and rare variants could explain a substantial fraction of the variation of complex traits, and thus it is likely that there are many unknown uncommon and rare variants associated with these cancers as well.	('cancers', 'Disease', (248, 255))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('associated', 'Reg', (226, 236))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('variants', 'Var', (67, 75))
46618	32620889	H.Z., D.F.E., J.S., P.H., K.M., J.D., J.C.-C., P.G., D.W., P.T.C., M.H., S.B.G., G.C., I.T., I.D.V., M.T.L., R.K., D.T.B., M.L.B., R.H., J.K.W., B.M., J.B.-S., B.K., R.J.H., P.B., J.M., N.E.C., P.K., N.R., S.L.	('P.K.', 'Var', (194, 198))	('P.T', 'Disease', (59, 62))	('P.T', 'Disease', 'MESH:C000656865', (59, 62))
46622	22695395	Developmental reprogramming of cancer susceptibility Gene-environment interactions have been traditionally understood to promote the acquisition of mutations that drive multistage carcinogenesis, and, in the case of inherited defects in tumour suppressor genes, additional mutations are required for cancer development.	('multistage carcinogenesis', 'Disease', (169, 194))	('mutations', 'Var', (148, 157))	('inherited defects', 'Disease', 'MESH:D030342', (216, 233))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('inherited defects', 'Disease', (216, 233))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (237, 243))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (169, 194))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))
46630	22695395	For example, in breast cancer, inherited genetic factors, such as alterations in BRCA1 and BRCA2 (which account for 5-10% of breast cancers), and environmental factors, such as exogenous hormone exposure (for example, hormone replacement therapy), contribute to the risk of developing several forms of this disease.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('breast cancer', 'Disease', (16, 29))	('BRCA1', 'Gene', (81, 86))	('rat', 'Species', '10116', (70, 73))	('breast cancers', 'Phenotype', 'HP:0003002', (125, 139))	('BRCA2', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancers', 'Disease', 'MESH:D001943', (125, 139))	('breast cancers', 'Disease', (125, 139))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BRCA2', 'Gene', '675', (91, 96))	('contribute', 'Reg', (248, 258))	('BRCA1', 'Gene', '672', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('alterations', 'Var', (66, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
46631	22695395	Exposure to tobacco carcinogens can induce mutations in genes such as TP53 (which encodes p53) in lung cancer; and defects in several genes, such as adenomatous polyposis coli (APC), KRAS and TP53, contribute to multistage carcinogenesis of the colon, as does a diet high in fat and red meat.	('multistage carcinogenesis', 'Disease', (212, 237))	('defects', 'Var', (115, 122))	('TP53', 'Gene', (70, 74))	('tobacco', 'Species', '4097', (12, 19))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('carcinogenesis of the colon', 'Disease', 'MESH:D063646', (223, 250))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (212, 237))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (149, 175))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (149, 175))	('multistage carcinogenesis of the colon', 'Phenotype', 'HP:0040276', (212, 250))	('adenomatous polyposis coli', 'Disease', (149, 175))	('TP53', 'Gene', (192, 196))	('KRAS', 'Gene', (183, 187))	('carcinogenesis of the colon', 'Disease', (223, 250))	('APC', 'Phenotype', 'HP:0005227', (177, 180))	('APC', 'Disease', 'MESH:D011125', (177, 180))	('APC', 'Disease', (177, 180))	('contribute', 'Reg', (198, 208))	('lung cancer', 'Disease', (98, 109))	('mutations', 'Var', (43, 52))	('induce', 'Reg', (36, 42))
46634	22695395	Typically, gene-environment interaction refers to an increased (or a decreased) sensitivity to an environmental carcinogen owing to a specific germline alteration that is carried by exposed individuals, often as a single nucleotide polymorphism (SNP).	('rat', 'Species', '10116', (156, 159))	('decreased', 'NegReg', (69, 78))	('increased', 'PosReg', (53, 62))	('sensitivity to an environmental carcinogen', 'MPA', (80, 122))	('single nucleotide polymorphism', 'Var', (214, 244))
46636	22695395	Similarly, SNPs in genes that encode metabolic enzymes, such as N-acetyltransferase 1 (NAT1 ) and NAT2 , which are involved in the activation (for example, polycyclic aromatic hydrocarbons (PAHs) in the colon) or the detoxication (such as arylamines in the bladder) of carcinogens can increase or decrease the potency of these carcinogens.	('decrease', 'NegReg', (297, 305))	('NAT2', 'Gene', (98, 102))	('NAT1', 'Gene', '9', (87, 91))	('N-acetyltransferase 1', 'Gene', (64, 85))	('N-acetyltransferase 1', 'Gene', '9', (64, 85))	('PAHs', 'Chemical', 'MESH:D011084', (190, 194))	('NAT1', 'Gene', (87, 91))	('arylamines', 'Chemical', 'MESH:C023650', (239, 249))	('NAT2', 'Gene', '10', (98, 102))	('SNPs', 'Var', (11, 15))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (156, 188))	('potency', 'MPA', (310, 317))
46639	22695395	In such settings, environmental exposures are thought to be an important determinant of penetrance by inducing 'second hits' in the normal allele of the tumour suppressor gene (which induces the loss of gene function) or additional mutations in other genes that are required for multistage carcinogenesis.	('tumour', 'Disease', (153, 159))	('inducing', 'Reg', (102, 110))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (279, 304))	('mutations', 'Var', (232, 241))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('multistage carcinogenesis', 'Disease', (279, 304))	('loss', 'NegReg', (195, 199))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
46640	22695395	Thus, for gene- environment interactions, in the setting of both highly prevalent, low penetrant genetic alterations (such as SNPs), and low prevalence, high penetrance genetic alterations (such as tumour suppressor gene defects), our understanding of how environmental factors contribute to cancer development has focused on how these exposures promote the acquisition of additional genetic alterations that participate in multistage carcinogenesis.	('tumour', 'Disease', (198, 204))	('multistage carcinogenesis', 'Disease', (424, 449))	('rat', 'Species', '10116', (396, 399))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('alterations', 'Var', (177, 188))	('rat', 'Species', '10116', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('rat', 'Species', '10116', (181, 184))	('cancer', 'Disease', (292, 298))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (424, 449))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
46643	22695395	For example, congenital limb malformations can be caused by exposure of the developing foetus to thalidomide; folate deficiency in utero is associated with spina bifida; and maternal alcohol consumption can cause a host of neurological deficits that are associated with foetal alcohol syndrome.	('spina bifida', 'Disease', (156, 168))	('folate', 'Protein', (110, 116))	('deficiency', 'Var', (117, 127))	('caused', 'Reg', (50, 56))	('foetal alcohol syndrome', 'Disease', 'MESH:D000437', (270, 293))	('maternal alcohol consumption', 'Phenotype', 'HP:0030955', (174, 202))	('alcohol syndrome', 'Phenotype', 'HP:0030955', (277, 293))	('cause', 'Reg', (207, 212))	('alcohol', 'Chemical', 'MESH:D000438', (277, 284))	('spina bifida', 'Phenotype', 'HP:0002414', (156, 168))	('congenital limb malformations', 'Disease', 'MESH:D000013', (13, 42))	('thalidomide', 'Chemical', 'MESH:D013792', (97, 108))	('host of neurological deficits', 'Disease', (215, 244))	('associated', 'Reg', (140, 150))	('congenital limb malformations', 'Disease', (13, 42))	('neurological deficits', 'Phenotype', 'HP:0000707', (223, 244))	('limb malformations', 'Phenotype', 'HP:0002813', (24, 42))	('foetal alcohol syndrome', 'Disease', (270, 293))	('folate deficiency', 'Phenotype', 'HP:0100507', (110, 127))	('host of neurological deficits', 'Disease', 'MESH:D009461', (215, 244))	('folate', 'Chemical', 'MESH:D005492', (110, 116))	('deficiency in utero', 'Phenotype', 'HP:0001511', (117, 136))	('alcohol', 'Chemical', 'MESH:D000438', (183, 190))
46653	22695395	In the case of histone modifications, the epigenetic programmes that are installed by these writers form a 'histone code' that is interpreted by 'readers' (which are effector molecules that recognize methylated arginine and lysine residues of histones) and that is modified by 'erasers' (histone demethylases).	('lysine', 'Chemical', 'MESH:D008239', (224, 230))	('methylated', 'Var', (200, 210))	('arginine', 'Chemical', 'MESH:D001120', (211, 219))	('modifications', 'Var', (23, 36))
46654	22695395	Histones H3 and H4 are the primary targets for methylation, and the methyl marks are by convention denoted by specific lysine or arginine residues that are monomethylated, dimethylated or trimethylated.	('trimethylated', 'Var', (188, 201))	('monomethylated', 'Var', (156, 170))	('arginine', 'Chemical', 'MESH:D001120', (129, 137))	('Histones H3', 'Protein', (0, 11))	('dimethylated', 'Var', (172, 184))	('lysine', 'Chemical', 'MESH:D008239', (119, 125))
46655	22695395	Gene-specific patterns of histone modifications can generate binding sites for histone code readers, such as proteins containing plant homeodomain (PHD) domains, as well as other epigenetic writers, such as DNMTs.	('rat', 'Species', '10116', (56, 59))	('PHD', 'Disease', 'MESH:D011547', (148, 151))	('PHD', 'Disease', (148, 151))	('modifications', 'Var', (34, 47))	('binding', 'Interaction', (61, 68))
46656	22695395	Prenatal exposure to the famine of the Dutch hunger winter and season of conception in areas of rural Gambia that experience dramatic seasonal fluctuations in nutritional status have both been associated with epigenetic changes at specific gene loci in affected individuals.	('epigenetic changes', 'Var', (209, 227))	('rural Gambia', 'Disease', 'None', (96, 108))	('Prenatal exposure', 'Phenotype', 'HP:0031437', (0, 17))	('rural Gambia', 'Disease', (96, 108))	('associated', 'Reg', (193, 203))
46667	22695395	Studies from the Jirtle laboratory and others using mutant agouti mice have convincingly demonstrated that changing the in utero environment by increasing or decreasing maternal dietary intake of the methyl donors methionine and choline, or folate (which participates in one-carbon metabolism that generates S-adenosylmethionine), increases or decreases DNA methylation, respectively, in the genome of the offspring.	('methionine', 'Chemical', 'MESH:D008715', (318, 328))	('folate', 'Chemical', 'MESH:D005492', (241, 247))	('mutant', 'Var', (52, 58))	('increases', 'PosReg', (331, 340))	('donor', 'Species', '9606', (207, 212))	('carbon', 'Chemical', 'MESH:D002244', (275, 281))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (308, 328))	('mice', 'Species', '10090', (66, 70))	('rat', 'Species', '10116', (96, 99))	('decreasing', 'NegReg', (158, 168))	('decreases', 'NegReg', (344, 353))	('DNA methylation', 'MPA', (354, 369))	('rat', 'Species', '10116', (302, 305))	('choline', 'Chemical', 'MESH:D002794', (229, 236))	('rat', 'Species', '10116', (28, 31))	('methionine', 'Chemical', 'MESH:D008715', (214, 224))
46676	22695395	Additional studies have demonstrated that exposure of the developing uterus to environmental oestrogens reprogrammed many oestrogen-responsive genes, including S100 calcium-binding protein G (S100G; also known as CALB3), glutamate receptor ionotropic AMPA2 (GRIA2), growth differentiation factor 10 (GDF10) and matrix metalloproteinase 3 (MMP3), causing them to become hyper-responsive to oestrogen.	('MMP3', 'Gene', (339, 343))	('matrix metalloproteinase 3', 'Gene', '4314', (311, 337))	('growth differentiation factor 10', 'Gene', '2662', (266, 298))	('rat', 'Species', '10116', (31, 34))	('GRIA2', 'Gene', '2891', (258, 263))	('GDF10', 'Gene', (300, 305))	('oestrogen-responsive genes', 'Gene', (122, 148))	('MMP3', 'Gene', '4314', (339, 343))	('glutamate receptor ionotropic AMPA2', 'Gene', '2891', (221, 256))	('CALB3', 'Gene', '795', (213, 218))	('S100 calcium-binding protein G', 'Gene', '795', (160, 190))	('CALB3', 'Gene', (213, 218))	('S100G', 'Var', (192, 197))	('become hyper-responsive', 'PosReg', (362, 385))	('GDF10', 'Gene', '2662', (300, 305))	('GRIA2', 'Gene', (258, 263))	('S100 calcium-binding protein G', 'Gene', (160, 190))	('matrix metalloproteinase 3', 'Gene', (311, 337))	('S100G', 'SUBSTITUTION', 'None', (192, 197))	('glutamate receptor ionotropic AMPA2', 'Gene', (221, 256))	('growth differentiation factor 10', 'Gene', (266, 298))
46677	22695395	As described above, increased gene expression as a result of this epigenetic reprogramming in early life may be triggered by later-life events such as the presence of ovarian steroid hormones during puberty.	('increased', 'PosReg', (20, 29))	('gene expression', 'MPA', (30, 45))	('epigenetic', 'Var', (66, 76))	('steroid hormones', 'Chemical', 'MESH:D013256', (175, 191))
46678	22695395	In these settings, ovariectomy before puberty completely eliminates the effect of epigenetic reprogramming on gene expression and uterine tumour development, pointing to the inter-dependency between early life reprogramming and later-life events.	('eliminates', 'NegReg', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('uterine tumour', 'Phenotype', 'HP:0010784', (130, 144))	('epigenetic', 'Var', (82, 92))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('gene expression', 'MPA', (110, 125))	('tumour', 'Disease', (138, 144))	('ovariectomy before puberty', 'Phenotype', 'HP:0008209', (19, 45))
46682	22695395	Although these epigenetic changes correlate with altered gene expression and increased susceptibility to cancer in the developmentally reprogrammed tissues, whether they are biomarkers of developmental reprogramming (as is the case for LTF) or contribute to increased cancer susceptibility (as might be the case for PDE4D4) remains to be fully explored.	('gene expression', 'MPA', (57, 72))	('cancer', 'Disease', (268, 274))	('LTF', 'Gene', '4057', (236, 239))	('altered', 'Reg', (49, 56))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('epigenetic changes', 'Var', (15, 33))	('LTF', 'Gene', (236, 239))
46689	22695395	In the male reproductive tract, prostate cancer has been linked to high birth weight, which increases the risk of more aggressive disease.	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('high birth weight', 'Var', (67, 84))	('aggressive disease', 'Disease', 'MESH:D001523', (119, 137))	('high birth weight', 'Phenotype', 'HP:0001520', (67, 84))	('linked', 'Reg', (57, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('aggressive disease', 'Disease', (119, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))
46714	22695395	Studies in Eker rats with a defect in Tsc2 first pointed to the fact that exposure to environmental oestrogens during development could cooperate with a tumour suppressor gene defect to increase the penetrance of the defective tumour suppressor gene.	('tumour', 'Disease', (153, 159))	('defect', 'Var', (176, 182))	('penetrance', 'MPA', (199, 209))	('rat', 'Species', '10116', (16, 19))	('increase', 'PosReg', (186, 194))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('Tsc2', 'Gene', (38, 42))	('tumour', 'Disease', (227, 233))	('rat', 'Species', '10116', (141, 144))	('defect', 'Var', (28, 34))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('rats', 'Species', '10116', (16, 20))
46717	22695395	This suggests that the combined increase in oestrogen responsiveness (reprogramming) and the defect in Tsc2 promoted the development of hormone-dependent leiomyoma, effectively increasing tumour suppressor gene penetrance.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('increasing', 'PosReg', (177, 187))	('leiomyoma', 'Disease', 'MESH:D007889', (154, 163))	('increase', 'PosReg', (32, 40))	('oestrogen responsiveness', 'MPA', (44, 68))	('defect', 'Var', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('promoted', 'PosReg', (108, 116))	('Tsc2', 'Gene', (103, 107))	('leiomyoma', 'Disease', (154, 163))
46719	22695395	Conversely, ovariectomy almost completely ablated tumour development in genetically predisposed animals, indicating that, in the absence of ovarian hormones, the tumour suppressor gene defect was not sufficient to induce tumorigenesis.	('tumour', 'Disease', (162, 168))	('tumorigenesis', 'CPA', (221, 234))	('defect', 'Var', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('ablated', 'NegReg', (42, 49))	('induce', 'Reg', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('absence of ovarian', 'Phenotype', 'HP:0010463', (129, 147))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
46720	22695395	Thus, developmental reprogramming can cooperate with a tumour suppressor gene defect to increase its penetrance, thereby functioning as a new type of gene-environment interaction.	('tumour', 'Disease', (55, 61))	('developmental reprogramming', 'CPA', (6, 33))	('rat', 'Species', '10116', (43, 46))	('increase', 'PosReg', (88, 96))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('defect', 'Var', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('penetrance', 'MPA', (101, 111))
46740	22695395	It is also an open question as to whether other types of environmental exposures : for example, exposure to classic genotoxic carcinogens such as ionizing radiation or nitrosoamines : can contribute to cancer risk not just via mutations, but via developmental reprogramming of the epigenome.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ionizing radiation', 'Disease', (146, 164))	('nitrosoamines', 'Chemical', '-', (168, 181))	('genotoxic carcinogens', 'Disease', (116, 137))	('ionizing radiation', 'Disease', 'MESH:D004194', (146, 164))	('contribute', 'Reg', (188, 198))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('developmental reprogramming of the epigenome', 'CPA', (246, 290))	('genotoxic carcinogens', 'Disease', 'MESH:D063646', (116, 137))	('mutations', 'Var', (227, 236))
46742	22695395	Although existing data provide proof-of-concept that reprogramming of the epigenome can interact with a tumour suppressor gene defect to increase risk, it is likely that alterations in the epigenome can cooperate with other less penetrant, more prevalent genetic defects such as SNPs to similarly increase cancer risk.	('risk', 'MPA', (146, 150))	('interact', 'Reg', (88, 96))	('rat', 'Species', '10116', (208, 211))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('alterations', 'Var', (170, 181))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('genetic defects', 'Disease', 'MESH:D030342', (255, 270))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('increase', 'PosReg', (137, 145))	('genetic defects', 'Disease', (255, 270))	('rat', 'Species', '10116', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('SNPs', 'Disease', (279, 283))	('tumour', 'Disease', (104, 110))	('cancer', 'Disease', (306, 312))
46748	22695395	In contrast to germline alterations in tumour suppressor genes and cancer-associated SNPs, which are generally irreversible, epigenetic alterations that are induced by developmental reprogramming are potentially reversible with epigenetic therapies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('epigenetic alterations', 'Var', (125, 147))	('cancer', 'Disease', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rat', 'Species', '10116', (140, 143))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('rat', 'Species', '10116', (28, 31))
46750	23773267	Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis Certain mutations in the Deadend1 (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats.	('intestinal polyposis', 'Disease', (122, 142))	('germ cell tumor', 'Phenotype', 'HP:0100728', (233, 248))	('intestinal polyp', 'Phenotype', 'HP:0005266', (122, 138))	('mice', 'Species', '10090', (274, 278))	('tumor', 'Disease', (243, 248))	('testicular cancer', 'Disease', (99, 116))	('testicular cancer', 'Phenotype', 'HP:0010788', (99, 116))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('mutations', 'Var', (151, 160))	('intestinal polyposis', 'Phenotype', 'HP:0200008', (122, 142))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Dnd1', 'Gene', (178, 182))	('Dnd1', 'Gene', '213236', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('Dnd1', 'Gene', (33, 37))	('Dnd1', 'Gene', '213236', (33, 37))	('intestinal polyposis', 'Disease', 'MESH:D044483', (122, 142))	('testicular cancer', 'Disease', 'MESH:D013736', (99, 116))	('rats', 'Species', '10116', (283, 287))	('mutations', 'Var', (65, 74))
46751	23773267	In the 129 family of mice, the Dnd1Ter mutation significantly increases occurrence of TGCT-affected males.	('TGCT-affected', 'Disease', (86, 99))	('mutation', 'Var', (39, 47))	('increases', 'PosReg', (62, 71))	('mice', 'Species', '10090', (21, 25))	('Dnd1Ter', 'Gene', (31, 38))
46752	23773267	To test the hypothesis that he Dnd1Ter allele is a loss-of-function mutation; we characterized the consequences of a genetically-engineered loss-of-function mutation in mice, and compared these results with those for Dnd1Ter.	('mice', 'Species', '10090', (169, 173))	('mutation', 'Var', (157, 165))	('loss-of-function', 'NegReg', (140, 156))
46755	23773267	Finally, we found that the action of Dnd1Ter was not limited to testicular cancer, but also significantly increased polyp number and burden in the Apc+/Min model of intestinal polyposis.	('intestinal polyposis', 'Disease', (165, 185))	('intestinal polyposis', 'Phenotype', 'HP:0200008', (165, 185))	('intestinal polyposis', 'Disease', 'MESH:D044483', (165, 185))	('testicular cancer', 'Phenotype', 'HP:0010788', (64, 81))	('testicular cancer', 'Disease', 'MESH:D013736', (64, 81))	('burden', 'CPA', (133, 139))	('intestinal polyp', 'Phenotype', 'HP:0005266', (165, 181))	('Dnd1Ter', 'Var', (37, 44))	('Apc', 'Gene', (147, 150))	('Apc', 'Gene', '11789', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('increased', 'PosReg', (106, 115))	('testicular cancer', 'Disease', (64, 81))	('polyp number', 'Disease', 'MESH:D011127', (116, 128))	('polyp number', 'Disease', (116, 128))
46763	23773267	The gr/gr deletion, which is a common cause of infertility in men, is associated with increased TGCT risk.	('men', 'Species', '9606', (62, 65))	('gr/gr', 'Gene', (4, 9))	('TGCT', 'Disease', (96, 100))	('associated', 'Reg', (70, 80))	('infertility', 'Disease', 'MESH:D007247', (47, 58))	('deletion', 'Var', (10, 18))	('infertility', 'Phenotype', 'HP:0000789', (47, 58))	('infertility', 'Disease', (47, 58))
46764	23773267	gr/gr results from a 1.6 Mb deletion at the AZFc locus at Yq11 of the human Y chromosome, a region that contains multiple copies of several genes that are involved in male germ cell development including DAZ (deleted in azospermia), BPY2 (basic charge, Y-linked 2) and CDY1 (chromodomain protein, Y-linked 1).	('men', 'Species', '9606', (189, 192))	('results from', 'Reg', (6, 18))	('AZFc', 'Gene', (44, 48))	('basic charge, Y-linked 2', 'Gene', '9083', (239, 263))	('human', 'Species', '9606', (70, 75))	('BPY2', 'Gene', '9083', (233, 237))	('CDY1', 'Gene', '9085', (269, 273))	('CDY1', 'Gene', (269, 273))	('deletion', 'Var', (28, 36))	('BPY2', 'Gene', (233, 237))
46765	23773267	Effects of the gr/gr deletion on germ cell development and differentiation are largely unknown.	('men', 'Species', '9606', (50, 53))	('gr/gr', 'Gene', (15, 20))	('deletion', 'Var', (21, 29))
46766	23773267	Several single nucleotide polymorphisms (SNPs) are associated with increased TGCT risk in humans.	('single nucleotide polymorphisms', 'Var', (8, 39))	('humans', 'Species', '9606', (90, 96))	('TGCT', 'Disease', (77, 81))
46769	23773267	Certain mutations in the Dead End 1 (Dnd1) gene are potent modifiers of TGCT susceptibility in both mice and rats.	('mice', 'Species', '10090', (100, 104))	('Dnd1', 'Gene', (37, 41))	('mutations', 'Var', (8, 17))	('Dead End 1', 'Gene', (25, 35))	('modifiers', 'Reg', (59, 68))	('TGCT', 'Disease', (72, 76))	('rats', 'Species', '10116', (109, 113))	('Dead End 1', 'Gene', '213236', (25, 35))
46770	23773267	In the mouse, the spontaneous Dnd1Ter mutation significantly increases TGCT susceptibility in the 129 family of inbred mouse strains.	('mouse', 'Species', '10090', (119, 124))	('mouse', 'Species', '10090', (7, 12))	('Dnd1Ter', 'Gene', (30, 37))	('mutation', 'Var', (38, 46))	('increases', 'PosReg', (61, 70))	('TGCT susceptibility', 'MPA', (71, 90))
46771	23773267	In particular, Dnd1Ter increases occurrence of TGCT-affected males from a baseline of ~5% in the 129S1/SvImJ strain to 17% in Dnd1+/Ter heterozygotes and 94% in Dnd1Ter/Ter homozygotes.	('Dnd1Ter/Ter', 'Gene', '213236', (161, 172))	('increases', 'PosReg', (23, 32))	('Dnd1Ter', 'Var', (15, 22))	('Dnd1Ter/Ter', 'Gene', (161, 172))
46774	23773267	In the rat, a spontaneous mutation has been identified where a G to A substitution in exon 4 produces a premature stop codon that is thought to result in a 62 amino acid truncation at the C-terminus of the DND1 protein (Figure 1, see also).	('G to A substitution', 'Var', (63, 82))	('rat', 'Species', '10116', (7, 10))	('truncation at the C-terminus', 'MPA', (170, 198))	('result in', 'Reg', (144, 153))	('substitution', 'Var', (70, 82))
46775	23773267	This mutation leads to germ cell tumors in males and females as well as to spontaneous metastases.	('germ cell tumor', 'Phenotype', 'HP:0100728', (23, 38))	('metastases', 'Disease', (87, 97))	('germ cell tumors', 'Phenotype', 'HP:0100728', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('leads to', 'Reg', (14, 22))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('mutation', 'Var', (5, 13))
46776	23773267	In humans, sequencing of TGCT candidate genes in several large studies failed to detect a significant number of DND1 mutations.	('mutations', 'Var', (117, 126))	('humans', 'Species', '9606', (3, 9))	('DND1', 'Gene', (112, 116))
46777	23773267	Of the two SNPs that were identified, one (Glu86Ala) is located within the conserved RRM of DND1 (Glu86Ala).	('Glu86Ala', 'Var', (98, 106))	('Glu86Ala', 'SUBSTITUTION', 'None', (98, 106))	('Glu86Ala', 'Var', (43, 51))	('Glu86Ala', 'SUBSTITUTION', 'None', (43, 51))
46778	23773267	Dnd1 shares significant sequence similarity with A1cf, a gene that encodes the RNA binding subunit of the Apobec1 cytidine deaminase that edits specific sites in specific mRNAs.	('A1cf', 'Gene', (49, 53))	('Apobec1', 'Gene', '11810', (106, 113))	('edits', 'Var', (138, 143))	('Dnd1', 'Gene', (0, 4))	('A1cf', 'Gene', '69865', (49, 53))	('Apobec1', 'Gene', (106, 113))
46779	23773267	Interestingly, DND1 blocks access of specific miRNAs to their 3' target in mRNAs such as p27, LATS2 and TDRD7.	('p27', 'Gene', (89, 92))	('TDRD7', 'Gene', '100121', (104, 109))	('blocks', 'NegReg', (20, 26))	('access', 'MPA', (27, 33))	('LATS2', 'Gene', '50523', (94, 99))	('DND1', 'Var', (15, 19))	('TDRD7', 'Gene', (104, 109))	('p27', 'Gene', '22428', (89, 92))	('LATS2', 'Gene', (94, 99))
46783	23773267	In zebrafish, ATPase activity has been attributed to a variant of this motif in Dnd1.	('Dnd1', 'Gene', (80, 84))	('variant', 'Var', (55, 62))	('zebrafish', 'Species', '7955', (3, 12))	('ATPase', 'Protein', (14, 20))	('activity', 'MPA', (21, 29))
46788	23773267	To test whether TGCT susceptibility depends on the nature of Dnd1 mutations, we generated a line of 129/SvImJ-DndKO mice.	('mutations', 'Var', (66, 75))	('mice', 'Species', '10090', (116, 120))	('rat', 'Species', '10116', (84, 87))	('Dnd1', 'Gene', (61, 65))
46790	23773267	We therefore tested whether Dnd1Ter affects intestinal tumorigenesis and found that Dnd1Ter significantly increases polyp number and burden in Apc+/Min mice.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('burden', 'CPA', (133, 139))	('tumor', 'Disease', (55, 60))	('Apc', 'Gene', (143, 146))	('Dnd1Ter', 'Var', (84, 91))	('mice', 'Species', '10090', (152, 156))	('increases', 'PosReg', (106, 115))	('Apc', 'Gene', '11789', (143, 146))	('polyp number', 'Disease', 'MESH:D011127', (116, 128))	('polyp number', 'Disease', (116, 128))
46799	23773267	To test this hypothesis, we intercrossed mice heterozygous for the Dnd1KO and Dnd1Ter mutations and examined occurrence of the four genotypic classes among the resulting offspring (Table 4).	('Dnd1Ter', 'Gene', (78, 85))	('mutations', 'Var', (86, 95))	('Dnd1KO', 'Gene', (67, 73))	('mice', 'Species', '10090', (41, 45))
46802	23773267	These results confirm that Dnd1KO but not Dnd1Ter mice showed reduced Dnd1 mRNA levels.	('mice', 'Species', '10090', (50, 54))	('Dnd1KO', 'Var', (27, 33))	('reduced', 'NegReg', (62, 69))	('Dnd1 mRNA levels', 'MPA', (70, 86))
46803	23773267	(This rate for Dnd1+/Ter males in our colony is significantly higher than published reports.	('higher', 'PosReg', (62, 68))	('Dnd1+/Ter', 'Var', (15, 24))	('rat', 'Species', '10116', (6, 9))
46811	23773267	Although Dnd1Ter is a potent modifier of TGCT susceptibility, we speculated that the tumorigenic properties of Dnd1Ter may also be relevant in the intestine where Dnd1 is also expressed.	('tumor', 'Disease', (85, 90))	('Dnd1Ter', 'Var', (111, 118))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
46816	23773267	Similarly, total polyp mass was also significantly elevated from 192.2 +- 11.6 mm2 in Apc+/MinDnd1+/+ mice to 352.6 +- 11.4 mm2 in Apc+/Min: Dnd1+/Ter males (t = 4.5, p<0.0001; two-tailed t-test; Figure 3B), suggesting that a single copy of Dnd1Ter exacerbates intestinal polyp initiation and development in mice that are genetically susceptible to intestinal polyposis and that the action of Dnd1Ter is not limited to TGCTs.	('mice', 'Species', '10090', (102, 106))	('intestinal polyposis', 'Disease', 'MESH:D044483', (349, 369))	('intestinal polyp initiation', 'Disease', (261, 288))	('single copy', 'Var', (226, 237))	('elevated', 'PosReg', (51, 59))	('Dnd1Ter', 'Gene', (241, 248))	('intestinal polyposis', 'Disease', (349, 369))	('Apc', 'Gene', (131, 134))	('Apc', 'Gene', '11789', (131, 134))	('intestinal polyp', 'Phenotype', 'HP:0005266', (349, 365))	('exacerbates', 'PosReg', (249, 260))	('intestinal polyp', 'Phenotype', 'HP:0005266', (261, 277))	('development', 'CPA', (293, 304))	('exacerbates intestinal polyp', 'Phenotype', 'HP:0200008', (249, 277))	('intestinal polyp initiation', 'Disease', 'MESH:D007417', (261, 288))	('Apc', 'Gene', '11789', (86, 89))	('Apc', 'Gene', (86, 89))	('intestinal polyposis', 'Phenotype', 'HP:0200008', (349, 369))	('men', 'Species', '9606', (300, 303))	('mice', 'Species', '10090', (308, 312))
46818	23773267	Discovery of the gr/gr deletion, together with validated SNPs in the ATF7IP, BAK1, DMRT1, KITLG, SPRY4, TERT, HPGDS, MAD1L1, RFWD3, TEX14, RAD51C, PPM1E, DAZL and PRDM14.	('RFWD3', 'Gene', '234736', (125, 130))	('DAZL', 'Gene', (154, 158))	('ATF7IP', 'Gene', (69, 75))	('BAK1', 'Gene', (77, 81))	('PRDM14', 'Gene', '383491', (163, 169))	('MAD1L1', 'Gene', '17120', (117, 123))	('MAD1L1', 'Gene', (117, 123))	('DMRT1', 'Gene', (83, 88))	('PPM1E', 'Gene', (147, 152))	('deletion', 'Var', (23, 31))	('HPGDS', 'Gene', '54486', (110, 115))	('PRDM14', 'Gene', (163, 169))	('DAZL', 'Gene', '13164', (154, 158))	('PPM1E', 'Gene', '320472', (147, 152))	('SPRY4', 'Gene', '24066', (97, 102))	('TEX14', 'Gene', (132, 137))	('TERT', 'Gene', '21752', (104, 108))	('RFWD3', 'Gene', (125, 130))	('KITLG', 'Gene', '17311', (90, 95))	('KITLG', 'Gene', (90, 95))	('TEX14', 'Gene', '83560', (132, 137))	('DMRT1', 'Gene', '50796', (83, 88))	('SPRY4', 'Gene', (97, 102))	('TERT', 'Gene', (104, 108))	('RAD51C', 'Gene', '114714', (139, 145))	('ATF7IP', 'Gene', '54343', (69, 75))	('RAD51C', 'Gene', (139, 145))	('HPGDS', 'Gene', (110, 115))	('gr/gr', 'Gene', (17, 22))	('BAK1', 'Gene', '12018', (77, 81))
46821	23773267	But much remains to be learned about the nature of mutations in these genes that lead to tumorigenesis and about the ways that these molecular changes disrupt these pathways.	('lead to', 'Reg', (81, 88))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('disrupt', 'Reg', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
46828	23773267	Although DND1Ter appears to be a novel variant that increases TGCT risk, its tumorigenic effects are limited to the 129 strain of mice, which is not surprising, since this is the mouse strain that is susceptible to spontaneous TGCTs.	('mouse', 'Species', '10090', (179, 184))	('mice', 'Species', '10090', (130, 134))	('DND1Ter', 'Var', (9, 16))	('increases', 'PosReg', (52, 61))	('TGCT', 'Disease', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
46831	23773267	The 129 strain interacts positively with DND1Ter to increase TGCT risk, whereas C56BL/6J and other strains only exhibit phenotypes related to some but not all aspects of mutations in genes such as Kit, Kitl, Pten, Eif2s2I and other TGCT modifier genes, but not TGCTs.	('TGCT', 'Disease', (61, 65))	('Kitl', 'Gene', '17311', (202, 206))	('Pten', 'Gene', (208, 212))	('increase', 'PosReg', (52, 60))	('mutations', 'Var', (170, 179))	('Kit', 'Gene', (197, 200))	('Pten', 'Gene', '19211', (208, 212))	('Kitl', 'Gene', (202, 206))	('Eif2s2', 'Gene', (214, 220))	('Eif2s2', 'Gene', '67204', (214, 220))	('DND1Ter', 'Var', (41, 48))
46832	23773267	However, the tumorigenic effects of Dnd1Ter are not limited to PGC transformation in the 129 strain mice.	('tumor', 'Disease', (13, 18))	('mice', 'Species', '10090', (100, 104))	('Dnd1Ter', 'Var', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
46833	23773267	C57BL/6J mice with the ApcMin mutation are highly susceptible to intestinal polyps.	('intestinal polyps', 'Disease', 'MESH:D007417', (65, 82))	('susceptible', 'Reg', (50, 61))	('mutation', 'Var', (30, 38))	('Apc', 'Gene', (23, 26))	('intestinal polyps', 'Disease', (65, 82))	('intestinal polyps', 'Phenotype', 'HP:0005266', (65, 82))	('Apc', 'Gene', '11789', (23, 26))	('mice', 'Species', '10090', (9, 13))	('intestinal polyp', 'Phenotype', 'HP:0005266', (65, 81))
46836	23773267	Embryonic lethality is the usual interpretation for biased genotypic distributions in intercrosses, especially with complete loss of homozygous mutants.	('mutants', 'Var', (144, 151))	('Embryonic lethality', 'Disease', (0, 19))	('loss', 'NegReg', (125, 129))	('Embryonic lethality', 'Disease', 'MESH:D020964', (0, 19))
46839	23773267	Interestingly, genetically and functionally related genes also show biased segregation, including Apobec1 and A1cf The contrasting effects of different classes of Dnd1 mutations may explain why sequencing studies failed to yield mutations within DND1 in human TGCT cases.	('A1cf', 'Gene', (110, 114))	('Dnd1', 'Gene', (163, 167))	('TGCT', 'Disease', (260, 264))	('human', 'Species', '9606', (254, 259))	('mutations', 'Var', (229, 238))	('Apobec1', 'Gene', (98, 105))	('A1cf', 'Gene', '69865', (110, 114))	('DND1', 'Gene', (246, 250))	('Apobec1', 'Gene', '11810', (98, 105))	('mutations', 'Var', (168, 177))
46840	23773267	Complete loss of DND1 function is not sufficient to promote TGCT formation, even on the TGCT-susceptible 129S1/SvImJ inbred genetic background; reducing the chances that DND1 mutations play a significant role in human TGCTs.	('DND1', 'Gene', (17, 21))	('human', 'Species', '9606', (212, 217))	('loss', 'NegReg', (9, 13))	('DND1', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('TGCT', 'Disease', (60, 64))	('promote', 'PosReg', (52, 59))
46842	23773267	Loss of Dnd1 inhibits PGC migration and results in PGC deficiency, but did not produce TGCTs.	('PGC', 'Protein', (22, 25))	('PGC deficiency', 'Disease', (51, 65))	('Dnd1', 'Gene', (8, 12))	('PGC deficiency', 'Disease', 'MESH:D007153', (51, 65))	('results in', 'Reg', (40, 50))	('rat', 'Species', '10116', (29, 32))	('Loss', 'Var', (0, 4))	('inhibits', 'NegReg', (13, 21))
46845	23773267	The role of DND1Ter in TGCT formation is further supported by recent results in a rat study where a spontaneous mutation producing a premature stop codon in exon 4, similar to DND1Ter, resulted in TGCTs.	('mutation', 'Var', (112, 120))	('TGCTs', 'Disease', (197, 202))	('premature stop codon', 'MPA', (133, 153))	('rat', 'Species', '10116', (82, 85))	('resulted in', 'Reg', (185, 196))
46846	23773267	To date, human DND1 mutations have not yet been reported that yield a similarly truncated DND1 protein.	('DND1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('human', 'Species', '9606', (9, 14))
46847	23773267	Through intercrosses with mice carrying a complete loss of function Dnd1KO allele our study showed that DND1 is necessary for embryonic viability and results in abnormal allelic segregation.	('DND1', 'Var', (104, 108))	('allelic segregation', 'MPA', (170, 189))	('Dnd1KO', 'Gene', (68, 74))	('results in abnormal', 'Reg', (150, 169))	('mice', 'Species', '10090', (26, 30))
46849	23773267	These results demonstrate that Dnd1Ter enhances tumorigenesis in two separate mouse models of cancer.	('Dnd1Ter', 'Var', (31, 38))	('tumor', 'Disease', (48, 53))	('enhances', 'PosReg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Disease', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mouse', 'Species', '10090', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('rat', 'Species', '10116', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
46851	23773267	ES cells with a targeted deletion of Dnd1 were generated from 129S6 mice by the Intrexon Corporation, (Blacksburg, VA).	('mice', 'Species', '10090', (68, 72))	('rat', 'Species', '10116', (94, 97))	('Dnd1', 'Gene', (37, 41))	('deletion', 'Var', (25, 33))	('rat', 'Species', '10116', (51, 54))
46886	23152360	Germ-cell cancer (GCC), cytogenetically characterized by abnormalities of 12p, is the most frequent malignancy in male Caucasians aged 15-40 years.	('malignancy', 'Disease', 'MESH:D009369', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Germ-cell cancer', 'Phenotype', 'HP:0100728', (0, 16))	('malignancy', 'Disease', (100, 110))	('abnormalities', 'Var', (57, 70))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('GCC', 'Phenotype', 'HP:0100728', (18, 21))
47064	22381132	In another study, predictors of distress in male BRCA1/2 carriers at 1 year included higher baseline cancer-specific distress and being unmarried.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('higher', 'PosReg', (85, 91))	('cancer', 'Disease', (101, 107))	('BRCA1/2', 'Gene', '672;675', (49, 56))	('distress', 'MPA', (32, 40))	('carriers', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA1/2', 'Gene', (49, 56))
47091	22381132	The researcher used a semi-structured script to guide the participant towards actively identifying, with differently colored symbols, the individuals who filled various social roles in their lives from within and outside the biological family-informational (blue dots), tangible (green dots), emotional (yellow dots), and spiritual/religious (red dots).	('green dots', 'Var', (280, 290))	('participant', 'Species', '9606', (58, 69))	('blue dots', 'Var', (258, 267))
47195	22381132	In a study of long-term distress in a sub-set of men with BRCA1/2 mutations, predictors of distress included higher baseline distress and being unmarried, whereas, most of our distressed participants were married and all but one were affected with TC.	('mutations', 'Var', (66, 75))	('men', 'Species', '9606', (49, 52))	('BRCA1/2', 'Gene', '672;675', (58, 65))	('TC', 'Phenotype', 'HP:0010788', (248, 250))	('higher', 'PosReg', (109, 115))	('baseline distress', 'MPA', (116, 133))	('BRCA1/2', 'Gene', (58, 65))	('participants', 'Species', '9606', (187, 199))
47257	22381132	This work was supported by the Division of Cancer Epidemiology and Genetics of the National Cancer Institute within the Intramural Research Programs of the U.S. National Institutes of Health, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD, USA.	('Cancer', 'Disease', (43, 49))	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('N02-CP-65504', 'Var', (246, 258))	('Cancer', 'Disease', (92, 98))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('NO2-CP-11019-50', 'Var', (226, 241))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
47352	20705572	used the United States Department of Defense Serum Repository to conduct a large nested case-control study that reported an association between persistent organochlorines and testicular cancer.	('testicular cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('testicular cancer', 'Phenotype', 'HP:0010788', (175, 192))	('persistent', 'Var', (144, 154))	('testicular cancer', 'Disease', 'MESH:D013736', (175, 192))	('men', 'Species', '9606', (29, 32))	('organochlorines', 'Chemical', 'MESH:D006843', (155, 170))
47362	20705572	It has also been suggested that DDT may be a tumor promoter through its strong inhibition of intercellular communication.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('intercellular communication', 'Pathway', (93, 120))	('DDT', 'Var', (32, 35))	('DDT', 'Chemical', 'MESH:D003634', (32, 35))	('inhibition', 'NegReg', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
47373	19627379	Using data from 568 cases and 698 controls enrolled in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study, we examined associations between TGCT and POPs, including p,p'-DDE, chlordane-related compounds, and polychlorinated biphenyls (PCBs), modified by polymorphisms in 5 hormone-metabolizing genes (CYP17A1, CYP1A1, HSD17B1, HSD17B4, and AR).	('Testicular Tumor', 'Phenotype', 'HP:0010788', (77, 93))	('chlordane', 'Chemical', 'MESH:D002706', (210, 219))	('polymorphisms', 'Var', (289, 302))	('POPs', 'Chemical', '-', (184, 188))	('associations', 'Interaction', (154, 166))	('AR', 'Gene', '367', (375, 377))	('men', 'Species', '9606', (71, 74))	('HSD17B4', 'Gene', '3295', (362, 369))	('HSD17B4', 'Gene', (362, 369))	('CYP1A1', 'Gene', (345, 351))	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (243, 268))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (200, 208))	('HSD17B1', 'Gene', '3292', (353, 360))	('HSD17B1', 'Gene', (353, 360))	('CYP1A1', 'Gene', '1543', (345, 351))	('men', 'Species', '9606', (101, 104))	('PCBs', 'Chemical', 'MESH:D011078', (270, 274))	('Tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CYP17A1', 'Gene', (336, 343))	('CYP17A1', 'Gene', '1586', (336, 343))
47374	19627379	Two polymorphisms in CYP1A1, rs1456432 and rs7495708, modified the association between trans-nonachlor and total chlordanes and TGCT risk.	('CYP1A1', 'Gene', '1543', (21, 27))	('rs1456432', 'Mutation', 'rs1456432', (29, 38))	('rs7495708', 'Var', (43, 52))	('modified', 'Reg', (54, 62))	('chlordanes', 'Chemical', 'MESH:D002706', (113, 123))	('TGCT', 'Disease', (128, 132))	('rs1456432', 'Var', (29, 38))	('rs7495708', 'Mutation', 'rs7495708', (43, 52))	('association', 'Interaction', (67, 78))	('CYP1A1', 'Gene', (21, 27))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (87, 102))
47375	19627379	Among men with a minor allele for rs1456432, those with the highest quartiles had an increased risk of TGCT (OR=1.90, 95% CI, 1.01-3.56) compare to those with the lowest; there were no increased risk among men with the homozygous major allele genotype (p-interaction=0.024).	('rs1456432', 'Var', (34, 43))	('TGCT', 'Disease', (103, 107))	('rs1456432', 'Mutation', 'rs1456432', (34, 43))	('men', 'Species', '9606', (206, 209))	('men', 'Species', '9606', (6, 9))
47377	19627379	HSD17B4 rs384346 modified the associations between TGCT risk and PCB-118 and PCB-138 concentrations: the 45-55% reductions in TGCT risk for men with the highest quartiles compared to the lowest quartiles were only present in those who had a major homozygous allele genotype (p-interactions<0.04).	('men', 'Species', '9606', (140, 143))	('rs384346', 'Var', (8, 16))	('TGCT', 'Disease', (126, 130))	('HSD17B4', 'Gene', '3295', (0, 7))	('reductions', 'NegReg', (112, 122))	('TGCT', 'Disease', (51, 55))	('rs384346', 'Mutation', 'rs384346', (8, 16))	('HSD17B4', 'Gene', (0, 7))	('associations', 'Interaction', (30, 42))	('PCB-138', 'Chemical', '-', (77, 84))	('modified', 'Reg', (17, 25))	('PCB-118', 'Chemical', '-', (65, 72))
47378	19627379	Thus, there are suggestions that certain CYP1A1 and HSD17B4 polymorphisms may modify the associations between POPs and TGCT risk.	('associations', 'Interaction', (89, 101))	('TGCT', 'Disease', (119, 123))	('polymorphisms', 'Var', (60, 73))	('CYP1A1', 'Gene', '1543', (41, 47))	('modify', 'Reg', (78, 84))	('HSD17B4', 'Gene', '3295', (52, 59))	('POPs', 'Chemical', '-', (110, 114))	('CYP1A1', 'Gene', (41, 47))	('HSD17B4', 'Gene', (52, 59))	('POPs', 'Disease', (110, 114))
47385	19627379	Genetic variation in these genes and risk of TGCT has been previously studied by our group; however, there was only a suggestion of an association between a CYP1A1 polymorphism and nonseminomatous testicular germ cell tumors.	('polymorphism', 'Var', (164, 176))	('CYP1A1', 'Gene', '1543', (157, 163))	('germ cell tumor', 'Phenotype', 'HP:0100728', (208, 223))	('nonseminomatous testicular germ cell tumors', 'Disease', (181, 224))	('nonseminomatous testicular germ cell tumors', 'Disease', 'MESH:C537844', (181, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('germ cell tumors', 'Phenotype', 'HP:0100728', (208, 224))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('CYP1A1', 'Gene', (157, 163))
47403	19627379	The selection of SNPs in 5 candidate genes (CYP1A1, CYP17A1, HSD17B1, HSD17B4, and AR) in the hormone-metabolizing pathway has been previously described in detail.	('AR', 'Gene', '367', (83, 85))	('CYP17A1', 'Gene', (52, 59))	('CYP17A1', 'Gene', '1586', (52, 59))	('SNPs', 'Var', (17, 21))	('HSD17B4', 'Gene', '3295', (70, 77))	('HSD17B4', 'Gene', (70, 77))	('CYP1A1', 'Gene', (44, 50))	('HSD17B1', 'Gene', '3292', (61, 68))	('HSD17B1', 'Gene', (61, 68))	('CYP1A1', 'Gene', '1543', (44, 50))
47407	19627379	There was >98% concordance for all SNPs in quality controls samples, except for CYP1A1 rs24272299 (97%), rs4646903 (97%), HSD17B1 rs2830 (97%), and HSD17B4 rs28943585 (94%).	('rs24272299', 'Mutation', 'rs24272299', (87, 97))	('CYP1A1', 'Gene', (80, 86))	('rs4646903', 'Mutation', 'rs4646903', (105, 114))	('rs24272299', 'Var', (87, 97))	('CYP1A1', 'Gene', '1543', (80, 86))	('HSD17B1', 'Gene', '3292', (122, 129))	('rs28943585', 'Var', (156, 166))	('rs2830', 'Mutation', 'rs2830', (130, 136))	('HSD17B4', 'Gene', '3295', (148, 155))	('rs4646903', 'Var', (105, 114))	('rs2830', 'Var', (130, 136))	('HSD17B1', 'Gene', (122, 129))	('rs28943585', 'Mutation', 'rs28943585', (156, 166))	('HSD17B4', 'Gene', (148, 155))
47408	19627379	All genotypes in the autosomal chromosomes (CYP1A1, CYP17A1, HSD17B1, and HSD17B4) were in Hardy-Weinberg equilibrium among the control population except for HSD17B1 rs2830 (p<0.001).	('HSD17B4', 'Gene', '3295', (74, 81))	('CYP17A1', 'Gene', (52, 59))	('HSD17B4', 'Gene', (74, 81))	('CYP17A1', 'Gene', '1586', (52, 59))	('rs2830', 'Mutation', 'rs2830', (166, 172))	('HSD17B1', 'Gene', '3292', (158, 165))	('CYP1A1', 'Gene', (44, 50))	('HSD17B1', 'Gene', '3292', (61, 68))	('rs2830', 'Var', (166, 172))	('HSD17B1', 'Gene', (158, 165))	('HSD17B1', 'Gene', (61, 68))	('CYP1A1', 'Gene', '1543', (44, 50))
47412	19627379	For our primary hypothesis, the POPs of interest included those that were found to be associated with TGCT risk: cis-nonachlor, trans-nonachlor, p,p'-DDE, PCB-118, PCB-138, PCB-153, PCB-156, PCB-163, PCB-170, PCB-180, and PCB-187 (Table 1).	('PCB-163', 'Var', (191, 198))	('PCB-118', 'Var', (155, 162))	('PCB-187', 'Chemical', '-', (222, 229))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (113, 126))	('POPs', 'Chemical', '-', (32, 36))	('PCB-138', 'Chemical', '-', (164, 171))	('PCB-170', 'Var', (200, 207))	('PCB-163', 'Chemical', '-', (191, 198))	('PCB-170', 'Chemical', '-', (200, 207))	('PCB-138', 'Var', (164, 171))	('PCB-153', 'Chemical', '-', (173, 180))	('PCB-180', 'Chemical', '-', (209, 216))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (145, 153))	('PCB-153', 'Var', (173, 180))	('PCB-118', 'Chemical', '-', (155, 162))	('TGCT', 'Disease', (102, 106))	('cis-nonachlor', 'Var', (113, 126))	('PCB-156', 'Chemical', '-', (182, 189))	('trans-nonachlor', 'Var', (128, 143))	('PCB-156', 'Var', (182, 189))	('PCB-180', 'Gene', (209, 216))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (128, 143))
47413	19627379	A secondary, exploratory hypothesis examined interactions between hormone-metabolizing SNPs and POPs that were not associated with TGCT risk (oxychlordane, p,p'-DDT, beta-hexachlorocyclohexane, mirex, PCB-99, PCB-101, and PCB-183).	('beta-hexachlorocyclohexane', 'Chemical', 'MESH:C023888', (166, 192))	('PCB-183', 'Chemical', '-', (222, 229))	('PCB-101', 'Chemical', '-', (209, 216))	("p,p'-DDT", 'Chemical', '-', (156, 164))	('PCB-99', 'Gene', (201, 207))	('beta-hexachlorocyclohexane', 'Var', (166, 192))	('interactions', 'Interaction', (45, 57))	('POPs', 'Chemical', '-', (96, 100))	('PCB-99', 'Chemical', '-', (201, 207))	('mirex', 'Chemical', 'MESH:D008917', (194, 199))	('TGCT', 'Disease', (131, 135))	('oxychlordane', 'Chemical', 'MESH:C008743', (142, 154))	('PCB-101', 'Gene', (209, 216))	('PCB-183', 'Gene', (222, 229))
47422	19627379	Men with the CYP1A1 rs4886605 AA genotype had lower oxychlordane concentrations than those with the GG genotype (9.20 ng/g lipid for AA versus 11.04 ng/g lipid for GG, p-trend=0.043).	('lipid', 'Chemical', 'MESH:D008055', (154, 159))	('lipid', 'Chemical', 'MESH:D008055', (123, 128))	('rs4886605 AA', 'Var', (20, 32))	('lower', 'NegReg', (46, 51))	('rs4886605', 'Mutation', 'rs4886605', (20, 29))	('oxychlordane concentrations', 'MPA', (52, 79))	('CYP1A1', 'Gene', (13, 19))	('CYP1A1', 'Gene', '1543', (13, 19))	('oxychlordane', 'Chemical', 'MESH:C008743', (52, 64))	('Men', 'Species', '9606', (0, 3))
47424	19627379	There were also trends in PCB-118, PCB-138, and PCB-187 concentrations associated with HSD17B4 genotype.	('PCB-187', 'Gene', (48, 55))	('PCB-138', 'Chemical', '-', (35, 42))	('genotype', 'Var', (95, 103))	('PCB-118', 'Chemical', '-', (26, 33))	('HSD17B4', 'Gene', '3295', (87, 94))	('HSD17B4', 'Gene', (87, 94))	('PCB-187', 'Chemical', '-', (48, 55))
47425	19627379	Men with the HSD17B4 rs2455463 GG genotype had lower PCB118 concentrations than men with the CC genotype (9.80 versus 11.24 ng/g lipid, respectively, p-trend=0.035).	('lower', 'NegReg', (47, 52))	('HSD17B4', 'Gene', '3295', (13, 20))	('rs2455463', 'Mutation', 'rs2455463', (21, 30))	('PCB118 concentrations', 'MPA', (53, 74))	('HSD17B4', 'Gene', (13, 20))	('men', 'Species', '9606', (80, 83))	('rs2455463', 'Var', (21, 30))	('PCB118', 'Chemical', 'MESH:C070055', (53, 59))	('lipid', 'Chemical', 'MESH:D008055', (129, 134))	('Men', 'Species', '9606', (0, 3))
47426	19627379	Men had higher PCB-138 concentrations if they had the AA genotype for HSD17B4 rs25640 compared to the GG genotype (p-trend=0.049), and the GG genotype for HSD17B4 rs246899 compared to the AA genotype (p-trend=0.041).	('rs25640', 'Mutation', 'rs25640', (78, 85))	('PCB-138', 'Chemical', '-', (15, 22))	('HSD17B4', 'Gene', '3295', (70, 77))	('rs25640', 'Var', (78, 85))	('HSD17B4', 'Gene', '3295', (155, 162))	('HSD17B4', 'Gene', (70, 77))	('HSD17B4', 'Gene', (155, 162))	('rs246899', 'Mutation', 'rs246899', (163, 171))	('PCB-138 concentrations', 'MPA', (15, 37))	('higher', 'PosReg', (8, 14))	('Men', 'Species', '9606', (0, 3))
47427	19627379	Men also had higher PCB187 concentrations if they had the TT genotype for HSD17B4 rs28943585 compared to the CC genotype (p-trend=0.047), and the GG genotype for HSD17B4 rs246899 compared to the AA genotype (p-trend=0.015).	('HSD17B4', 'Gene', '3295', (74, 81))	('rs28943585', 'Mutation', 'rs28943585', (82, 92))	('PCB187', 'Chemical', '-', (20, 26))	('HSD17B4', 'Gene', (74, 81))	('rs246899', 'Var', (170, 178))	('Men', 'Species', '9606', (0, 3))	('higher', 'PosReg', (13, 19))	('rs246899', 'Mutation', 'rs246899', (170, 178))	('HSD17B4', 'Gene', '3295', (162, 169))	('rs28943585', 'Var', (82, 92))	('PCB187 concentrations', 'MPA', (20, 41))	('HSD17B4', 'Gene', (162, 169))
47429	19627379	Similarly, HapMap found that the CYP1A1 SNPs rs7495708 (-4404G>A) and rs4886605 (-10549G>A) were highly correlated (r2=0.92) and had a high level of linkage disequilibrium (D'=1.0).	('rs7495708 (-4404G>A', 'Var', (45, 64))	('-10549G>A', 'Var', (81, 90))	('rs7495708', 'Mutation', 'rs7495708', (45, 54))	('rs4886605 (-10549G>A', 'Var', (70, 90))	('CYP1A1', 'Gene', (33, 39))	('-10549G>A', 'Mutation', 'rs4886605', (81, 90))	('-4404G>A', 'Mutation', 'rs7495708', (56, 64))	('CYP1A1', 'Gene', '1543', (33, 39))	('rs4886605', 'Mutation', 'rs4886605', (70, 79))
47430	19627379	As the associations with TGCT risk were similar for these correlated pairs of SNPs, only POP associations with TGCT risk, modified by rs1456432 and rs7495708, are presented in Table 3.	('rs7495708', 'Mutation', 'rs7495708', (148, 157))	('TGCT', 'Disease', (111, 115))	('rs1456432', 'Mutation', 'rs1456432', (134, 143))	('rs7495708', 'Var', (148, 157))	('rs1456432', 'Var', (134, 143))
47432	19627379	For both the CYP1A1 rs1456432 and rs7495708 SNPs, among men with the homozygous major allele genotype, there were no associations between quartiles of trans-nonachlor and total chlordanes and TGCT risk.	('TGCT', 'Disease', (192, 196))	('rs1456432', 'Var', (20, 29))	('chlordanes', 'Chemical', 'MESH:D002706', (177, 187))	('men', 'Species', '9606', (56, 59))	('rs7495708', 'Mutation', 'rs7495708', (34, 43))	('rs7495708', 'Var', (34, 43))	('rs1456432', 'Mutation', 'rs1456432', (20, 29))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (151, 166))	('CYP1A1', 'Gene', (13, 19))	('CYP1A1', 'Gene', '1543', (13, 19))
47433	19627379	Among men with any minor allele for the CYP1A1 rs1456432 SNP (AG or GG genotype), those with the highest quartile of trans-nonachlor had a 1.90 times (95% CI, 1.01-3.56) the risk of TGCT compared with men with the lowest (p-interaction=0.024).	('men', 'Species', '9606', (201, 204))	('TGCT', 'Disease', (182, 186))	('rs1456432', 'Mutation', 'rs1456432', (47, 56))	('CYP1A1', 'Gene', (40, 46))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (117, 132))	('rs1456432 SNP', 'Var', (47, 60))	('CYP1A1', 'Gene', '1543', (40, 46))	('men', 'Species', '9606', (6, 9))
47435	19627379	There was no effect modification by the CYP1A1 rs1456432 SNP for cis-nonachlor (data not shown).	('cis-nonachlor', 'MPA', (65, 78))	('rs1456432', 'Mutation', 'rs1456432', (47, 56))	('CYP1A1', 'Gene', (40, 46))	('rs1456432', 'Var', (47, 56))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (65, 78))	('CYP1A1', 'Gene', '1543', (40, 46))
47436	19627379	Among men with any minor allele for the CYP1A1 rs7495708 SNP (GA or AA genotype), those with the highest quartile of trans-nonachlor had an almost 2-fold (OR=1.92, 95% CI, 1.03-3.58) increased risk of TGCT compared with men with the lowest (p-interaction=0.014).	('rs7495708', 'Mutation', 'rs7495708', (47, 56))	('TGCT', 'Disease', (201, 205))	('CYP1A1', 'Gene', (40, 46))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (117, 132))	('CYP1A1', 'Gene', '1543', (40, 46))	('rs7495708 SNP', 'Var', (47, 60))	('men', 'Species', '9606', (220, 223))	('men', 'Species', '9606', (6, 9))
47440	19627379	HSD17B4 rs384346 was the only SNP to modify the association of TGCT risk with PCB-118 and PCB-138 concentrations.	('rs384346', 'Var', (8, 16))	('HSD17B4', 'Gene', '3295', (0, 7))	('PCB-138', 'Chemical', '-', (90, 97))	('association', 'Interaction', (48, 59))	('rs384346', 'Mutation', 'rs384346', (8, 16))	('TGCT', 'Disease', (63, 67))	('HSD17B4', 'Gene', (0, 7))	('PCB-118', 'Chemical', '-', (78, 85))
47441	19627379	Among men with the homozygous major allele genotype (AA), there was a statistically significant reduction in risk with the highest PCB-118 and PCB-138 quartiles (p-trends<0.001); men with the highest quartile of PCB-118 had an almost 50% reduction in TGCT risk (OR=0.46, 95% CI, 0.31-0.70) compared to men with the lowest.	('men', 'Species', '9606', (179, 182))	('TGCT', 'Disease', (251, 255))	('PCB-118', 'Var', (212, 219))	('men', 'Species', '9606', (302, 305))	('PCB-118', 'Chemical', '-', (131, 138))	('reduction', 'NegReg', (238, 247))	('PCB-118', 'Chemical', '-', (212, 219))	('reduction', 'NegReg', (96, 105))	('PCB-138', 'Chemical', '-', (143, 150))	('men', 'Species', '9606', (6, 9))
47443	19627379	Among men with any minor allele for HSD17B4 rs384346, there were no associations between PCB-118 and PCB-138 concentrations and TGCT risk (p-interaction<0.001 for PCB-118 and p-interaction=0.034 for PCB-138).	('HSD17B4', 'Gene', (36, 43))	('PCB-138', 'Chemical', '-', (199, 206))	('PCB-118', 'Chemical', '-', (163, 170))	('PCB-138', 'Gene', (101, 108))	('rs384346', 'Var', (44, 52))	('TGCT', 'Disease', (128, 132))	('PCB-138', 'Chemical', '-', (101, 108))	('PCB-118', 'Chemical', '-', (89, 96))	('rs384346', 'Mutation', 'rs384346', (44, 52))	('PCB-118', 'Gene', (89, 96))	('associations', 'Interaction', (68, 80))	('HSD17B4', 'Gene', '3295', (36, 43))	('men', 'Species', '9606', (6, 9))
47444	19627379	No other interactions between other PCB congeners of interest (PCB-153, PCB-156, PCB-163, PCB170, PCB-180.	('PCB', 'Chemical', 'MESH:D011078', (63, 66))	('PCB170', 'Var', (90, 96))	('PCB-180', 'Chemical', '-', (98, 105))	('PCB-163', 'Var', (81, 88))	('PCB', 'Chemical', 'MESH:D011078', (90, 93))	('PCB', 'Chemical', 'MESH:D011078', (36, 39))	('PCB', 'Chemical', 'MESH:D011078', (72, 75))	('PCB-163', 'Chemical', '-', (81, 88))	('PCB', 'Chemical', 'MESH:D011078', (81, 84))	('PCB170', 'Chemical', 'MESH:C541131', (90, 96))	('interactions', 'Interaction', (9, 21))	('PCB-156', 'Chemical', '-', (72, 79))	('PCB', 'Chemical', 'MESH:D011078', (98, 101))	('PCB-153', 'Chemical', '-', (63, 70))
47447	19627379	HSD17B4 rs28943585 and rs28943586 modified the association between PCB-99 concentrations and TGCT risk (p-interactions<0.003).	('rs28943585', 'Var', (8, 18))	('HSD17B4', 'Gene', '3295', (0, 7))	('HSD17B4', 'Gene', (0, 7))	('PCB-99', 'Gene', (67, 73))	('TGCT', 'Disease', (93, 97))	('PCB-99', 'Chemical', '-', (67, 73))	('rs28943585', 'Mutation', 'rs28943585', (8, 18))	('modified', 'Reg', (34, 42))	('rs28943586', 'Var', (23, 33))	('association', 'Interaction', (47, 58))	('rs28943586', 'Mutation', 'rs28943586', (23, 33))
47448	19627379	Among men with a minor allele for rs28943585, those in the highest quartiles of PCB-99 had a suggestion, although not statistically significant, of a reduced TGCT risk (OR=0.65, 95% CI, 0.31-1.36, p-trend=0.004) compared to men in the lowest quartile; there was no association between PCB-99 concentrations and TGCT risk among men with the homozygote major allele genotype.	('men', 'Species', '9606', (224, 227))	('TGCT', 'Disease', (311, 315))	('rs28943585', 'Mutation', 'rs28943585', (34, 44))	('TGCT', 'Disease', (158, 162))	('PCB-99', 'Chemical', '-', (285, 291))	('PCB-99', 'Chemical', '-', (80, 86))	('men', 'Species', '9606', (327, 330))	('reduced', 'NegReg', (150, 157))	('rs28943585', 'Var', (34, 44))	('PCB-99', 'Gene', (80, 86))	('men', 'Species', '9606', (6, 9))
47449	19627379	Similar associations were seen for rs28943586, which has been shown by HapMap data to be in LD with rs28943585 (r2=1.0, D'=1.0).	('rs28943585', 'Var', (100, 110))	('rs28943586', 'Var', (35, 45))	('rs28943586', 'Mutation', 'rs28943586', (35, 45))	('rs28943585', 'Mutation', 'rs28943585', (100, 110))
47450	19627379	The association between PCB-183 and TGCT risk was also modified by HSD17B4 rs426899.	('HSD17B4', 'Gene', (67, 74))	('PCB-183', 'Chemical', '-', (24, 31))	('association', 'Interaction', (4, 15))	('PCB-183', 'Gene', (24, 31))	('rs426899', 'Var', (75, 83))	('TGCT', 'Disease', (36, 40))	('HSD17B4', 'Gene', '3295', (67, 74))	('rs426899', 'Mutation', 'rs426899', (75, 83))
47452	19627379	No effect modification was observed for TGCT risk associated with oxychlordane, p,p'-DDT, beta-hexachlorocyclohexane, mirex, or PCB-101 (data not shown).	('PCB-101', 'Var', (128, 135))	('mirex', 'Chemical', 'MESH:D008917', (118, 123))	('beta-hexachlorocyclohexane', 'Chemical', 'MESH:C023888', (90, 116))	('beta-hexachlorocyclohexane', 'Var', (90, 116))	('PCB-101', 'Chemical', '-', (128, 135))	('TGCT', 'Disease', (40, 44))	('oxychlordane', 'Chemical', 'MESH:C008743', (66, 78))	("p,p'-DDT", 'Chemical', '-', (80, 88))
47454	19627379	In our population, we previously reported that among various organochlorine pesticide exposures, men with the highest quartiles of trans-nonachlor and total chlordanes had an approximate 1.5-fold increased risk of TGCT compared to men with the lowest quartiles.	('increased', 'PosReg', (196, 205))	('men', 'Species', '9606', (97, 100))	('men', 'Species', '9606', (231, 234))	('chlordanes', 'Chemical', 'MESH:D002706', (157, 167))	('trans-nonachlor', 'Var', (131, 146))	('organochlorine', 'Chemical', 'MESH:D006843', (61, 75))	('TGCT', 'Disease', (214, 218))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (131, 146))
47455	19627379	In this study, we observed that these increased risks were only present in men who had a minor allele for CYP1A1 rs1456432 and rs7495708.	('rs1456432', 'Var', (113, 122))	('CYP1A1', 'Gene', '1543', (106, 112))	('men', 'Species', '9606', (75, 78))	('rs1456432', 'Mutation', 'rs1456432', (113, 122))	('rs7495708', 'Var', (127, 136))	('CYP1A1', 'Gene', (106, 112))	('rs7495708', 'Mutation', 'rs7495708', (127, 136))
47457	19627379	There were suggestions that polymorphisms in CYP1A1 and HSD17B4 may be associated with concentrations of oxychlordane and PCBs, respectively; thus, it may be plausible that these polymorphisms may also affect TGCT risk by altering the metabolism of oxychlordane and PCB PCB-118, PCB-138, and PCB-187.	('altering', 'Reg', (222, 230))	('HSD17B4', 'Gene', '3295', (56, 63))	('PCB', 'Chemical', 'MESH:D011078', (122, 125))	('PCB', 'Chemical', 'MESH:D011078', (279, 282))	('associated', 'Reg', (71, 81))	('HSD17B4', 'Gene', (56, 63))	('TGCT', 'Disease', (209, 213))	('PCB-118', 'Chemical', '-', (270, 277))	('PCB', 'Chemical', 'MESH:D011078', (270, 273))	('PCB', 'Chemical', 'MESH:D011078', (292, 295))	('affect', 'Reg', (202, 208))	('PCB-187', 'Gene', (292, 299))	('CYP1A1', 'Gene', (45, 51))	('oxychlordane', 'Chemical', 'MESH:C008743', (105, 117))	('metabolism of oxychlordane', 'MPA', (235, 261))	('oxychlordane', 'Chemical', 'MESH:C008743', (249, 261))	('PCBs', 'Chemical', 'MESH:D011078', (122, 126))	('PCB-138', 'Chemical', '-', (279, 286))	('PCB-138', 'Gene', (279, 286))	('CYP1A1', 'Gene', '1543', (45, 51))	('PCB', 'Chemical', 'MESH:D011078', (266, 269))	('polymorphisms', 'Var', (28, 41))	('PCB-187', 'Chemical', '-', (292, 299))
47458	19627379	Examining polychlorinated biphenyl exposures, we previously found that men with the highest quartiles of PCB-118 and PCB-138 concentrations had an approximate 45-55% reduction in risk of TGCT compared to men with the lowest quartiles.	('reduction', 'NegReg', (166, 175))	('PCB-138', 'Chemical', '-', (117, 124))	('men', 'Species', '9606', (71, 74))	('TGCT', 'Disease', (187, 191))	('men', 'Species', '9606', (204, 207))	('PCB-118', 'Chemical', '-', (105, 112))	('PCB-118', 'Gene', (105, 112))	('PCB-138', 'Var', (117, 124))
47459	19627379	In this study, we observed that these decreased risks were only present in men who had a major homozygous allele genotype for HSD17B4 rs384346.	('rs384346', 'Mutation', 'rs384346', (134, 142))	('HSD17B4', 'Gene', '3295', (126, 133))	('men', 'Species', '9606', (75, 78))	('HSD17B4', 'Gene', (126, 133))	('rs384346', 'Var', (134, 142))
47463	19627379	of Sweden men observed that of the 8 POPs measured, only cis-nonachlordane was associated with an increased risk of testicular cancer (OR=2.6, 95% CI, 1.2-5.7).	('testicular cancer', 'Disease', (116, 133))	('men', 'Species', '9606', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cis-nonachlordane', 'Var', (57, 74))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))	('cis-nonachlordane', 'Chemical', 'MESH:C001870', (57, 74))	('POPs', 'Chemical', '-', (37, 41))
47467	19627379	The study also genotyped microsatellite repeat polymorphisms in the AR gene (CAG genotype: <23 versus >=23 repeats, GGN genotype: <17 versus >= 17 repeats).	('AR', 'Gene', '367', (68, 70))	('GGN', 'Gene', '199720', (116, 119))	('microsatellite repeat polymorphisms', 'Var', (25, 60))	('GGN', 'Gene', (116, 119))
47474	19627379	In addition, epidemiologic studies in women have observed interactions between CYP1A1 polymorphisms and PCB exposure on breast cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('CYP1A1', 'Gene', (79, 85))	('PCB', 'Chemical', 'MESH:D011078', (104, 107))	('CYP1A1', 'Gene', '1543', (79, 85))	('interactions', 'Interaction', (58, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('women', 'Species', '9606', (38, 43))	('polymorphisms', 'Var', (86, 99))
47476	19627379	These studies all included two polymorphisms that we also examined, CYP1A1 M1 (also known as CYP1A1*2A, rs4646903) and CYP1A1 M2 (also known as CYP1A1*2C, rs1048943), and consistently observed that CYP1A1 M2 modified the association between PCB exposure and breast cancer risk.	('CYP1A1', 'Gene', '1543', (68, 74))	('CYP1A1', 'Gene', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('association', 'Interaction', (221, 232))	('CYP1A1', 'Gene', (119, 125))	('CYP1A1', 'Gene', '1543', (144, 150))	('modified', 'Reg', (208, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('rs4646903', 'Mutation', 'rs4646903', (104, 113))	('CYP1A1', 'Gene', '1543', (198, 204))	('rs1048943', 'Mutation', 'rs1048943', (155, 164))	('CYP1A1', 'Gene', '1543', (119, 125))	('CYP1A1', 'Gene', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('breast cancer', 'Disease', (258, 271))	('rs1048943', 'Var', (155, 164))	('CYP1A1', 'Gene', (68, 74))	('rs4646903', 'Var', (104, 113))	('CYP1A1', 'Gene', '1543', (93, 99))	('CYP1A1', 'Gene', (144, 150))	('PCB', 'Chemical', 'MESH:D011078', (241, 244))
47478	19627379	Based on HapMap data, the CYP1A1 M1 and M2 polymorphisms are in strong linkage disequilibrium with CYP1A1 rs1456432, which we did find to interact with the pesticide, trans-nonachlor.	('trans-nonachlor', 'Chemical', 'MESH:C001870', (167, 182))	('rs1456432', 'Mutation', 'rs1456432', (106, 115))	('CYP1A1', 'Gene', (26, 32))	('linkage', 'Interaction', (71, 78))	('CYP1A1', 'Gene', (99, 105))	('CYP1A1', 'Gene', '1543', (99, 105))	('interact', 'Reg', (138, 146))	('CYP1A1', 'Gene', '1543', (26, 32))	('rs1456432', 'Var', (106, 115))
47483	19627379	This is the first study to assess risk of TGCT and interactions between polymorphisms in several common hormone-metabolizing genes and pre-diagnostic serum concentrations of POPs.	('TGCT', 'Disease', (42, 46))	('POPs', 'Chemical', '-', (174, 178))	('interactions', 'Interaction', (51, 63))	('polymorphisms', 'Var', (72, 85))
47487	19627379	In conclusion, the current study suggests that some CYP1A1 and HSD17B4 polymorphisms may modify the associations between chlordanes and PCBs, respectively, and risk of TGCT.	('polymorphisms', 'Var', (71, 84))	('associations', 'Interaction', (100, 112))	('PCBs', 'Chemical', 'MESH:D011078', (136, 140))	('CYP1A1', 'Gene', '1543', (52, 58))	('chlordanes', 'Chemical', 'MESH:D002706', (121, 131))	('TGCT', 'Disease', (168, 172))	('modify', 'Reg', (89, 95))	('HSD17B4', 'Gene', '3295', (63, 70))	('chlordanes', 'Disease', (121, 131))	('CYP1A1', 'Gene', (52, 58))	('HSD17B4', 'Gene', (63, 70))	('PCBs', 'Disease', (136, 140))
26798	21207375	Seminoma testicular cancer was defined as ICD-O morphology codes: 9060/3, 9061/3, 9062/3 and 9063/3.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Seminoma testicular cancer', 'Disease', 'MESH:D018239', (0, 26))	('Seminoma testicular cancer', 'Disease', (0, 26))	('9063/3', 'Var', (93, 99))	('testicular cancer', 'Phenotype', 'HP:0010788', (9, 26))
47682	21303994	(S-11/06, S-04/07, S-02/08 to L.R.	('S-11/06', 'Gene', '6267', (1, 8))	('S-11/06', 'Gene', (1, 8))	('S-02/08', 'Var', (19, 26))	('S-04/07', 'Var', (10, 17))
47736	19491264	This was confirmed by RT-PCR for three of them, whereas one (THC2341283) did not give any bands and one (THC2378933) resulted in multiple bands (not shown).	('THC2341283', 'Chemical', '-', (61, 71))	('THC2341283', 'Var', (61, 71))	('THC2378933', 'Chemical', '-', (105, 115))	('resulted in', 'Reg', (117, 128))	('THC2378933', 'Var', (105, 115))
47827	23928699	In recent years, studies have demonstrated that aberrant expression of certain stem cell-associated nuclear transcription factors, such as octamer-binding transcription factor 4 (OCT4), SOX2, NANOG and KLF4, could contribute to the tumorigenesis of various somatic cancers.	('KLF4', 'Gene', '9314', (202, 206))	('octamer-binding transcription factor 4', 'Gene', (139, 177))	('SOX2', 'Gene', '6657', (186, 190))	('somatic cancers', 'Disease', 'MESH:D009369', (257, 272))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('SOX2', 'Gene', (186, 190))	('expression', 'MPA', (57, 67))	('aberrant', 'Var', (48, 56))	('tumor', 'Disease', (232, 237))	('octamer-binding transcription factor 4', 'Gene', '5460', (139, 177))	('NANOG', 'Gene', '79923', (192, 197))	('KLF4', 'Gene', (202, 206))	('NANOG', 'Gene', (192, 197))	('rat', 'Species', '10116', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('OCT4', 'Gene', (179, 183))	('somatic cancers', 'Disease', (257, 272))	('contribute', 'Reg', (214, 224))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))
47832	23928699	reported that ectopic OCT4 expression in somatic cells causes epithelial dysplasia.	('epithelial dysplasia', 'Disease', (62, 82))	('epithelial dysplasia', 'Disease', 'MESH:C567703', (62, 82))	('OCT4', 'Protein', (22, 26))	('ectopic', 'Var', (14, 21))	('causes', 'Reg', (55, 61))
47862	23928699	Tumors formed by OCT4-expressing cells contained fewer apoptotic cells than control cells (Figure 3b, P<0.05, Student's t-test), indicating that OCT4 may promote tumor formation by inhibiting apoptosis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('promote', 'PosReg', (154, 161))	('inhibiting', 'NegReg', (181, 191))	('tumor', 'Disease', (162, 167))	('OCT4', 'Var', (145, 149))	('apoptosis', 'CPA', (192, 201))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
47863	23928699	To further explore the mechanism by which OCT4 inhibits apoptosis in cervical cancer cells, we determined the expression levels of several apoptosis-related genes (Supplementary Figure 1) and microRNAs (miRNAs; Figure 4a) in each cell line.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('OCT4', 'Var', (42, 46))	('miR', 'Gene', '220972', (203, 206))	('miR', 'Gene', (203, 206))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('apoptosis', 'CPA', (56, 65))	('cervical cancer', 'Disease', (69, 84))	('apoptosis-related genes', 'Gene', (139, 162))	('inhibits', 'NegReg', (47, 55))
47872	23928699	Sequence analyses revealed the presence of two conserved octamer regulatory regions (RRs) in this region, named RR1 (between -4280 nt and -4287 nt, pink oval) and RR2 (between -439 nt and -446 nt, red oval; Figure 4d).	('RR1', 'Gene', (112, 115))	('RR2', 'Gene', (163, 166))	('RR1', 'Gene', '6240', (112, 115))	('between -4280 nt and -4287 nt', 'Var', (117, 146))	('RR2', 'Gene', '6241', (163, 166))	('between -439 nt', 'Var', (168, 183))
47884	23928699	Taken together, these results indicate that HeLa cell apoptosis was negatively correlated with miR-125b expression, and inactivation of miR-125b can abolish the effect induced by OCT4.	('inactivation', 'Var', (120, 132))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('HeLa', 'CellLine', 'CVCL:0030', (44, 48))	('abolish', 'NegReg', (149, 156))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('expression', 'MPA', (104, 114))	('negatively', 'NegReg', (68, 78))
47902	23928699	As shown in Supplementary Figure 4, after OCT4 inhibition, the level of miR-125b was downregulated, BAK1 was upregulated and the proportion of apoptotic cells were significantly increased, emphasizing the notion that OCT4 regulates cell apoptosis by activating miR-125b.	('downregulated', 'NegReg', (85, 98))	('upregulated', 'PosReg', (109, 120))	('OCT4', 'Gene', (42, 46))	('activating', 'PosReg', (250, 260))	('inhibition', 'Var', (47, 57))	('level', 'MPA', (63, 68))	('BAK1', 'Gene', '578', (100, 104))	('miR', 'Gene', '220972', (261, 264))	('miR', 'Gene', (261, 264))	('BAK1', 'Gene', (100, 104))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))	('increased', 'PosReg', (178, 187))
47913	23928699	found that OCT4 overexpression could promote tumor formation by human colorectal cancer cells, and Kim and Nam determined that Oct4 in a mouse model of breast cancer enhanced tumorigenesis and increased the number of cancer stem cells.	('mouse', 'Species', '10090', (137, 142))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('tumor', 'Disease', (45, 50))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Disease', (159, 165))	('Nam', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('enhanced', 'PosReg', (166, 174))	('Nam', 'Gene', '246329', (107, 110))	('human', 'Species', '9606', (64, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('tumor', 'Disease', (175, 180))	('Oct4', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('colorectal cancer', 'Disease', (70, 87))	('increased', 'PosReg', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('promote', 'PosReg', (37, 44))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('cancer', 'Disease', (217, 223))	('breast cancer', 'Disease', (152, 165))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
47918	23928699	In murine lung carcinoma and human breast cancer cell lines, knockdown of Oct4 expression by small interfering RNA results in apoptosis of cancer stem cell-like cells through the Oct4/Tcl1/Akt1 pathway.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('apoptosis', 'CPA', (126, 135))	('knockdown', 'Var', (61, 70))	('Oct4', 'Gene', (74, 78))	('lung carcinoma', 'Disease', 'MESH:D008175', (10, 24))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Akt1', 'Gene', (189, 193))	('murine', 'Species', '10090', (3, 9))	('Tcl1', 'Gene', (184, 188))	('human', 'Species', '9606', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('Tcl1', 'Gene', '8115', (184, 188))	('lung carcinoma', 'Disease', (10, 24))	('cancer', 'Disease', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('cancer', 'Disease', (42, 48))	('breast cancer', 'Disease', (35, 48))	('Akt1', 'Gene', '207', (189, 193))
47919	23928699	In mouse ESCs, knockdown of Oct4 expression induced apoptosis via the Stat3/survival pathway or the Trp53 pathway.	('Stat3', 'Gene', (70, 75))	('mouse', 'Species', '10090', (3, 8))	('knockdown', 'Var', (15, 24))	('Oct4', 'Gene', (28, 32))	('Trp53', 'Gene', (100, 105))	('Stat3', 'Gene', '20848', (70, 75))	('Trp53', 'Gene', '22059', (100, 105))	('apoptosis', 'CPA', (52, 61))
47939	23928699	To our knowledge, this is the first study on the mechanism by which OCT4 deregulation contributes to cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (101, 116))	('cervical cancer', 'Disease', (101, 116))	('deregulation', 'Var', (73, 85))	('OCT4', 'Protein', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('contributes', 'Reg', (86, 97))
47950	23928699	After treating with 3% H2O2 and washing with phosphatebuffered saline (PBS) at room temperature, the sections were incubated at 4  C with the following primary antibodies: anti-OCT4 (1:100, H-134, sc-9081, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and anti-BAK1 (1:100, N-20, sc-1035, Santa Cruz Biotechnology).	('1:100', 'Var', (183, 188))	('phosphatebuffered saline', 'Chemical', '-', (45, 69))	('PBS', 'Chemical', '-', (71, 74))	('BAK1', 'Gene', '578', (262, 266))	('rat', 'Species', '10116', (89, 92))	('H2O2', 'Chemical', 'MESH:D006861', (23, 27))	('BAK1', 'Gene', (262, 266))
47965	23928699	For promoter analyses, both a fragment (from position -5000 to -1 bp relative to the 5'-end of pre-miR-125b-1) and a series of 5' deletion mutants were cloned into the pGL3-Basic Vector (Promega, Madison, WI, USA) to generate miR-125b-1 promoter reporter constructs.	('rat', 'Species', '10116', (221, 224))	('miR-125b-1', 'Gene', '406911', (99, 109))	('miR-125b-1', 'Gene', (99, 109))	('miR-125b-1', 'Gene', '406911', (226, 236))	('miR-125b-1', 'Gene', (226, 236))	('mutants', 'Var', (139, 146))
47981	23928699	After blocking with 5% fat-free milk, the membranes were incubated with primary antibodies as follows: anti-OCT4 (1:500, H-134, sc-9081, Santa Cruz Biotechnology), anti-BAK1 (1:500, N-20, sc-1035, Santa Cruz Biotechnology) and anti-beta-actin (1:500, C4, sc-47778, Santa Cruz Biotechnology).	('BAK1', 'Gene', (169, 173))	('beta-actin', 'Gene', '728378', (232, 242))	('beta-actin', 'Gene', (232, 242))	('anti-OCT4', 'Var', (103, 112))	('1:500', 'Var', (114, 119))	('BAK1', 'Gene', '578', (169, 173))
48115	33573132	Very often, human cancer is induced by the alteration of several cell cycle regulators.	('alteration', 'Var', (43, 53))	('induced by', 'Reg', (28, 38))	('rat', 'Species', '10116', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('human', 'Species', '9606', (12, 17))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
48125	33573132	In particular, cancer research has been revolutionized by miRNAs discovery, since the deregulation of several miRNAs has been involved in the pathogenesis of many human cancer types.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('deregulation', 'Var', (86, 98))	('involved', 'Reg', (126, 134))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human', 'Species', '9606', (163, 168))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
48127	33573132	Given their importance in cancer phenomena, alterations of the miRNA signature in cancer cells vs. normal cells have been used to better determine the diagnosis, the prognosis and the response to cancer treatment in several human cancers.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('alterations', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('rat', 'Species', '10116', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('men', 'Species', '9606', (208, 211))	('human', 'Species', '9606', (224, 229))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR', 'Gene', '220972', (63, 66))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('men', 'Species', '9606', (38, 41))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('miR', 'Gene', (63, 66))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
48132	33573132	In fact, miR-302 induces the fast proliferation of these cells interacting with promoters and inhibitors of genes that regulate the cell cycle.	('induces', 'Reg', (17, 24))	('miR-302', 'Var', (9, 16))	('fast proliferation', 'CPA', (29, 47))	('miR-302', 'Chemical', '-', (9, 16))	('rat', 'Species', '10116', (41, 44))
48134	33573132	Akt oncogene expression has been found to be suppressed by miR-302 in teratomas.	('miR-302', 'Chemical', '-', (59, 66))	('teratoma', 'Phenotype', 'HP:0009792', (70, 78))	('expression', 'MPA', (13, 23))	('suppressed', 'NegReg', (45, 55))	('Akt', 'Gene', '207', (0, 3))	('teratomas', 'Phenotype', 'HP:0009792', (70, 79))	('teratomas', 'Disease', (70, 79))	('teratomas', 'Disease', 'MESH:D013724', (70, 79))	('Akt', 'Gene', (0, 3))	('miR-302', 'Var', (59, 66))
48138	33573132	It has been demonstrated that miR-302 accelerates the cell cycle switch from the G1 to the S phase, inhibiting cyclin-dependent kinase (CDK) 2 and 4.	('cyclin-dependent', 'MPA', (111, 127))	('accelerates', 'PosReg', (38, 49))	('cell cycle switch', 'CPA', (54, 71))	('inhibiting', 'NegReg', (100, 110))	('rat', 'Species', '10116', (44, 47))	('rat', 'Species', '10116', (19, 22))	('miR-302', 'Chemical', '-', (30, 37))	('miR-302', 'Var', (30, 37))
48139	33573132	The blood of TGCT patients contains high levels of miR-302, whereas this is downregulated in liver, stomach and colon cancer.	('stomach', 'Disease', (100, 107))	('miR-302', 'Chemical', '-', (51, 58))	('miR-302', 'Var', (51, 58))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('downregulated', 'NegReg', (76, 89))	('patients', 'Species', '9606', (18, 26))	('liver', 'Disease', (93, 98))
48140	33573132	Interestingly, the levels of miR-302a-3p, miR-302b-3p and miR-302c-3p diminished in TGCT cell lines after cisplatin treatment.	('miR-302b-3p', 'Var', (42, 53))	('miR-302', 'Chemical', '-', (42, 49))	('men', 'Species', '9606', (121, 124))	('miR-302a-3p', 'Var', (29, 40))	('miR-302', 'Chemical', '-', (29, 36))	('diminished', 'NegReg', (70, 80))	('miR-302c-3p', 'Var', (58, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('miR-302', 'Chemical', '-', (58, 65))
48147	33573132	Interestingly, miR-367-3p was strongly upregulated in TGCT patients compared to healthy ones.	('upregulated', 'PosReg', (39, 50))	('patients', 'Species', '9606', (59, 67))	('miR-367-3p', 'Chemical', '-', (15, 25))	('miR-367-3p', 'Var', (15, 25))	('TGCT', 'Disease', (54, 58))
48155	33573132	Although many papers have underlined the molecular mechanisms by which this cluster participates in tumor transformation, only miR-371a-3p has been extensively analyzed as a TGCT biomarker in follow-up, staging and diagnosis, and to estimate TGCT prognosis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('miR-371a-3p', 'Var', (127, 138))	('tumor', 'Disease', (100, 105))	('participates', 'Reg', (84, 96))	('miR-371a-3p', 'Chemical', '-', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
48159	33573132	Importantly, seminomas patients displayed the highest miR-371a-3p expression, followed by embryonic carcinomas, teratomas and yolk sac tumors (Table 1).	('seminomas', 'Disease', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (23, 31))	('teratomas', 'Phenotype', 'HP:0009792', (112, 121))	('miR-371a-3p', 'Chemical', '-', (54, 65))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('teratoma', 'Phenotype', 'HP:0009792', (112, 120))	('teratomas and yolk sac tumors', 'Disease', 'MESH:D018240', (112, 141))	('embryonic carcinomas', 'Disease', (90, 110))	('embryonic carcinomas', 'Disease', 'MESH:D018236', (90, 110))	('miR-371a-3p', 'Var', (54, 65))	('highest', 'Reg', (46, 53))	('seminomas', 'Disease', 'MESH:D018239', (13, 22))
48168	33573132	The scientific literature reports that miR-223-3p has been found to be deregulated in gastric and esophageal tumors, as well as in acute T-cell lymphoblastic leukemia.	('esophageal tumors', 'Disease', 'MESH:D004938', (98, 115))	('gastric', 'Disease', (86, 93))	('deregulated', 'PosReg', (71, 82))	('esophageal tumors', 'Disease', (98, 115))	('esophageal tumors', 'Phenotype', 'HP:0100751', (98, 115))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('miR-223-3p', 'Var', (39, 49))	('acute T-cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (131, 166))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (144, 166))	('miR-223-3p', 'Chemical', '-', (39, 49))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('acute T-cell lymphoblastic leukemia', 'Disease', (131, 166))
48169	33573132	In prostate cancer (PCa) tissue, miR-223-3p expression is recurrently reduced in comparison to the normal tissues, where miR-223-3p works as a tumor suppressor preventing cancer cell migration and invasion.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('expression', 'MPA', (44, 54))	('miR-223-3p', 'Gene', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PCa', 'Phenotype', 'HP:0012125', (20, 23))	('prostate cancer', 'Disease', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('reduced', 'NegReg', (70, 77))	('miR-223-3p', 'Chemical', '-', (121, 131))	('cancer', 'Disease', (171, 177))	('miR-223-3p', 'Chemical', '-', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('invasion', 'CPA', (197, 205))	('tumor', 'Disease', (143, 148))	('cancer', 'Disease', (12, 18))	('rat', 'Species', '10116', (186, 189))	('preventing', 'NegReg', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('miR-223-3p', 'Var', (121, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
48170	33573132	Moreover, miR-223-3p is upregulated in TGCTs with respect to normal testis.	('miR-223-3p', 'Chemical', '-', (10, 20))	('upregulated', 'PosReg', (24, 35))	('TGCTs', 'Disease', (39, 44))	('miR-223-3p', 'Var', (10, 20))
48172	33573132	Additionally, a negative correlation was found between miR-223-3p and FBXW7 mRNA expression levels.	('negative', 'NegReg', (16, 24))	('FBXW7', 'Gene', '55294', (70, 75))	('miR-223-3p', 'Chemical', '-', (55, 65))	('FBXW7', 'Gene', (70, 75))	('mRNA expression levels', 'MPA', (76, 98))	('miR-223-3p', 'Var', (55, 65))
48174	33573132	Additionally, the ectopic expression of the full-length coding sequence of FBXW7 rescued the cell growth and apoptosis mediated by miR-223-3p.	('miR-223-3p', 'Var', (131, 141))	('cell growth', 'CPA', (93, 104))	('rescued', 'PosReg', (81, 88))	('FBXW7', 'Gene', (75, 80))	('apoptosis', 'CPA', (109, 118))	('miR-223-3p', 'Chemical', '-', (131, 141))	('FBXW7', 'Gene', '55294', (75, 80))
48175	33573132	As demonstrated in gastric cancer, miR-223-3p may influence chemotherapeutic agents' sensitivity in TGCTs.	('gastric cancer', 'Disease', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (19, 33))	('TGCTs', 'Disease', (100, 105))	('miR-223-3p', 'Chemical', '-', (35, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('rat', 'Species', '10116', (10, 13))	('influence', 'Reg', (50, 59))	('miR-223-3p', 'Var', (35, 45))
48176	33573132	Finally, more studies are needed to use miR-223-3p as a tumor marker.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('miR-223-3p', 'Var', (40, 50))	('miR-223-3p', 'Chemical', '-', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
48177	33573132	A main role in spermatogenesis has been found for miR-449.	('miR-449', 'Var', (50, 57))	('spermatogenesis', 'CPA', (15, 30))	('miR-449', 'Chemical', '-', (50, 57))
48208	33573132	A main contribution could come from the combination of miRNAs with other canonical biomarkers, which could also result in a comprehensive view of miRNAs, known and unknown, long non-coding RNAs (lncRNAs), circular-RNAs, and other ncRNAs.	('result in', 'Reg', (112, 121))	('miR', 'Gene', '220972', (55, 58))	('circular-RNAs', 'Var', (205, 218))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (146, 149))	('miR', 'Gene', (146, 149))
48294	33072332	It proposes that disturbed testicular development in utero during the specific window called the masculinization programming window (MPW - around week 8-14 of gestation in humans) may result in the occurrence of one or a combination of reproductive disorders such as cryptorchidism, hypospadias, low sperm count and testicular germ cell cancer.	('l', 'Gene', '21832', (34, 35))	('l', 'Gene', '21832', (42, 43))	('l', 'Gene', '21832', (296, 297))	('cryptorchidism', 'Disease', 'MESH:D003456', (267, 281))	('l', 'Gene', '21832', (88, 89))	('hypospadias', 'Disease', (283, 294))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('l', 'Gene', '21832', (89, 90))	('l', 'Gene', '21832', (335, 336))	('reproductive disorders', 'Phenotype', 'HP:0000078', (236, 258))	('germ cell cancer', 'Phenotype', 'HP:0100728', (327, 343))	('hypospadias', 'Disease', 'MESH:D007021', (283, 294))	('cryptorchidism', 'Disease', (267, 281))	('l', 'Gene', '21832', (334, 335))	('humans', 'Species', '9606', (172, 178))	('l', 'Gene', '21832', (102, 103))	('l', 'Gene', '21832', (323, 324))	('low sperm count', 'Phenotype', 'HP:0000798', (296, 311))	('cancer', 'Disease', (337, 343))	('disturbed', 'Var', (17, 26))	('cryptorchidism', 'Phenotype', 'HP:0000028', (267, 281))	('l', 'Gene', '21832', (188, 189))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('men', 'Species', '9606', (45, 48))	('hypospadias', 'Phenotype', 'HP:0000047', (283, 294))	('occurrence', 'Reg', (198, 208))
48406	33072332	Genetic susceptibility or epigenetic modifications are thought to be important mediators explaining interactions between a stressful environment and sperm/offspring outcomes.	('epigenetic modifications', 'Var', (26, 50))	('men', 'Species', '9606', (140, 143))	('l', 'Gene', '21832', (18, 19))	('interactions', 'Interaction', (100, 112))	('l', 'Gene', '21832', (131, 132))	('l', 'Gene', '21832', (92, 93))
48413	33072332	Reactive oxygen species (ROS) levels were measured and RF-EMR were shown to induce DNA damage due to increased levels of oxidative stress which was suggested to accelerate sperm cell death and promote testicular carcinogenesis.	('promote', 'PosReg', (193, 200))	('l', 'Gene', '21832', (34, 35))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('increased', 'PosReg', (101, 110))	('l', 'Gene', '21832', (208, 209))	('carcinogenesis', 'Disease', (212, 226))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))	('death', 'Disease', (183, 188))	('l', 'Gene', '21832', (111, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('DNA', 'CPA', (83, 86))	('l', 'Gene', '21832', (181, 182))	('l', 'Gene', '21832', (165, 166))	('l', 'Gene', '21832', (180, 181))	('death', 'Disease', 'MESH:D003643', (183, 188))	('l', 'Gene', '21832', (30, 31))	('RF-EMR', 'Var', (55, 61))	('induce', 'Reg', (76, 82))	('l', 'Gene', '21832', (115, 116))	('oxidative stress', 'Phenotype', 'HP:0025464', (121, 137))
48423	33072332	The mechanism of action by which RF-EMF is suggested to affect sperm motility involves potentially an RF-induced increase in superoxide anions concentrations due to an increased level of oxidative stress.	('affect', 'Reg', (56, 62))	('increased', 'PosReg', (168, 177))	('l', 'Gene', '21832', (182, 183))	('l', 'Gene', '21832', (178, 179))	('l', 'Gene', '21832', (96, 97))	('RF-EMF', 'Chemical', '-', (33, 39))	('superoxide anions concentrations', 'MPA', (125, 157))	('increase', 'PosReg', (113, 121))	('l', 'Gene', '21832', (73, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (187, 203))	('l', 'Gene', '21832', (95, 96))	('superoxide anions', 'Chemical', 'MESH:D013481', (125, 142))	('RF-EMF', 'Var', (33, 39))	('l', 'Gene', '21832', (82, 83))
48425	33072332	In rodents, EMFs have been shown to decrease fertilization rates and spermatogenic cell numbers as well as inducing apoptosis.	('EMFs', 'Var', (12, 16))	('apoptosis', 'CPA', (116, 125))	('inducing', 'Reg', (107, 115))	('l', 'Gene', '21832', (86, 87))	('l', 'Gene', '21832', (101, 102))	('l', 'Gene', '21832', (50, 51))	('l', 'Gene', '21832', (85, 86))	('l', 'Gene', '21832', (102, 103))	('decrease', 'NegReg', (36, 44))
48528	31851716	TGCT treatment is associated with potentially life-threatening late effects such as second cancer (SC) and cardiovascular disease (CVD), which can manifest decades after chemo- or radiotherapy.	('treatment', 'Var', (5, 14))	('men', 'Species', '9606', (10, 13))	('CVD', 'Phenotype', 'HP:0001626', (131, 134))	('cardiovascular disease', 'Disease', (107, 129))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('CVD', 'Disease', 'MESH:D002318', (131, 134))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (107, 129))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cardiovascular disease', 'Disease', 'MESH:D002318', (107, 129))	('TGCT', 'Gene', (0, 4))	('CVD', 'Disease', (131, 134))
48625	31851716	Bleomycin can cause life-threatening pulmonary toxicity.	('Bleomycin', 'Chemical', 'MESH:D001761', (0, 9))	('Bleomycin', 'Var', (0, 9))	('pulmonary toxicity', 'Disease', 'MESH:D008171', (37, 55))	('cause', 'Reg', (14, 19))	('pulmonary toxicity', 'Disease', (37, 55))
48676	29872091	Among the dysregulated sex differentiation-related lncRNAs, TCONS_00092301 was the most down-regulated (log2(FC) -5.73649) and TCONS_00068006 was the most up-regulated (log2(FC) 3.760947) (details are presented in Supplementary File S2 and S3).	('Supplementary File S2', 'Disease', (214, 235))	('Supplementary File S2', 'Disease', 'MESH:D017034', (214, 235))	('TCONS_00092301', 'Var', (60, 74))	('TCONS_00068006', 'Var', (127, 141))	('down-regulated', 'NegReg', (88, 102))	('up-regulated', 'PosReg', (155, 167))
48678	29872091	Interestingly, many lncRNAs were predicted to target sex differentiation-related genes; these included TCONS_00099273, TCONS_00068006, TCONS_00088824, TCONS_00019214, and TCONS_00019442, which targeted the PC genes dmrt1, sox9, cyp19a, sox3, and sox8.	('TCONS_00099273', 'Var', (103, 117))	('TCONS_00068006', 'Var', (119, 133))	('sox8', 'Gene', '102463615', (246, 250))	('dmrt1', 'Gene', (215, 220))	('TCONS_00019442', 'Var', (171, 185))	('TCONS_00019214', 'Var', (151, 165))	('sox8', 'Gene', (246, 250))	('TCONS_00088824', 'Var', (135, 149))	('sox3', 'Gene', (236, 240))	('sox9', 'Gene', (222, 226))	('sox3', 'Gene', '102464046', (236, 240))	('sox9', 'Gene', '102461964', (222, 226))	('dmrt1', 'Gene', '102462572', (215, 220))
48680	29872091	Dmrt1 (XM_006137866.2), gata4 (XM_014569886.1) and cyp19a (XM_006135075.2) have been identified as key sex differentiation-related genes and were shown to be regulated by several lncRNAs actin in cis or in trans in the network.	('XM_014569886.1', 'Var', (31, 45))	('gata4', 'Gene', (24, 29))	('cyp19a', 'Gene', (51, 57))	('gata4', 'Gene', '102452046', (24, 29))	('Dmrt1', 'Gene', (0, 5))	('XM_006137866.2', 'Var', (7, 21))	('XM_006135075.2', 'Var', (59, 73))
48681	29872091	The differentially expressed lncRNA transcripts TCONS_00088824 and TCONS_00068006 and the PC genes XM_006135075.2 (Cyp19a) and XM_014576568.1 (Sox9) identified in the RNA-seq data were obtained according to gene expression, the lncRNA and mRNA regulatory network, and gene function to validate their expression patterns in female and male gonad tissues by qRT-PCR.	('Sox9', 'Gene', (143, 147))	('TCONS_00088824', 'Var', (48, 62))	('Sox9', 'Gene', '102461964', (143, 147))
48686	29872091	Most notably, we discovered a positive correlation between the expression of lncRNAs TCONS_00088824 and TCONS_00068006 and their respective target PC genes XM_006135075.2 (Cyp19a) and XM_014576568.1 (Sox9) (Fig.	('TCONS_00088824', 'Var', (85, 99))	('Sox9', 'Gene', (200, 204))	('TCONS_00068006', 'Var', (104, 118))	('Sox9', 'Gene', '102461964', (200, 204))
48696	28471449	Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear.	('germ cell tumor', 'Phenotype', 'HP:0100728', (272, 287))	('tumor', 'Disease', (282, 287))	('men', 'Species', '9606', (170, 173))	('NF-kappa B', 'Gene', (53, 63))	('cancer', 'Disease', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('microRNAs', 'MPA', (125, 134))	('PEG3', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (102, 108))	('miR-514a-3', 'Gene', (8, 18))	('PEG3', 'Gene', '5178', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('germ cell tumors', 'Phenotype', 'HP:0100728', (92, 108))	('tumor', 'Disease', (102, 107))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('NF-kappa B', 'Gene', '4790', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('miR-514a-3', 'Gene', '574518', (8, 18))	('human', 'Species', '9606', (75, 80))	('germ cell tumor', 'Phenotype', 'HP:0100728', (92, 107))
48699	28471449	Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-kappaB reporter activity.	('p50', 'Gene', (80, 83))	('PEG3', 'Gene', '5178', (13, 17))	('NF-kappaB', 'Gene', (88, 97))	('p50', 'Gene', '4790', (80, 83))	('reduced', 'NegReg', (48, 55))	('PEG3', 'Gene', (13, 17))	('miR-514a-3p', 'Gene', '574518', (21, 32))	('miR-514a-3p', 'Gene', (21, 32))	('Silencing', 'Var', (0, 9))	('NF-kappaB', 'Gene', '4790', (88, 97))
48702	28471449	Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis.	('expression', 'MPA', (54, 64))	('miR-514a-3p', 'Gene', (8, 19))	('NF-kappa B', 'Gene', (103, 113))	('TRAF2', 'Gene', '7186', (79, 84))	('miR-514a-3p', 'Gene', '574518', (8, 19))	('activates', 'PosReg', (89, 98))	('PEG3', 'Gene', '5178', (49, 53))	('TRAF2', 'Gene', (79, 84))	('increases', 'PosReg', (39, 48))	('NF-kappa B', 'Gene', '4790', (103, 113))	('Loss', 'Var', (0, 4))	('PEG3', 'Gene', (49, 53))
48732	28471449	miR-21 and miR-223 expression levels were increased in TGCTs, whereas the eight miRNAs in the miR-506~514 cluster (miR-506, miR-507, miR-508-5p, miR-510, miR-513a-5p, miR-513b, miR-513c and miR-514a-3p) were reduced in TGCTs as compared with NT.	('NT', 'Chemical', '-', (242, 244))	('miR-514a-3p', 'Gene', (190, 201))	('miR-513c', 'Gene', '100302114', (177, 185))	('miR-506', 'Gene', '574511', (115, 122))	('miR-507', 'Gene', '574512', (124, 131))	('miR-21', 'Gene', (0, 6))	('miR-513c', 'Gene', (177, 185))	('miR-513a-5p', 'Var', (154, 165))	('miR-223', 'Gene', '407008', (11, 18))	('miR-508', 'Gene', '574513', (133, 140))	('miR-514a-3p', 'Gene', '574518', (190, 201))	('miR-506~514 cluster', 'Gene', (94, 113))	('reduced', 'NegReg', (208, 215))	('miR-508', 'Gene', (133, 140))	('miR-506', 'Gene', '574511', (94, 101))	('increased', 'PosReg', (42, 51))	('miR-506', 'Gene', (115, 122))	('miR-510', 'Gene', (145, 152))	('miR-506~514 cluster', 'Gene', '574511', (94, 113))	('expression levels', 'MPA', (19, 36))	('miR-21', 'Gene', '406991', (0, 6))	('TGCTs', 'Disease', (55, 60))	('miR-510', 'Gene', '574515', (145, 152))	('miR-507', 'Gene', (124, 131))	('miR-223', 'Gene', (11, 18))	('TGCTs', 'Disease', (219, 224))	('miR-513b', 'Gene', '100313822', (167, 175))	('miR-506', 'Gene', (94, 101))	('miR-513b', 'Gene', (167, 175))
48749	28471449	We observed an enrichment of PEG3 mRNA in the cells with miR-514a-3p overexpression compared with the control (Figure 2j).	('miR-514a-3p', 'Gene', '574518', (57, 68))	('miR-514a-3p', 'Gene', (57, 68))	('PEG3', 'Gene', (29, 33))	('overexpression', 'Var', (69, 83))	('men', 'Species', '9606', (21, 24))	('PEG3', 'Gene', '5178', (29, 33))
48765	28471449	As shown in Figure 3d, ectopic expression of PEG3 significantly decreased the apoptotic effect caused by miR-514a-3p overexpression.	('miR-514a-3p', 'Gene', '574518', (105, 116))	('miR-514a-3p', 'Gene', (105, 116))	('ectopic expression', 'Var', (23, 41))	('PEG3', 'Gene', '5178', (45, 49))	('overexpression', 'PosReg', (117, 131))	('PEG3', 'Gene', (45, 49))	('apoptotic effect', 'CPA', (78, 94))	('decreased', 'NegReg', (64, 73))
48770	28471449	Reduction of nuclear p50 expression was observed both in cells overexpressing miR-514a-3p and with silencing of PEG3 expression (Figure 4b).	('PEG3', 'Gene', '5178', (112, 116))	('nuclear', 'MPA', (13, 20))	('miR-514a-3p', 'Gene', '574518', (78, 89))	('miR-514a-3p', 'Gene', (78, 89))	('p50', 'Gene', (21, 24))	('PEG3', 'Gene', (112, 116))	('p50', 'Gene', '4790', (21, 24))	('Reduction', 'NegReg', (0, 9))	('silencing', 'Var', (99, 108))
48775	28471449	Silencing of PEG3 expression resulted in a significant decrease in nuclear p50 and p52 expression (Figures 4c-e).	('p50', 'Gene', (75, 78))	('PEG3', 'Gene', '5178', (13, 17))	('p50', 'Gene', '4790', (75, 78))	('p52', 'Gene', (83, 86))	('PEG3', 'Gene', (13, 17))	('decrease', 'NegReg', (55, 63))	('p52', 'Gene', '4791', (83, 86))	('Silencing', 'Var', (0, 9))
48792	28471449	Deregulation of miRNA expressions is known to be involved in testicular germ cell tumorigenesis.	('Deregulation', 'Var', (0, 12))	('germ cell tumor', 'Phenotype', 'HP:0100728', (72, 87))	('involved', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('miRNA expressions', 'Protein', (16, 33))
48795	28471449	This cluster is conserved in primates, and consists of seven distinct miRNAs, that is, miR-506, miR-507, miR-508, miR-509, miR-510, miR-513 and miR-514.	('miR-506', 'Gene', '574511', (87, 94))	('miR-506', 'Gene', (87, 94))	('miR-507', 'Gene', '574512', (96, 103))	('miR-510', 'Gene', (123, 130))	('miR-509', 'Var', (114, 121))	('miR-508', 'Gene', (105, 112))	('miR-510', 'Gene', '574515', (123, 130))	('miR-514', 'Var', (144, 151))	('miR-508', 'Gene', '574513', (105, 112))	('miR-513', 'Var', (132, 139))	('miR-507', 'Gene', (96, 103))
48808	28471449	Here, we show that silencing of PEG3 expression reduces p105 proteolysis, p50 nuclear translocation and NF-kappaB reporter activity, which provide additional evidence supporting the involvement of PEG3 in the NF-kappaB pathway.	('PEG3', 'Gene', '5178', (197, 201))	('men', 'Species', '9606', (189, 192))	('NF-kappaB', 'Gene', '4790', (209, 218))	('p50', 'Gene', (74, 77))	('PEG3', 'Gene', (32, 36))	('PEG3', 'Gene', (197, 201))	('silencing', 'Var', (19, 28))	('p50', 'Gene', '4790', (74, 77))	('reduces', 'NegReg', (48, 55))	('NF-kappaB', 'Gene', (209, 218))	('p105', 'Gene', (56, 60))	('p105', 'Gene', '4790', (56, 60))	('NF-kappaB', 'Gene', '4790', (104, 113))	('PEG3', 'Gene', '5178', (32, 36))	('NF-kappaB', 'Gene', (104, 113))
48816	28471449	In conclusion, we provide evidence to support a model of PEG3-mediated activation of NF-kappaB in TGCT, in which loss of miR-514a-3p in TGCT increases PEG3 expression that recruits TRAF2 and activate the NF-kappaB pathway for protecting cells from apoptosis.	('NF-kappaB', 'Gene', (204, 213))	('NF-kappaB', 'Gene', '4790', (85, 94))	('PEG3', 'Gene', '5178', (57, 61))	('increases', 'PosReg', (141, 150))	('PEG3', 'Gene', '5178', (151, 155))	('TRAF2', 'Gene', '7186', (181, 186))	('NF-kappaB', 'Gene', (85, 94))	('PEG3', 'Gene', (57, 61))	('miR-514a-3p', 'Gene', (121, 132))	('loss', 'Var', (113, 117))	('NF-kappaB', 'Gene', '4790', (204, 213))	('activate', 'PosReg', (191, 199))	('TRAF2', 'Gene', (181, 186))	('TGCT', 'Gene', (136, 140))	('PEG3', 'Gene', (151, 155))	('miR-514a-3p', 'Gene', '574518', (121, 132))	('recruits', 'PosReg', (172, 180))
48834	28471449	For mature miRNAs, cDNA was synthesized from 150 ng of total RNA and used to quantitate miR-506 (ID 001050), miR-510 (ID 002241), miR-514a-3p (ID 242955_mat), miR-513c (ID 002756), miR-513b (ID 002757), miR-513a-5p (ID 002090), miR-507 (ID 001051), miR-508-5p (ID 002092), miR-21 (ID 000397), miR-223 (ID 002295), miR-372 (ID 000560) and miR-373 (ID 000561).	('ID 002092', 'Var', (261, 270))	('miR-513c', 'Gene', (159, 167))	('miR-372', 'Gene', '442917', (314, 321))	('miR-21', 'Gene', '406991', (273, 279))	('ID 002295', 'Var', (302, 311))	('ID 002757', 'Var', (191, 200))	('miR-513b', 'Gene', '100313822', (181, 189))	('miR-510', 'Gene', (109, 116))	('miR-513b', 'Gene', (181, 189))	('miR-514a-3p', 'Gene', (130, 141))	('ID 001051', 'Var', (237, 246))	('miR-506', 'Gene', '574511', (88, 95))	('miR-223', 'Gene', (293, 300))	('miR-510', 'Gene', '574515', (109, 116))	('miR-21', 'Gene', (273, 279))	('miR-373', 'Gene', (338, 345))	('ID 242955_mat', 'Var', (143, 156))	('ID 002090', 'Var', (216, 225))	('miR-514a-3p', 'Gene', '574518', (130, 141))	('miR-507', 'Gene', (228, 235))	('ID 000397', 'Var', (281, 290))	('miR-508', 'Gene', '574513', (249, 256))	('miR-373', 'Gene', '442918', (338, 345))	('miR-372', 'Gene', (314, 321))	('miR-223', 'Gene', '407008', (293, 300))	('miR-508', 'Gene', (249, 256))	('miR-507', 'Gene', '574512', (228, 235))	('miR-506', 'Gene', (88, 95))	('ID 000560', 'Var', (323, 332))	('miR-513c', 'Gene', '100302114', (159, 167))	('ID 002756', 'Var', (169, 178))
48837	28471449	Relative expression was normalized against the geometric mean of GAPDH (Hs02758991_g1) and 18S (Hs99999901_s1; Supplementary Figure 5).	('GAPDH', 'Gene', (65, 70))	('men', 'Species', '9606', (117, 120))	('Hs02758991_g1', 'Var', (72, 85))	('Hs99999901_s1', 'Var', (96, 109))	('GAPDH', 'Gene', '2597', (65, 70))
48865	28471449	After blocking with 5% skim milk powder (Merck, Darmstadt, Germany) diluted in TBS/0.05% Tween 20, membranes were incubated with anti-ZIM2/PEG3 (ab139166; Abcam; at dilution 1:750), anti-TRAF2 (ab12122; Abcam; 1:750), anti-cleaved PARP (ab32064; Abcam; 1:65 000), anti-human AGO2 antibody (ab57113; Abcam; 1:400), anti-H3 (9715; Cell Signaling Technologies, Danvers, MA, USA; 1:10 000) or anti-p105/p50 (ab31412; Abcam; 1:500).	('PEG3', 'Gene', (139, 143))	('PARP', 'Gene', '142', (231, 235))	('TRAF2', 'Gene', (187, 192))	('p105', 'Gene', '4790', (394, 398))	('ZIM2', 'Gene', '23619', (134, 138))	('p105', 'Gene', (394, 398))	('AGO2', 'Gene', (275, 279))	('human', 'Species', '9606', (269, 274))	('ab12122', 'Var', (194, 201))	('p50', 'Gene', '4790', (399, 402))	('ZIM2', 'Gene', (134, 138))	('AGO2', 'Gene', '27161', (275, 279))	('TRAF2', 'Gene', '7186', (187, 192))	('PARP', 'Gene', (231, 235))	('PEG3', 'Gene', '5178', (139, 143))	('p50', 'Gene', (399, 402))
48869	28471449	Cells were transfected with 3 mug of pCMV6-PEG3-CDS or pCMV6-entry for 48 h and then harvested in modified RIPA lysis buffer without SDS.	('PEG3', 'Gene', '5178', (43, 47))	('pCMV6-entry', 'Var', (55, 66))	('SDS', 'Chemical', 'MESH:D012967', (133, 136))	('PEG3', 'Gene', (43, 47))	('RIPA lysis buffer', 'Chemical', '-', (107, 124))
48874	28471449	Alexa Fluor 488 and 546-conjugated secondary antibodies (A11008 and A11003, respectively; Life Technologies) were diluted to 1:400 and applied on the cells for an hour at room temperature.	('A11003', 'Var', (68, 74))	('Alexa Fluor 488', 'Chemical', '-', (0, 15))	('A11008', 'Var', (57, 63))
48932	19903067	The factors for which there is some evidence of association include hormone use during pregnancy, bleeding during pregnancy, maternal body weight, maternal socioeconomic status, breech presentation, twin birth and trisomy 21 (Down syndrome).	('twin', 'Disease', (199, 203))	('bleeding', 'Disease', 'MESH:D006470', (98, 106))	('bleeding', 'Disease', (98, 106))	('maternal body weight', 'CPA', (125, 145))	('trisomy', 'Var', (214, 221))	('breech presentation', 'Phenotype', 'HP:0001623', (178, 197))	('breech presentation', 'Disease', (178, 197))
48971	19903067	Several studies have reported that cryptorchidism, low birth weight and low birth order are factors predominantly associated with an increased risk of seminoma.	('cryptorchidism', 'Disease', (35, 49))	('cryptorchidism', 'Phenotype', 'HP:0000028', (35, 49))	('seminoma', 'Disease', (151, 159))	('low birth weight', 'Phenotype', 'HP:0001518', (51, 67))	('low birth weight', 'Var', (51, 67))	('associated', 'Reg', (114, 124))	('low birth order', 'Phenotype', 'HP:0001518', (72, 87))	('seminoma', 'Disease', 'MESH:D018239', (151, 159))
48981	19903067	Candidate locus studies have provided evidence of risk associated with the gr/gr deletion on the Y chromosome and with variation in the phosphodiesterase 11A (PDE11A) gene.	('gr/gr', 'Gene', (75, 80))	('phosphodiesterase 11A', 'Gene', (136, 157))	('deletion', 'Var', (81, 89))	('PDE11A', 'Gene', '50940', (159, 165))	('PDE11A', 'Gene', (159, 165))	('phosphodiesterase 11A', 'Gene', '50940', (136, 157))
48982	19903067	The strongest of these associations, that of genetic variants in the region of the KITLG locus on the short arm of chromosome 12, may be particularly important as the KITLG gene is a key factor in primordial germ cell migration and proliferation.	('KITLG', 'Gene', '4254', (167, 172))	('short arm', 'Phenotype', 'HP:0009824', (102, 111))	('KITLG', 'Gene', (167, 172))	('variants', 'Var', (53, 61))	('KITLG', 'Gene', '4254', (83, 88))	('KITLG', 'Gene', (83, 88))
49006	33643710	Importantly, abnormal Wnt/beta-catenin signaling is commonly associated with cancer initiation.	('beta-catenin', 'Gene', '1499', (26, 38))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('abnormal', 'Var', (13, 21))	('beta-catenin', 'Gene', (26, 38))	('associated', 'Reg', (61, 71))
49031	33643710	Finally, the KnockTF database was queried to search for publicly available experiments correlating the knockdown of TEAD TFs with changes in WNT5A expression.	('WNT5A', 'Gene', (141, 146))	('changes', 'Reg', (130, 137))	('expression', 'MPA', (147, 157))	('TFs', 'Gene', (121, 124))	('WNT5A', 'Gene', '7474', (141, 146))	('knockdown', 'Var', (103, 112))
49059	33643710	Finally, using the KnockTF database to search for genes down-regulated after knockdown of TEAD TFs indicates that WNT5A is among the most down-regulated genes after TEAD4 knockdown in the SNU216 gastric cell line (Fig.	('SNU216', 'CellLine', 'CVCL:3946', (188, 194))	('WNT5A', 'Gene', (114, 119))	('knockdown', 'Var', (171, 180))	('down-regulated', 'NegReg', (138, 152))	('TEAD4', 'Gene', '7004', (165, 170))	('WNT5A', 'Gene', '7474', (114, 119))	('TEAD4', 'Gene', (165, 170))
49062	33643710	Given that both Wnt5a and abnormal YAP/TAZ signaling have been linked to cancer (see 'Introduction'), this relationship was further explored using cancer gene expression data.	('cancer', 'Disease', (73, 79))	('TAZ', 'Gene', '6901', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('YAP', 'Gene', (35, 38))	('TAZ', 'Gene', (39, 42))	('linked', 'Reg', (63, 69))	('Wnt5a', 'Gene', '7474', (16, 21))	('YAP', 'Gene', '10413', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('Wnt5a', 'Gene', (16, 21))	('abnormal', 'Var', (26, 34))
49081	33643710	Interestingly, both JNK (pT183, Y185) and AKT (pT308) phosphorylation were highly correlated with YAP expression in TGCT cancer (Fig.	('pT183', 'Var', (25, 30))	('JNK', 'Gene', '5599', (20, 23))	('AKT', 'Gene', '207', (42, 45))	('AKT', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('YAP', 'Gene', '10413', (98, 101))	('correlated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('JNK', 'Gene', (20, 23))	('Y185', 'Var', (32, 36))	('cancer', 'Disease', (121, 127))	('YAP', 'Gene', (98, 101))	('phosphorylation', 'MPA', (54, 69))
49083	33643710	These results must be interpreted with caution since high Wnt5a expression might lead to activation of other intracellular effectors, such as Rho GTPases, in these cancer types.	('intracellular effectors', 'MPA', (109, 132))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Wnt5a', 'Gene', (58, 63))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('activation', 'PosReg', (89, 99))	('Wnt5a', 'Gene', '7474', (58, 63))
49153	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))	('600,000', 'Var', (88, 95))	('patients', 'Species', '9606', (43, 51))	('IL2', 'Gene', '3558', (83, 86))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('HD', 'Disease', 'MESH:D006816', (80, 82))
49206	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))
49247	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))
49288	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))
49289	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))
49291	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))	('sipuleucel-T', 'Var', (68, 80))	('patients', 'Species', '9606', (45, 53))	('Cerebrovascular events', 'Phenotype', 'HP:0001297', (0, 22))	('Cerebrovascular', 'Disease', (0, 15))
49294	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))
49321	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))
49351	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))
49367	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))
49371	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))
49373	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))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
49374	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.	('mutations', 'Var', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (138, 143))
49377	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))
49385	24292451	Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis Developmental arrest of fetal germ cells may lead to neoplastic transformation and formation of germ cell tumours via carcinoma in situ (CIS) cells.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (69, 86))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('formation of germ cell', 'Phenotype', 'HP:0012862', (211, 233))	('tumours via carcinoma in situ', 'Disease', (234, 263))	('CIS', 'Phenotype', 'HP:0030075', (265, 268))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('tumours via carcinoma in situ', 'Disease', 'MESH:D002278', (234, 263))	('formation', 'CPA', (211, 220))	('carcinoma', 'Disease', (246, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('hypomethylated', 'Var', (93, 107))	('carcinoma', 'Disease', (69, 78))	('men', 'Species', '9606', (135, 138))	('Developmental arrest', 'Phenotype', 'HP:0007281', (128, 148))	('carcinoma', 'Disease', 'MESH:D002277', (246, 255))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (246, 263))	('neoplastic transformation', 'CPA', (181, 206))	('carcinoma', 'Disease', 'MESH:D002277', (69, 78))	('lead to', 'Reg', (173, 180))
49411	24292451	High expression of Aid and Apobec1 is found in murine PGCs at E10.5-E12.5, and Aid-/- PGCs were found to be less demethylated than the wild-type PGCs.	('Aid', 'Gene', (19, 22))	('Apobec1', 'Gene', '11810', (27, 34))	('Aid', 'Gene', '11628', (19, 22))	('murine', 'Species', '10090', (47, 53))	('E10.5-E12.5', 'Var', (62, 73))	('Aid', 'Gene', (79, 82))	('Apobec1', 'Gene', (27, 34))	('Aid', 'Gene', '11628', (79, 82))	('less', 'NegReg', (108, 112))	('demethylated', 'MPA', (113, 125))
49420	24292451	Testicular-germ-cell-cancer-derived cell lines, NTera2 and TCam-2, were obtained from Dr PW Andrews (UK), and Dr J Shipley (UK), respectively, after permission from Dr S Kitazawa (Japan).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Dr J', 'Var', (110, 114))	('TCam-2', 'CellLine', 'CVCL:T012', (59, 65))	('NTera2', 'CellLine', 'CVCL:0034', (48, 54))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
49421	24292451	In brief, cells were grown at 37  C in a 5% CO2 atmosphere, in DMEM (NTera2 cells) or RPMI 1640 (TCam-2 cells) supplemented with 10% fetal calf serum, glutamine (58.5 mg ml-1), penicillin (100 U ml-1) and streptomycin (100 mg ml-1).	('penicillin', 'Chemical', 'MESH:D010406', (177, 187))	('DMEM', 'Chemical', '-', (63, 67))	('streptomycin', 'Chemical', 'MESH:D013307', (205, 217))	('men', 'Species', '9606', (117, 120))	('CO2', 'Chemical', '-', (44, 47))	('58.5', 'Var', (162, 166))	('100 U', 'Var', (189, 194))	('TCam-2', 'CellLine', 'CVCL:T012', (97, 103))	('NTera2', 'CellLine', 'CVCL:0034', (69, 75))	('calf', 'Species', '9913', (139, 143))	('RPMI', 'Chemical', '-', (86, 90))	('glutamine', 'Chemical', 'MESH:D005973', (151, 160))
49442	24292451	The following secondary antibodies were applied in pairs according to the respective primary antibodies: Alexa Fluor 488 goat anti-rabbit, Alexa Fluor 488 donkey anti-goat, Alexa Fluor 568 donkey anti-mouse (Life Technologies, Naerum, Denmark), all diluted 1 : 600, and incubation took place for 45 min at RT.	('donkey', 'Species', '9793', (155, 161))	('Alexa Fluor 568', 'Chemical', '-', (173, 188))	('donkey', 'Species', '9793', (189, 195))	('goat', 'Species', '9925', (167, 171))	('rabbit', 'Species', '9986', (131, 137))	('Alexa Fluor 568', 'Var', (173, 188))	('Alexa Fluor 488', 'Chemical', '-', (105, 120))	('Alexa Fluor 488', 'Chemical', '-', (139, 154))	('Alexa Fluor 488', 'Var', (139, 154))	('goat', 'Species', '9925', (121, 125))	('mouse', 'Species', '10090', (201, 206))
49448	24292451	Secondary antibodies were HRP-conjugated rabbit anti-mouse (P0260, Dako, Glostrup, Denmark), HRP-conjugated rabbit anti-goat (P0160, Dako) and HRP-conjugated swine anti-rabbit (P0217, Dako), all diluted at 1 : 1000.	('rabbit', 'Species', '9986', (108, 114))	('P0217', 'Var', (177, 182))	('rabbit', 'Species', '9986', (169, 175))	('goat', 'Species', '9925', (120, 124))	('P0160', 'Var', (126, 131))	('P0260', 'Var', (60, 65))	('swine', 'Species', '9823', (158, 163))	('mouse', 'Species', '10090', (53, 58))	('rabbit', 'Species', '9986', (41, 47))
49481	24292451	DNA hypomethylation may also facilitate aberrant expression of pluripotency genes, like POU5F1, NANOG and TFAP2C, which indeed are highly expressed in CIS cells.	('aberrant expression', 'MPA', (40, 59))	('POU5F1', 'Gene', '5460', (88, 94))	('TFAP2C', 'Gene', (106, 112))	('hypomethylation', 'Var', (4, 19))	('POU5F1', 'Gene', (88, 94))	('NANOG', 'Gene', '79923', (96, 101))	('TFAP2C', 'Gene', '7022', (106, 112))	('CIS', 'Phenotype', 'HP:0030075', (151, 154))	('facilitate', 'PosReg', (29, 39))	('NANOG', 'Gene', (96, 101))	('pluripotency genes', 'Gene', (63, 81))
49482	24292451	Aberrant expression of other epigenetic modifiers in CIS cells, like BLIMP/PRMT5, might also add to abnormal epigenetic reprogramming and thereby genomic instability.	('Aberrant', 'Var', (0, 8))	('CIS', 'Phenotype', 'HP:0030075', (53, 56))	('PRMT5', 'Gene', (75, 80))	('PRMT5', 'Gene', '10419', (75, 80))	('epigenetic reprogramming', 'CPA', (109, 133))	('genomic', 'MPA', (146, 153))	('add to', 'Reg', (93, 99))
49487	24292451	However, knock out of Tet1 in mouse did not impair fertility and only resulted slightly increased methylation levels.	('impair fertility', 'Phenotype', 'HP:0000144', (44, 60))	('methylation levels', 'MPA', (98, 116))	('Tet1', 'Gene', '52463', (22, 26))	('increased', 'PosReg', (88, 97))	('Tet1', 'Gene', (22, 26))	('mouse', 'Species', '10090', (30, 35))	('knock out', 'Var', (9, 18))
49498	24292451	Epigenetic modifications occurring during embryonic development are well recognised as being susceptible to alterations by exposure to environmental factors.	('men', 'Species', '9606', (59, 62))	('men', 'Species', '9606', (142, 145))	('alterations', 'Reg', (108, 119))	('Epigenetic modifications', 'Var', (0, 24))
49636	33718812	The clinical diagnosis was left testicular cancer T2N1M0S2, Stage IIA according to the Japanese Urological Association; the prognosis was considered to be good according to the International Germ Cell Consensus Classification.	('testicular cancer', 'Phenotype', 'HP:0010788', (32, 49))	('T2N1M0S2', 'Var', (50, 58))	('left testicular cancer', 'Disease', 'MESH:D013736', (27, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('left testicular cancer', 'Disease', (27, 49))
49656	33268348	The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (>=20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23).	('lower', 'NegReg', (77, 82))	('people', 'Species', '9606', (28, 34))	('non-chromosomal', 'Var', (44, 59))	('children', 'Species', '9606', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('birth defect', 'Disease', 'MESH:D000014', (60, 72))	('birth defect', 'Disease', (60, 72))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
49724	33268348	In the total population, the strongest associations were between defects involving genetic syndromes and microdeletions and cancers of urinary organs (odds ratio 35, 18 to 69), soft tissue (17, 5.6 to 49), and other endocrine glands (9.6, 3.0 to 31); between Down's syndrome and lymphoid/ haematopoietic malignancies (19, 16 to 23); between anomalies of the eye and eye cancer (18, 7.5 to 44); between nervous system defects and central nervous system tumours (16, 13 to 21); and between urinary organs defects and cancer of urinary organs (8.0, 4.5 to 14).	('haematopoietic malignancies', 'Disease', (289, 316))	('central nervous system tumours', 'Disease', (429, 459))	('anomalies of the eye and eye cancer', 'Disease', 'MESH:D005134', (341, 376))	("Down's syndrome", 'Disease', (259, 274))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('nervous system defects', 'Disease', (402, 424))	('haematopoietic malignancies', 'Disease', 'MESH:D009369', (289, 316))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('defects', 'Var', (65, 72))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('central nervous system tumours', 'Disease', 'MESH:D016543', (429, 459))	('nervous system defects', 'Disease', 'MESH:D009421', (402, 424))	('cancer', 'Disease', (515, 521))	('cancer', 'Phenotype', 'HP:0002664', (515, 521))	('anomalies of the eye', 'Phenotype', 'HP:0000478', (341, 361))	('cancer', 'Disease', (370, 376))	('associations', 'Interaction', (39, 51))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('tumour', 'Phenotype', 'HP:0002664', (452, 458))	('cancers', 'Disease', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('cancer', 'Disease', (124, 130))	('eye cancer', 'Phenotype', 'HP:0100012', (366, 376))	('tumours', 'Phenotype', 'HP:0002664', (452, 459))	('genetic syndromes', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nervous system defects', 'Phenotype', 'HP:0000707', (402, 424))	('genetic syndromes', 'Disease', 'MESH:D030342', (83, 100))	('microdeletions', 'Var', (105, 119))	('central nervous system tumours', 'Phenotype', 'HP:0100006', (429, 459))	('cancer', 'Disease', 'MESH:D009369', (515, 521))
49726	33268348	In this large population based nested case-control study in four Nordic countries, people with chromosomal and non-chromosomal birth defects were at increased risk of overall cancer into adulthood (investigated for individuals up to the age of 46).	('people', 'Species', '9606', (83, 89))	('chromosomal', 'Var', (95, 106))	('birth defects', 'Disease', 'MESH:D000014', (127, 140))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('birth defects', 'Disease', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
49749	33268348	Furthermore, we were able to look at anatomical subgroups of birth defects and observed that the increased risk at younger ages was more pronounced for some subgroups, such as nervous system defects, genetic syndromes and microdeletions, and chromosomal anomalies.	('birth defects', 'Disease', (61, 74))	('genetic syndromes', 'Disease', 'MESH:D030342', (200, 217))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (242, 263))	('chromosomal anomalies', 'Disease', (242, 263))	('genetic syndromes', 'Disease', (200, 217))	('microdeletions', 'Var', (222, 236))	('nervous system defects', 'Phenotype', 'HP:0000707', (176, 198))	('nervous system defects', 'Disease', (176, 198))	('nervous system defects', 'Disease', 'MESH:D009421', (176, 198))	('birth defects', 'Disease', 'MESH:D000014', (61, 74))
49752	33268348	The exception was for people with defects in genital organs relative those without such defects, for which the odds ratio for cancer (one third of which were testicular) was 1.43 (99% confidence interval 1.14 to 1.78) for adults compared with 1.25 (0.92 to 1.70) for children.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('defects', 'Var', (34, 41))	('defects in genital', 'Phenotype', 'HP:0000078', (34, 52))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('children', 'Species', '9606', (267, 275))	('people', 'Species', '9606', (22, 28))
49771	30282530	Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in an SD rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated with antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque and rete ovarii proliferative ovarian lesions in various aged rat strains.	('gallbladder mucinous hyperplasia', 'Disease', 'MESH:D005705', (215, 247))	('antisense', 'Var', (403, 412))	('intestinal leiomyositis', 'Disease', 'MESH:D007410', (174, 197))	('choriocarcinoma', 'Disease', 'MESH:D002822', (448, 463))	('seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (71, 101))	('rat', 'Species', '10116', (144, 147))	('rat', 'Species', '10116', (546, 549))	('choriocarcinoma', 'Disease', (448, 463))	('rat', 'Species', '10116', (302, 305))	('rhesus macaque', 'Species', '9544', (469, 483))	('rats', 'Species', '10116', (105, 109))	('myositis', 'Phenotype', 'HP:0100614', (189, 197))	('rete ovarii proliferative ovarian lesions', 'Disease', 'MESH:D010049', (488, 529))	('renal tubule cytoplasmic vacuolation', 'Phenotype', 'HP:0001922', (320, 356))	('mice', 'Species', '10090', (385, 389))	('rat', 'Species', '10116', (507, 510))	('rat', 'Species', '10116', (277, 280))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (448, 463))	('degeneration/necrosis', 'Disease', (138, 159))	('beagle dog', 'Species', '9615', (203, 213))	('degeneration/necrosis', 'Disease', 'MESH:D009336', (138, 159))	('rat', 'Species', '10116', (169, 172))	('gallbladder mucinous hyperplasia', 'Disease', (215, 247))	('rat', 'Species', '10116', (105, 108))	('ovarian lesions', 'Phenotype', 'HP:0100615', (514, 529))	('carcinoma', 'Phenotype', 'HP:0030731', (454, 463))	('rete ovarii proliferative ovarian lesions', 'Disease', (488, 529))	('intestinal leiomyositis', 'Disease', (174, 197))
49775	30282530	Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in Hsd:Sprague Dawley (SD) rats, ameloblast and odontoblast degeneration/necrosis with dentin matrix alteration in an SD rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters (Lutra lutra), renal tubule cytoplasmic vacuolation with basophilic granules in CRL:CD1(ICR) mice treated with antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque (Macaca mulatta) and rete ovarii proliferative ovarian lesions in various aged rat strains.	('rete ovarii proliferative ovarian lesions', 'Disease', 'MESH:D010049', (586, 627))	('rat', 'Species', '10116', (207, 210))	('Macaca mulatta', 'Species', '9544', (566, 580))	('rat', 'Species', '10116', (644, 647))	('intestinal leiomyositis', 'Disease', (228, 251))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (529, 544))	('seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (71, 101))	('dentin matrix alteration', 'Phenotype', 'HP:0011060', (189, 213))	('gallbladder mucinous hyperplasia', 'Disease', 'MESH:D005705', (269, 301))	('rats', 'Species', '10116', (129, 133))	('rat', 'Species', '10116', (223, 226))	('intestinal leiomyositis', 'Disease', 'MESH:D007410', (228, 251))	('mice', 'Species', '10090', (466, 470))	('antisense oligonucleotide therapy', 'Var', (484, 517))	('myositis', 'Phenotype', 'HP:0100614', (243, 251))	('rat', 'Species', '10116', (356, 359))	('degeneration/necrosis', 'Disease', (162, 183))	('degeneration/necrosis', 'Disease', 'MESH:D009336', (162, 183))	('rat', 'Species', '10116', (331, 334))	('Lutra lutra', 'Species', '9657', (374, 385))	('Sprague', 'Species', '10116', (109, 116))	('ovarian lesions', 'Phenotype', 'HP:0100615', (612, 627))	('rete ovarii proliferative ovarian lesions', 'Disease', (586, 627))	('choriocarcinoma', 'Disease', 'MESH:D002822', (529, 544))	('rat', 'Species', '10116', (605, 608))	('renal tubule cytoplasmic vacuolation', 'Phenotype', 'HP:0001922', (388, 424))	('beagle dog', 'Species', '9615', (257, 267))	('choriocarcinoma', 'Disease', (529, 544))	('rat', 'Species', '10116', (129, 132))	('rhesus macaque', 'Species', '9544', (550, 564))	('carcinoma', 'Phenotype', 'HP:0030731', (535, 544))	('rat', 'Species', '10116', (168, 171))	('gallbladder mucinous hyperplasia', 'Disease', (269, 301))
49788	30282530	Seminiferous tubule dysgenesis is characterized in experimental studies as a developmental malformation seen microscopically as aberrant or misshapen seminiferous tubules.	('Seminiferous tubule dysgenesis', 'Disease', (0, 30))	('misshapen', 'Var', (140, 149))	('men', 'Species', '9606', (84, 87))	('Seminiferous tubule dysgenesis', 'Phenotype', 'HP:0008660', (0, 30))	('men', 'Species', '9606', (57, 60))
49821	30282530	However, in utero phthalate exposure does cause a disorder of embryonic germ cells that manifests as multinucleated gonocytes in the neonatal rat.	('multinucleated gonocytes', 'CPA', (101, 125))	('phthalate', 'Var', (18, 27))	('cause', 'Reg', (42, 47))	('disorder of embryonic germ cells', 'Phenotype', 'HP:0012862', (50, 82))	('phthalate', 'Chemical', 'MESH:C032279', (18, 27))	('rat', 'Species', '10116', (142, 145))
49868	30282530	All cases were zebrafish (wild-type, mutant and transgenic) that presented from the same facility.	('transgenic', 'Var', (48, 58))	('mutant', 'Var', (37, 43))	('zebrafish', 'Species', '7955', (15, 24))
49981	30282530	The voting choices and results were: (1) delayed organogenesis, deformed yolk sac, eye abnormalities, pigmentation defects (2%); (2) stunted growth, axial skeletal deformities, craniofacial deformities, underdeveloped swim bladder (32%); (3) both 1 & 2 (66%) and (4) none of the above (0%).	('axial skeletal deformities', 'Phenotype', 'HP:0009121', (149, 175))	('stunted growth', 'Phenotype', 'HP:0001510', (133, 147))	('craniofacial deformities', 'Disease', 'MESH:D019465', (177, 201))	('craniofacial deformities', 'Phenotype', 'HP:0004484', (177, 201))	('pigmentation defects', 'Disease', (102, 122))	('eye abnormalities', 'Phenotype', 'HP:0000478', (83, 100))	('stunted growth', 'CPA', (133, 147))	('delayed organogenesis', 'CPA', (41, 62))	('axial skeletal deformities', 'Disease', (149, 175))	('pigmentation defects', 'Phenotype', 'HP:0001000', (102, 122))	('axial skeletal deformities', 'Disease', 'MESH:D009139', (149, 175))	('eye abnormalities', 'Disease', (83, 100))	('pigmentation defects', 'Disease', 'MESH:D010859', (102, 122))	('eye abnormalities', 'Disease', 'MESH:D005124', (83, 100))	('skeletal deformities', 'Phenotype', 'HP:0000924', (155, 175))	('craniofacial deformities', 'Disease', (177, 201))	('deformed', 'Var', (64, 72))
50035	30282530	Commonly used strains include New Zealand White (NZW), New Zealand Red (NZR), NZW x NZR F1 crosses, Dutch Belted (for ocular studies requiring a pigmented iris), and Watanabe (atherosclerosis).	('crosses', 'Var', (91, 98))	('atherosclerosis', 'Disease', (176, 191))	('Zealand Red', 'Chemical', 'MESH:C523279', (59, 70))	('pigmented iris', 'Disease', (145, 159))	('pigmented iris', 'Disease', 'MESH:D007499', (145, 159))	('atherosclerosis', 'Disease', 'MESH:D050197', (176, 191))	('atherosclerosis', 'Phenotype', 'HP:0002621', (176, 191))
50082	30282530	While the majority of the lesion was negative for CD10, there were rare foci of CD10 positivity which were negative for hCG and pancytokeratin (Figure 8F).	('positivity', 'Var', (85, 95))	('CD10', 'Gene', (80, 84))	('CD10', 'Gene', '24590', (80, 84))	('CD10', 'Gene', '24590', (50, 54))	('CD10', 'Gene', (50, 54))	('hCG', 'Gene', '93659', (120, 123))	('rat', 'Species', '10116', (137, 140))	('hCG', 'Gene', (120, 123))
50088	30282530	Trophoblastic tumors are rare neoplasms in domestic and laboratory animal species, and in non-human primates have been reported in the uterus and ovary In humans, most occur following a normal or ectopic pregnancy, abortion, or molar pregnancy.	('Trophoblastic tumors', 'Disease', (0, 20))	('molar pregnancy', 'CPA', (228, 243))	('domestic', 'Species', '9825', (43, 51))	('neoplasms', 'Phenotype', 'HP:0002664', (30, 39))	('ectopic pregnancy', 'Phenotype', 'HP:0031456', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('neoplasm', 'Phenotype', 'HP:0002664', (30, 38))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('humans', 'Species', '9606', (155, 161))	('neoplasms', 'Disease', 'MESH:D009369', (30, 39))	('rat', 'Species', '10116', (60, 63))	('ectopic', 'Var', (196, 203))	('human', 'Species', '9606', (94, 99))	('neoplasms', 'Disease', (30, 39))	('abortion', 'Disease', 'MESH:D000031', (215, 223))	('human', 'Species', '9606', (155, 160))	('Trophoblastic tumors', 'Disease', 'MESH:D014328', (0, 20))	('abortion', 'Disease', (215, 223))	('Trophoblastic tumors', 'Phenotype', 'HP:0031502', (0, 20))
50273	28353667	For example, many heavy metals, dioxins, PCBs, polycyclic aromatic hydrocarbons (PAHs), and other carcinogens have been shown to cause oxidative stress.	('PAHs', 'Chemical', 'MESH:D011084', (81, 85))	('PCBs', 'Chemical', 'MESH:D011078', (41, 45))	('cause', 'Reg', (129, 134))	('oxidative stress', 'MPA', (135, 151))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (47, 79))	('polycyclic aromatic', 'Var', (47, 66))	('dioxins', 'Chemical', 'MESH:D004147', (32, 39))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
50298	19077426	On Combining Triads and Unrelated Subjects Data in Candidate Gene Studies: An Application to Data on Testicular Cancer Combining data collected from different sources is a cost-effective and time-efficient approach for enhancing the statistical efficiency in estimating weak-to-modest genetic effects or gene-gene or gene-environment interactions.	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('enhancing', 'PosReg', (219, 228))	('Testicular Cancer', 'Phenotype', 'HP:0010788', (101, 118))	('Testicular Cancer', 'Disease', (101, 118))	('Testicular Cancer', 'Disease', 'MESH:D013736', (101, 118))	('men', 'Species', '9606', (329, 332))	('weak-to-modest', 'Var', (270, 284))
50311	19077426	To demonstrate our method, we present results from an analysis of several candidate polymorphisms in a study of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('testicular cancer', 'Phenotype', 'HP:0010788', (112, 129))	('testicular cancer', 'Disease', 'MESH:D013736', (112, 129))	('testicular cancer', 'Disease', (112, 129))	('polymorphisms', 'Var', (84, 97))
50318	19077426	Specifically, let Git = (Gip1, Gip2, Gi) denote the number of copies of the variant allele at a given locus carried by the first parent, the second parent, and the case in the ith triad.	('variant', 'Var', (76, 83))	('Gip', 'Gene', (25, 28))	('Gip', 'Gene', (31, 34))	('Gip', 'Gene', '2695', (25, 28))	('Gip', 'Gene', '2695', (31, 34))
50326	19077426	The true values for beta's were 0.405, 0.405, 0.405, 0.693, and 1.100, respectively, yielding ORs of 1.5 for the main effects of candidate genes, an OR of 2 for the environmental covariate, and an OR of 3 for the interaction.	('0.405', 'Var', (46, 51))	('0.405', 'Var', (39, 44))	('men', 'Species', '9606', (172, 175))	('interaction', 'Interaction', (213, 224))
50343	19077426	The specific polymorphisms examined included three SNPs (rs274057, CYP3A4 A-392G; rs2665802, GH1 T1663A; rs2854744, IGFBP3 A-202C) and one microsatellite polymorphism in IGF1 ((CA)n located at approximately -940 bp relative to the transcription start site).	('T1663A', 'Mutation', 'rs2665802', (97, 103))	('GH1', 'Gene', '2688', (93, 96))	('IGFBP3', 'Gene', '3486', (116, 122))	('T1663A; rs2854744', 'Var', (97, 114))	('A-392G', 'Mutation', 'rs2740574', (74, 80))	('rs274057', 'Var', (57, 65))	('CYP3A4', 'Gene', '1576', (67, 73))	('rs2665802', 'Mutation', 'rs2665802', (82, 91))	('GH1', 'Gene', (93, 96))	('rs2854744', 'Mutation', 'rs2854744', (105, 114))	('rs274057', 'Mutation', 'rs274057', (57, 65))	('IGF1', 'Gene', '3479', (170, 174))	('rs2665802', 'Var', (82, 91))	('A-202C', 'Mutation', 'rs2854744', (123, 129))	('rs2854744', 'Var', (105, 114))	('CYP3A4', 'Gene', (67, 73))	('IGFBP3', 'Gene', (116, 122))	('IGF1', 'Gene', (170, 174))
50347	19077426	Because the proteins encoded by IGFBP3 and GH1 modulate the levels and bioavailability of IGF1, respectively, we also examined interactions between the IGF1 and GH1 polymorphisms and between IGFBP3 and IGF1 polymorphisms (Table 9).	('bioavailability', 'MPA', (71, 86))	('IGFBP3', 'Gene', (191, 197))	('IGFBP3', 'Gene', (32, 38))	('IGF1', 'Gene', (90, 94))	('IGF1', 'Gene', (152, 156))	('IGF1', 'Gene', '3479', (202, 206))	('IGFBP3', 'Gene', '3486', (32, 38))	('IGFBP3', 'Gene', '3486', (191, 197))	('interactions', 'Interaction', (127, 139))	('polymorphisms', 'Var', (165, 178))	('examined', 'Reg', (118, 126))	('levels', 'MPA', (60, 66))	('GH1', 'Gene', (43, 46))	('GH1', 'Gene', (161, 164))	('IGF1', 'Gene', (202, 206))	('IGF1', 'Gene', '3479', (90, 94))	('IGF1', 'Gene', '3479', (152, 156))	('GH1', 'Gene', '2688', (43, 46))	('GH1', 'Gene', '2688', (161, 164))	('modulate', 'Reg', (47, 55))
50348	19077426	There was little evidence to suggest that GH1 or IGFBP3 genotypes modified the association between the IGF1 polymorphism and TGCC risk.	('modified', 'Reg', (66, 74))	('IGF1', 'Gene', '3479', (103, 107))	('polymorphism', 'Var', (108, 120))	('GH1', 'Gene', (42, 45))	('IGFBP3', 'Gene', (49, 55))	('association', 'Interaction', (79, 90))	('IGF1', 'Gene', (103, 107))	('IGFBP3', 'Gene', '3486', (49, 55))	('TGCC', 'Disease', (125, 129))	('GH1', 'Gene', '2688', (42, 45))
50353	19077426	The results of our simulation experiments suggest that the efficiency of the case-parents design is the same as or slightly better than the case-unrelated control design for main effects, and substantially better for gene-gene or gene-environment interaction effects when the same number of cases is used and there is an equal number of controls.	('gene-gene', 'Var', (217, 226))	('better', 'PosReg', (206, 212))	('men', 'Species', '9606', (36, 39))	('men', 'Species', '9606', (242, 245))	('better', 'PosReg', (124, 130))
50363	19077426	The data also consist of parental genotypes {Gpi Di = 1, Deltai = 1, i = 1, ..., I} for cases with Deltai = 1.	('Gpi', 'Gene', '2821', (45, 48))	('Deltai = 1', 'Var', (99, 109))	('Gpi', 'Gene', (45, 48))
50369	21564132	Using a multiplicative model, we estimated that white men in the top 1% of genetic risk as defined by eight risk variants had a relative risk that was 10.5-fold greater than that for the general white male population.	('greater', 'PosReg', (161, 168))	('variants', 'Var', (113, 121))	('men', 'Species', '9606', (54, 57))
50380	21564132	Single nucleotide polymorphisms (SNPs) with significant associations were identified in or near KITLG (ligand for the tyrosine kinase KIT), SPRY4 (an inhibitor of the mitogen-activated protein kinase pathway acting downstream of KITLG-KIT) and BAK1 (also acting downstream of KITLG).	('KITLG', 'Gene', (96, 101))	('KITLG', 'Gene', '4254', (229, 234))	('KITLG', 'Gene', (276, 281))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('BAK1', 'Gene', '578', (244, 248))	('KITLG', 'Gene', (229, 234))	('SPRY4', 'Gene', '81848', (140, 145))	('BAK1', 'Gene', (244, 248))	('KITLG', 'Gene', '4254', (96, 101))	('KITLG', 'Gene', '4254', (276, 281))	('SPRY4', 'Gene', (140, 145))
50381	21564132	Additional risk variants were discovered in or near DMRT1 (involved in gender determination), TERT and ATF7IP (both genes are involved in telomere maintenance).	('DMRT1', 'Gene', (52, 57))	('ATF7IP', 'Gene', (103, 109))	('ATF7IP', 'Gene', '55729', (103, 109))	('DMRT1', 'Gene', '1761', (52, 57))	('TERT', 'Gene', (94, 98))	('variants', 'Var', (16, 24))	('TERT', 'Gene', '7015', (94, 98))
50383	21564132	Notably, the calculated association effect size of variants in the region of KITLG (OR = 2.69) is the highest reported for any cancer to date.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('KITLG', 'Gene', '4254', (77, 82))	('variants', 'Var', (51, 59))	('KITLG', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
50385	21564132	The first GWAS published by investigators from the UK reported evidence that the two SNPs, rs995030 and rs1508595, in the KITLG locus were independently associated with disease risk.	('disease', 'Disease', (169, 176))	('rs995030', 'Var', (91, 99))	('rs1508595', 'Var', (104, 113))	('rs995030', 'Mutation', 'rs995030', (91, 99))	('KITLG', 'Gene', '4254', (122, 127))	('associated with', 'Reg', (153, 168))	('KITLG', 'Gene', (122, 127))	('rs1508595', 'Mutation', 'rs1508595', (104, 113))
50403	21564132	However, under the assumption that clinical factors are not correlated with TGCT risk variants, and do not interact with the TGCT loci as contributors to TGCT risk, a stratified genetic risk assessment (Figs 1c and 2) may be worth exploring in men with these clinical risk factors.	('TGCT', 'Phenotype', 'HP:0010788', (125, 129))	('men', 'Species', '9606', (244, 247))	('TGCT', 'Phenotype', 'HP:0010788', (76, 80))	('TGCT', 'Gene', (76, 80))	('variants', 'Var', (86, 94))	('men', 'Species', '9606', (197, 200))	('TGCT', 'Phenotype', 'HP:0010788', (154, 158))
50406	21564132	It has been suggested that before incorporating risk variants into individualized cancer risk assessment, the GWAS findings require validation in prospective studies to confirm the efficacy of these variants in predicting disease risk.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('men', 'Species', '9606', (100, 103))	('variants', 'Var', (199, 207))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('variants', 'Var', (53, 61))
50415	21564132	We found that a TGCT risk model that included seven SNPs and the gr/gr deletion (Table 1) would have a discriminative power that is considerably higher than that calculated for other common cancers such as breast, prostate and colon cancer.	('colon cancer', 'Disease', (227, 239))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancers', 'Disease', (190, 197))	('breast', 'Disease', (206, 212))	('prostate', 'Disease', (214, 222))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('TGCT', 'Phenotype', 'HP:0010788', (16, 20))	('deletion', 'Var', (71, 79))	('gr/gr', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('higher', 'PosReg', (145, 151))
50452	33922989	Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('alterations', 'Var', (197, 208))	('enhanced', 'PosReg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('drug accumulation', 'MPA', (99, 116))	('apoptosis', 'CPA', (254, 263))	('reduced', 'NegReg', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('drug detoxification', 'MPA', (127, 146))
50453	33922989	Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('colorectal cancer', 'Disease', (10, 27))	('defects', 'Var', (29, 36))	('p53', 'Gene', (68, 71))	('altered', 'Reg', (60, 67))	('mismatch repair', 'Protein', (40, 55))	('p53', 'Gene', '7157', (68, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
50454	33922989	In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis.	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('associated', 'Reg', (46, 56))	('chemoresistance', 'CPA', (62, 77))	('inactivation', 'Var', (19, 31))
50467	33922989	Crosslinks between two guanine bases on the opposite strands of DNA (DNA ICLs) are less abundant accounting for 1-2% of cisplatin-induced lesions.	('cisplatin-induced', 'MPA', (120, 137))	('guanine', 'Chemical', 'MESH:D006147', (23, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('Crosslinks', 'Var', (0, 10))
50475	33922989	Therefore, inactivation or mutation of p53 alters the cytotoxicity of cisplatin.	('cytotoxicity', 'Disease', (54, 66))	('alters', 'Reg', (43, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('inactivation', 'Var', (11, 23))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('mutation', 'Var', (27, 35))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))
50487	33922989	The efficiency, with which the different cisplatin-induced intrastrand crosslinks are repaired, varies, most likely due to the extent of the helical distortions caused by the lesions.	('helical', 'MPA', (141, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('lesions', 'Var', (175, 182))
50503	33922989	Furthermore, a number of studies have attempted to identify an association between genetic alterations in repair genes and cancer treatment, with a special emphasis given to NER genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('genetic alterations', 'Var', (83, 102))	('repair genes', 'Gene', (106, 118))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
50505	33922989	It is further postulated that SNPs not only affect the response to cancer treatment, but also increase the susceptibility to carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('increase', 'PosReg', (94, 102))	('SNPs', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('affect', 'Reg', (44, 50))
50508	33922989	However, in contrast to the protective effects of NER and ICL repair, MMR potentiates the toxicity of cisplatin.	('toxicity', 'Disease', 'MESH:D064420', (90, 98))	('potentiates', 'PosReg', (74, 85))	('toxicity', 'Disease', (90, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('MMR', 'Var', (70, 73))
50513	33922989	Mutations in MMR genes play an important role in carcinogenesis and increase cancer susceptibility.	('increase cancer', 'Disease', (68, 83))	('increase cancer', 'Disease', 'MESH:D009369', (68, 83))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MMR', 'Gene', (13, 16))	('carcinogenesis', 'CPA', (49, 63))
50514	33922989	The loss of MMR function is observed in both sporadic and hereditary colorectal cancer and is linked to mutations in either MLH1, MSH2, MSH6 or PMS2.	('PMS2', 'Gene', (144, 148))	('MLH1', 'Gene', '4292', (124, 128))	('mutations', 'Var', (104, 113))	('MSH6', 'Gene', '2956', (136, 140))	('MSH2', 'Gene', (130, 134))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (58, 86))	('MMR', 'Gene', (12, 15))	('MSH2', 'Gene', '4436', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('PMS2', 'Gene', '5395', (144, 148))	('MSH6', 'Gene', (136, 140))	('MLH1', 'Gene', (124, 128))	('loss', 'NegReg', (4, 8))	('function', 'MPA', (16, 24))	('hereditary colorectal cancer', 'Disease', (58, 86))
50516	33922989	Various studies revealed that MMR deficient cells are considerably more tolerant to cisplatin or alkylating agents indicating that intact MMR is necessary for maximal activity of these drugs and absence of MMR is associated with increased resistance.	('more', 'PosReg', (67, 71))	('resistance', 'MPA', (239, 249))	('MMR deficient', 'Disease', 'MESH:C536928', (30, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('absence', 'Var', (195, 202))	('MMR deficient', 'Disease', (30, 43))	('tolerant', 'MPA', (72, 80))
50523	33922989	TLS polymerases are error prone polymerases causing mis-incorporations of bases opposite the 1,2-intrastrand crosslinks, which are targets and recognized by the MUTSalpha complex.	('TLS', 'Disease', 'None', (0, 3))	('mis-incorporations', 'Var', (52, 70))	('causing', 'Reg', (44, 51))	('TLS', 'Disease', (0, 3))
50531	33922989	Even though in these cell culture models defective MMR is considered a minor contributor for the cisplatin resistance phenotype, the preclinical observations still imply that the loss of MMR function might have an adverse effect on cisplatin efficacy in cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('MMR', 'Gene', (187, 190))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cisplatin efficacy', 'MPA', (232, 250))	('cancer', 'Disease', (254, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (232, 241))	('loss', 'Var', (179, 183))
50533	33922989	With regards to colorectal cancer, a MMR deficient phenotype is frequently observed, either due to mutations in MMR genes or as a result of hypermethylation of the MLH1 gene.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MMR deficient', 'Disease', 'MESH:C536928', (37, 50))	('MMR genes', 'Gene', (112, 121))	('MLH1', 'Gene', '4292', (164, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('MLH1', 'Gene', (164, 168))	('MMR deficient', 'Disease', (37, 50))	('mutations', 'Var', (99, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))	('hypermethylation', 'Var', (140, 156))
50534	33922989	As an intact MMR system appears to be essential for the linkage of cisplatin damage with initiation of apoptosis, the MMR defect is therefore considered to strongly contribute to the intrinsic cisplatin resistance observed in patients with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('colorectal cancer', 'Disease', (240, 257))	('intrinsic cisplatin resistance', 'MPA', (183, 213))	('defect', 'Var', (122, 128))	('contribute', 'Reg', (165, 175))	('patients', 'Species', '9606', (226, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (240, 257))
50535	33922989	In response to cisplatin lesions, cell cycle checkpoints will be activated to delay cell cycle progression, which will facilitate DNA repair.	('delay', 'NegReg', (78, 83))	('lesions', 'Var', (25, 32))	('DNA', 'MPA', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('cell cycle progression', 'CPA', (84, 106))	('facilitate', 'PosReg', (119, 129))
50539	33922989	It is assumed that the platination damage might cause a block of the replication machinery resulting in replication-mediated DNA double strand breaks (DSBs).	('DSBs', 'Chemical', '-', (151, 155))	('replication machinery', 'CPA', (69, 90))	('replication-mediated', 'MPA', (104, 124))	('platination', 'Var', (23, 34))
50554	33922989	The p53 is mutated in approximately 50% of common human cancers, such as cancers of the breast, colon, and lung.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('p53', 'Gene', '7157', (4, 7))	('cancers of the breast', 'Phenotype', 'HP:0100013', (73, 94))	('lung', 'Disease', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('colon', 'Disease', (96, 101))	('human', 'Species', '9606', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('p53', 'Gene', (4, 7))	('mutated', 'Var', (11, 18))
50555	33922989	Due to its central role in DNA damage signaling, one would assume that the p53 status determines the response of tumor cells to cisplatin, and mutations in p53 would lead to failure of cell death pathways.	('tumor', 'Disease', (113, 118))	('response', 'MPA', (101, 109))	('cell death pathways', 'CPA', (185, 204))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('p53', 'Gene', (75, 78))	('failure', 'NegReg', (174, 181))	('p53', 'Gene', '7157', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lead to', 'Reg', (166, 173))	('mutations', 'Var', (143, 152))
50557	33922989	An anticancer drug screen performed by the National Cancer Institute in a panel of 60 cancer cell lines including seven colorectal cancer cell lines demonstrated that the growth inhibition following the cisplatin treatment correlated with the presence of wildtype p53, while the lack of functional p53 was associated with resistance to cisplatin.	('p53', 'Gene', '7157', (264, 267))	('growth', 'MPA', (171, 177))	('Cancer', 'Disease', (52, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('p53', 'Gene', (264, 267))	('colorectal cancer', 'Disease', (120, 137))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('presence', 'Var', (243, 251))	('p53', 'Gene', '7157', (298, 301))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (336, 345))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('p53', 'Gene', (298, 301))
50558	33922989	Similarly, the p53 inactivation rendered astrocytic tumor cells more resistant to the drug.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('resistant', 'CPA', (69, 78))	('more', 'PosReg', (64, 68))	('astrocytic tumor', 'Disease', (41, 57))	('astrocytic tumor', 'Disease', 'MESH:D001254', (41, 57))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('inactivation', 'Var', (19, 31))	('astrocytic tumor', 'Phenotype', 'HP:0009592', (41, 57))
50566	33922989	In contrast to the findings in pre-clinical studies with cancer cell lines, data obtained in tumor tissues derived from different cancers suggest a clear relationship between the p53 status and response to platinum-based chemotherapy.	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('status', 'Var', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Disease', (57, 63))	('cancers', 'Disease', (130, 137))	('cancer', 'Disease', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('platinum', 'Chemical', 'MESH:D010984', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
50567	33922989	Several studies have shown that patients with p53 wildtype tumors responded significantly better to cisplatin-based therapy, while inactivation of p53 has been linked to a poor response to the drug.	('patients', 'Species', '9606', (32, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('p53', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (59, 65))	('p53', 'Gene', '7157', (46, 49))	('better', 'PosReg', (90, 96))	('p53', 'Gene', '7157', (147, 150))	('inactivation', 'Var', (131, 143))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('wildtype', 'Var', (50, 58))	('p53', 'Gene', (147, 150))
50569	33922989	In contrast to most human cancers, p53 mutations are rare in TGCTs.	('human', 'Species', '9606', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
50570	33922989	Therefore, it was hypothesized that p53-controlled apoptotic signaling plays an important role in the response of TGCTs to chemotherapeutic drugs, and the lack of p53 mutations explains at least in part the therapeutic response of this type of tumor to cisplatin.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('p53', 'Gene', '7157', (163, 166))	('p53', 'Gene', (163, 166))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('mutations', 'Var', (167, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (253, 262))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
50571	33922989	Regarding colorectal cancer, one of the most frequently identified gene mutations occurs in the p53 gene, with 40-50% of sporadic colorectal cancer bearing p53 mutations.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Disease', (130, 147))	('p53', 'Gene', (96, 99))	('mutations', 'Var', (160, 169))	('p53', 'Gene', '7157', (96, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('colorectal cancer', 'Disease', (10, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
50572	33922989	For patients with colorectal cancer, it has been observed that tumors with mutant p53 are more chemo-resistant than those with wildtype p53 indicating a correlation between the status of p53 and cancer progression/poorer prognosis.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('colorectal cancer', 'Disease', (18, 35))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (136, 139))	('tumors', 'Disease', (63, 69))	('patients', 'Species', '9606', (4, 12))	('p53', 'Gene', (136, 139))	('cancer', 'Disease', (29, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('cancer', 'Disease', (195, 201))	('p53', 'Gene', '7157', (187, 190))	('chemo-resistant', 'CPA', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('correlation', 'Reg', (153, 164))	('p53', 'Gene', (187, 190))	('mutant', 'Var', (75, 81))	('p53', 'Gene', '7157', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
50574	33922989	In cell culture models, the defective p53 appears to be the major source of cisplatin resistance, while the MMR defect is considered a minor independent contributor, which induces a 2-fold factor of resistance.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('defective', 'Var', (28, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('cisplatin resistance', 'MPA', (76, 96))	('source', 'Reg', (66, 72))
50587	33922989	In response to oxaliplatin DNA damage, cell death is induced, which is mainly executed by the intrinsic apoptosis pathway, mediated by translocation of BAX to the mitochondria followed by cytochrome C release into the cytoplasm and activation of caspase 3.	('caspase 3', 'Gene', '836', (246, 255))	('cytochrome C', 'Gene', (188, 200))	('caspase 3', 'Gene', (246, 255))	('BAX', 'Gene', (152, 155))	('oxaliplatin DNA', 'Var', (15, 30))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (15, 26))	('translocation', 'MPA', (135, 148))	('cytochrome C', 'Gene', '54205', (188, 200))	('BAX', 'Gene', '581', (152, 155))	('cell death', 'CPA', (39, 49))
50590	33922989	The findings obtained in cell culture models suggested that oxaliplatin might possess clinical activity against intrinsically cisplatin resistant colorectal cancer, which is frequently characterized by a MMR deficient phenotype due to defects in MMR genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MMR genes', 'Gene', (246, 255))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('MMR deficient', 'Disease', 'MESH:C536928', (204, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('MMR deficient', 'Disease', (204, 217))	('defects', 'Var', (235, 242))	('colorectal cancer', 'Disease', (146, 163))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (60, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('intrinsically cisplatin resistant', 'MPA', (112, 145))
50594	33922989	Therefore, picoplatin is less susceptible to detoxification by intracellular thiols, and it was shown that picoplatin retained activity against a wide range of cisplatin resistant tumor cell lines including colorectal cancer cells as well as antitumor activity in vivo in tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('thiols', 'Chemical', 'MESH:D013438', (77, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('colorectal cancer', 'Disease', (207, 224))	('activity', 'MPA', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('picoplatin', 'Var', (107, 117))	('picoplatin', 'Chemical', 'MESH:C110525', (107, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('tumor', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('picoplatin', 'Chemical', 'MESH:C110525', (11, 21))	('tumor', 'Disease', (180, 185))	('cisplatin resistant', 'MPA', (160, 179))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
50608	33922989	The Pt (II) complex phenanthriplatin induces monofunctional adducts at guanine bases, which interfere with the normal function of RNA polymerase II that ultimately will lead to apoptosis in cancer cells.	('induces', 'Reg', (37, 44))	('apoptosis', 'CPA', (177, 186))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('phenanthriplatin', 'Chemical', 'MESH:C587603', (20, 36))	('interfere', 'NegReg', (92, 101))	('phenanthriplatin', 'Var', (20, 36))	('guanine bases', 'MPA', (71, 84))	('Pt (II)', 'Chemical', '-', (4, 11))	('function', 'MPA', (118, 126))	('guanine', 'Chemical', 'MESH:D006147', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('lead to', 'Reg', (169, 176))	('monofunctional adducts', 'MPA', (45, 67))
50609	33922989	Phenanthriplatin has been shown to be more cytotoxic than cisplatin and oxaliplatin in a number of cell lines derived from cancers of the lung, cervix, bones, and prostate.	('Phenanthriplatin', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Phenanthriplatin', 'Chemical', 'MESH:C587603', (0, 16))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (72, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('cytotoxic', 'CPA', (43, 52))
50621	33922989	About 50% of cancers harbor mutations in the TP53 gene, while in tumors retaining wildtype p53, MDM2 plays an important role in regulating the p53 protein.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('p53', 'Gene', '7157', (143, 146))	('MDM2', 'Gene', '4193', (96, 100))	('tumors', 'Disease', (65, 71))	('p53', 'Gene', (91, 94))	('MDM2', 'Gene', (96, 100))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('p53', 'Gene', '7157', (91, 94))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('cancers', 'Disease', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('p53', 'Gene', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mutations', 'Var', (28, 37))
50630	33922989	The NHEJ inhibitors SCR7 and NU7441 showed a sensitizing effect to cisplatin in the colon cancer cell line LoVo, but the sensitizing effect was rather small and to date has been observed solely in vitro.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('LoVo', 'CellLine', 'CVCL:0399', (107, 111))	('sensitizing', 'MPA', (45, 56))	('NU7441', 'Var', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Disease', (84, 96))	('SCR7', 'Var', (20, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('NHEJ', 'Gene', (4, 8))
50637	33922989	Inhibition of Chk1/2 may disable cell cycle checkpoints and therefore allow the cells to progress through the cell cycle despite the presence of DNA damage, which ultimately results in apoptosis.	('disable', 'NegReg', (25, 32))	('Chk1/2', 'Gene', '1111;11200', (14, 20))	('cell cycle checkpoints', 'CPA', (33, 55))	('apoptosis', 'CPA', (185, 194))	('allow', 'Reg', (70, 75))	('results in', 'Reg', (174, 184))	('Inhibition', 'Var', (0, 10))	('Chk1/2', 'Gene', (14, 20))	('progress through the cell cycle', 'CPA', (89, 120))
50664	33095756	ROS can have a negative influence on sperm function and quality due to the reduced motility of spermatozoa, DNA damage and the impaired integrity of the cellular membrane.	('ROS', 'Var', (0, 3))	('integrity', 'MPA', (136, 145))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('reduced motility of spermatozoa', 'Phenotype', 'HP:0012207', (75, 106))	('reduced', 'NegReg', (75, 82))	('DNA damage', 'CPA', (108, 118))	('impaired', 'NegReg', (127, 135))	('motility of spermatozoa', 'CPA', (83, 106))	('sperm function', 'CPA', (37, 51))
50667	33095756	It has been confirmed that antioxidant capacity in semen is decreased in infertile men and men with testicular cancer with a high ROS proportion, compared to men with a normal proportion of ROS.	('ROS', 'Var', (130, 133))	('decreased', 'NegReg', (60, 69))	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('infertile', 'Disease', 'MESH:D007247', (73, 82))	('men', 'Species', '9606', (83, 86))	('high ROS', 'Var', (125, 133))	('testicular cancer', 'Phenotype', 'HP:0010788', (100, 117))	('infertile', 'Disease', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('men', 'Species', '9606', (91, 94))	('antioxidant capacity', 'MPA', (27, 47))	('men', 'Species', '9606', (53, 56))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('men', 'Species', '9606', (158, 161))
50688	33095756	A total of 80 infertile men with O+-A+-T were enrolled after they signed a written informed consent to participate in this trial.	('infertile', 'Disease', 'MESH:D007247', (14, 23))	('infertile', 'Disease', (14, 23))	('O+-A+-T', 'Var', (33, 40))	('men', 'Species', '9606', (24, 27))
50759	31888467	The results were validated by using the well-known TERT regulation by the ETS1 transcription factor in a subset of melanomas with mutations in the TERT promoter.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('TERT', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('TERT', 'Gene', (51, 55))	('TERT', 'Gene', '7015', (147, 151))	('mutations', 'Var', (130, 139))	('TERT', 'Gene', '7015', (51, 55))	('melanomas', 'Disease', (115, 124))	('ETS1', 'Gene', '2113', (74, 78))	('ETS1', 'Gene', (74, 78))
50769	31888467	Previous studies showed that TERT promoter mutations can induce its expression in cancer cells.	('TERT', 'Gene', '7015', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (43, 52))	('induce', 'Reg', (57, 63))	('TERT', 'Gene', (29, 33))
50771	31888467	Here, we performed an in silico pan-cancer analysis of TERT regulation by using an evolved version of the "Mixed Integer linear Programming based Regulatory Interaction Predictor" (MIPRIP, version 2.0) to predict TFs regulating the gene expression of TERT.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TERT', 'Gene', (251, 255))	('cancer', 'Disease', (36, 42))	('MIPRIP', 'Chemical', '-', (181, 187))	('TERT', 'Gene', '7015', (251, 255))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TFs', 'Var', (213, 216))	('gene expression', 'MPA', (232, 247))
50772	31888467	The new version bases on MIPRIP (https://github.com/KoenigLabNM/MIPRIP) which was previously developed to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in Saccharomyces cerevisiae between yeast deletion strains with shorter telomeres and strains with wild-type telomere length.	('MIPRIP', 'Chemical', '-', (64, 70))	('MIPRIP', 'Chemical', '-', (25, 31))	('deletion', 'Var', (247, 255))	('yeast', 'Species', '4932', (241, 246))	('Saccharomyces cerevisiae', 'Species', '4932', (208, 232))	('telomerase', 'MPA', (176, 186))
50795	31888467	To show that the prediction of TERT expression from our models is better than expected by a set of TFs selected by random chance, we randomly selected non-TERT TFs used by our model to predict the expression of TERT in the melanoma samples with a TERT promoter mutation.	('melanoma', 'Disease', (223, 231))	('TERT', 'Gene', '7015', (211, 215))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('TERT', 'Gene', (247, 251))	('TERT', 'Gene', '7015', (247, 251))	('mutation', 'Var', (261, 269))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', (211, 215))	('TERT', 'Gene', '7015', (155, 159))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
50798	31888467	Melanoma skin cancer was the first cancer type for which a high frequency of TERT promoter mutations was discovered, mainly in two hotspot C > T mutations at position 124 bp and 146 bp upstream of the translational start codon.	('cancer', 'Disease', (14, 20))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('C > T', 'Var', (139, 144))	('skin cancer', 'Phenotype', 'HP:0008069', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (35, 41))	('Melanoma skin cancer', 'Disease', 'MESH:D012878', (0, 20))	('Melanoma skin cancer', 'Disease', (0, 20))
50801	31888467	Considering this and the high rate of TERT promoter mutations we divided the dataset into samples with and without TERT promoter mutation objecting to improve our predictions.	('mutations', 'Var', (52, 61))	('TERT', 'Gene', '7015', (115, 119))	('TERT', 'Gene', (38, 42))	('TERT', 'Gene', '7015', (38, 42))	('TERT', 'Gene', (115, 119))
50806	31888467	Indeed, TERT expression was lower in the ETS1 knockdown sample compared to controls (fold change: 0.82).	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('knockdown', 'Var', (46, 55))	('ETS1', 'Gene', '2113', (41, 45))	('ETS1', 'Gene', (41, 45))	('lower', 'NegReg', (28, 33))
50811	31888467	In summary, splitting up the melanoma dataset into two pre-defined cancer subgroups with and without the TERT promoter mutations led to more reliable modelling results (r = 0.29).	('TERT', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('TERT', 'Gene', '7015', (105, 109))	('cancer', 'Disease', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (119, 128))
50818	31888467	It is known that a TERT promoter mutation leads to a further binding site of TFs of the ETS family.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('mutation', 'Var', (33, 41))	('TFs', 'Gene', (77, 80))	('binding', 'Interaction', (61, 68))
50835	31888467	In their model, loss of MYC led to suppression of TERT, which was substantially rescued only by a co-suppression of AR.	('suppression', 'NegReg', (35, 46))	('MYC', 'Gene', (24, 27))	('TERT', 'Gene', '7015', (50, 54))	('AR', 'Gene', '367', (116, 118))	('loss', 'Var', (16, 20))	('MYC', 'Gene', '4609', (24, 27))	('TERT', 'Gene', (50, 54))
50843	31888467	As described in the literature, cutaneous melanoma skin cancer patients have a high rate of TERT promoter mutations, being responsible for an upregulation of TERT by enabling a further binding site of TFs from the ETS family.	('TERT', 'Gene', (92, 96))	('upregulation', 'PosReg', (142, 154))	('TERT', 'Gene', '7015', (92, 96))	('TFs', 'Protein', (201, 204))	('TERT', 'Gene', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TERT', 'Gene', '7015', (158, 162))	('enabling', 'PosReg', (166, 174))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('cutaneous melanoma skin cancer', 'Disease', 'MESH:D012878', (32, 62))	('binding site', 'Interaction', (185, 197))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (63, 71))	('cutaneous melanoma skin cancer', 'Disease', (32, 62))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
50845	31888467	We identified ETS1 as a highly significant regulator for TERT in tumors with TERT promoter mutation.	('mutation', 'Var', (91, 99))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (57, 61))	('TERT', 'Gene', '7015', (77, 81))	('ETS1', 'Gene', '2113', (14, 18))	('ETS1', 'Gene', (14, 18))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
50846	31888467	To further validate this finding we analyzed publicly available expression data of an ETS1 siRNA knockdown experiment in a melanoma cell line with TERT promoter mutation and found a downregulation of TERT compared to controls.	('TERT', 'Gene', (147, 151))	('mutation', 'Var', (161, 169))	('TERT', 'Gene', '7015', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('downregulation', 'NegReg', (182, 196))	('melanoma', 'Disease', (123, 131))	('ETS1', 'Gene', '2113', (86, 90))	('ETS1', 'Gene', (86, 90))	('TERT', 'Gene', (200, 204))	('TERT', 'Gene', '7015', (200, 204))
50848	31888467	Furthermore, it was shown elsewhere that TERT promoter mutations can lead to a two- to four-fold higher TERT promoter activity in melanoma cells.	('higher', 'PosReg', (97, 103))	('mutations', 'Var', (55, 64))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('TERT', 'Gene', (104, 108))	('TERT', 'Gene', '7015', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))
50851	31888467	AR and E2F were also predicted as common TERT regulators in our multi-mode MIPRIP analysis.	('MIPRIP', 'Chemical', '-', (75, 81))	('E2F', 'Var', (7, 10))	('E2', 'Chemical', 'MESH:D004958', (7, 9))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('AR', 'Gene', '367', (0, 2))
50859	31888467	While only a few samples showed a TERT promoter mutation, it is still unclear if there is an association between HMGA2 expression and TERT promoter mutations.	('HMGA2', 'Gene', '8091', (113, 118))	('TERT', 'Gene', (134, 138))	('TERT', 'Gene', (34, 38))	('HMGA2', 'Gene', (113, 118))	('TERT', 'Gene', '7015', (134, 138))	('mutation', 'Var', (48, 56))	('TERT', 'Gene', '7015', (34, 38))
50860	31888467	According to our predictions, we suggest that TERT regulation by HMGA2 and TERT promoter mutations are mutually exclusive, which has to be validated in future experiments.	('TERT', 'Gene', '7015', (46, 50))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('HMGA2', 'Gene', '8091', (65, 70))	('HMGA2', 'Gene', (65, 70))	('mutations', 'Var', (89, 98))	('TERT', 'Gene', (46, 50))
50862	31888467	Using the specific application of known ETS binding site in the TERT promoter of melanoma samples with a TERT promoter mutation as a case study, we compared the results from MIPRIP 2.0 with ISMARA.	('TERT', 'Gene', (105, 109))	('TERT', 'Gene', (64, 68))	('mutation', 'Var', (119, 127))	('TERT', 'Gene', '7015', (105, 109))	('TERT', 'Gene', '7015', (64, 68))	('MIPRIP', 'Chemical', '-', (174, 180))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('ISMARA', 'Chemical', '-', (190, 196))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
50864	31888467	Particularly, ISMARA did not identify ETS1 as a regulator for TERT in samples with a TERT promoter mutation.	('TERT', 'Gene', (85, 89))	('ETS1', 'Gene', '2113', (38, 42))	('ETS1', 'Gene', (38, 42))	('ISMARA', 'Chemical', '-', (14, 20))	('TERT', 'Gene', '7015', (85, 89))	('mutation', 'Var', (99, 107))	('TERT', 'Gene', (62, 66))	('TERT', 'Gene', '7015', (62, 66))
50866	31888467	It was shown elsewhere that GABPA can bind only to the TERT promoter mutation at site C228T, but not at C250T.	('C228T', 'Mutation', 'rs533877788', (86, 91))	('C228T', 'Var', (86, 91))	('GABPA', 'Gene', (28, 33))	('C250T', 'Mutation', 'rs770668556', (104, 109))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('bind', 'Interaction', (38, 42))	('GABPA', 'Gene', '2551', (28, 33))
50867	31888467	However, only one third of the mutated samples had the mutation at C228T, while two-third showed a C250T mutation.	('C228T', 'Mutation', 'rs533877788', (67, 72))	('C228T', 'Var', (67, 72))	('C250T', 'Mutation', 'rs770668556', (99, 104))	('C250T', 'Var', (99, 104))
50875	31888467	Furthermore, the predicted TERT regulators were compared in melanoma samples with wildtype versus mutated TERT promoters.	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('TERT', 'Gene', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('TERT', 'Gene', '7015', (27, 31))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutated', 'Var', (98, 105))
50913	31888467	performed siRNA mediated knockdowns of 45 TFs and signaling molecules in the melanoma cell line A375.	('A375', 'CellLine', 'CVCL:0132', (96, 100))	('TFs', 'Gene', (42, 45))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('knockdowns', 'Var', (25, 35))
50915	31888467	A fold change was calculated for TERT upon ETS1 knockdown compared to the controls.	('ETS1', 'Gene', '2113', (43, 47))	('ETS1', 'Gene', (43, 47))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('knockdown', 'Var', (48, 57))
50921	31888467	For both datasets, the regulators AR, JUND, E2F1, E2F2 and ETS1 were selected most often (Additional file 1: Table S6, column "FPKM").	('E2F1', 'Var', (44, 48))	('E2F2', 'Gene', (50, 54))	('ETS1', 'Gene', '2113', (59, 63))	('ETS1', 'Gene', (59, 63))	('E2F2', 'Gene', '1870', (50, 54))	('JUND', 'Gene', '3727', (38, 42))	('AR', 'Gene', '367', (34, 36))	('JUND', 'Gene', (38, 42))
50926	31888467	This work was supported by the project CancerTelSys (01ZX1302B, 01ZX1602B) in the e:Med program and the project CSCC (01EO1002, 01EO1502) of the German Federal Ministry of Education and Research (BMBF), and the Deutsche Forschungsgemeinschaft (KO 3678/5-1).	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('01ZX1302B', 'Var', (53, 62))	('Cancer', 'Disease', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))
50958	25751759	Androgen deficiency can cause endothelial dysfunction, decreased activity of smooth muscle cells in the vessel wall, thickening of the intima and media of the vessels and increased synthesis of pro-inflammatory cytokines.	('activity', 'MPA', (65, 73))	('endothelial dysfunction', 'Disease', (30, 53))	('thickening', 'CPA', (117, 127))	('synthesis of pro-inflammatory cytokines', 'MPA', (181, 220))	('decreased', 'NegReg', (55, 64))	('endothelial dysfunction', 'Disease', 'MESH:C536439', (30, 53))	('deficiency', 'Var', (9, 19))	('Androgen deficiency', 'Phenotype', 'HP:0008226', (0, 19))	('Androgen', 'Gene', (0, 8))	('increased', 'PosReg', (171, 180))
50978	25751759	A Dutch study found that 16.5% of all patients treated for GCC developed cardiovascular disease within 25 years of treatment cessation, with BEP being independently associated with a 1.5-fold increase in cardiovascular disease risk.	('cardiovascular disease', 'Disease', 'MESH:D002318', (73, 95))	('BEP', 'Chemical', '-', (141, 144))	('cardiovascular disease', 'Disease', (204, 226))	('cardiovascular disease', 'Disease', (73, 95))	('developed', 'Reg', (63, 72))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (204, 226))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (73, 95))	('patients', 'Species', '9606', (38, 46))	('cardiovascular disease', 'Disease', 'MESH:D002318', (204, 226))	('BEP', 'Var', (141, 144))	('men', 'Species', '9606', (120, 123))
50983	25751759	In support of this, 3 cycles of BEP was associated with 5-10%-reduction in capillary-per-myofiber ratio in muscle biopsies taken from m. vastus lateralis, indicating that BEP may cause vascular damage in both central and peripheral blood vessels.	('BEP', 'Chemical', '-', (171, 174))	('cause', 'Reg', (179, 184))	('capillary-per-myofiber ratio', 'MPA', (75, 103))	('vascular damage', 'Disease', 'MESH:D000783', (185, 200))	('BEP', 'Var', (171, 174))	('BEP', 'Chemical', '-', (32, 35))	('-reduction', 'NegReg', (61, 71))	('vascular damage', 'Disease', (185, 200))
50985	25751759	The mechanisms responsible for these muscular alterations are not clear, but studies in mice have found that cisplatin cause induction of muscle atrophy-related genes, proteosomal proteolysis and inflammation.	('muscular alterations', 'Phenotype', 'HP:0003011', (37, 57))	('cisplatin', 'Var', (109, 118))	('muscle atrophy', 'Phenotype', 'HP:0003202', (138, 152))	('muscle atrophy', 'Disease', (138, 152))	('induction', 'PosReg', (125, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('inflammation', 'Disease', 'MESH:D007249', (196, 208))	('mice', 'Species', '10090', (88, 92))	('proteosomal proteolysis', 'MPA', (168, 191))	('muscle atrophy', 'Disease', 'MESH:D009133', (138, 152))	('inflammation', 'Disease', (196, 208))
50986	25751759	Also, cisplatin is associated with strong neurotoxic actions which can induce muscle atrophy signals and a switch towards more glycolytic muscle fiber phenotypes.	('muscle atrophy', 'Phenotype', 'HP:0003202', (78, 92))	('muscle atrophy', 'Disease', (78, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (6, 15))	('more glycolytic muscle fiber phenotypes', 'MPA', (122, 161))	('neurotoxic', 'Disease', 'MESH:D020258', (42, 52))	('muscle atrophy', 'Disease', 'MESH:D009133', (78, 92))	('switch', 'Reg', (107, 113))	('neurotoxic', 'Disease', (42, 52))	('cisplatin', 'Var', (6, 15))	('induce', 'Reg', (71, 77))
51010	25751759	Collectively, these adaptations can improve regulation of whole-body homeostasis by increasing the basal metabolic rate, and lowering plasma concentrations of glucose, insulin, lipids and inflammatory cytokines.	('lowering', 'NegReg', (125, 133))	('increasing', 'PosReg', (84, 94))	('improve', 'PosReg', (36, 43))	('glucose', 'Chemical', 'MESH:D005947', (159, 166))	('basal metabolic rate', 'MPA', (99, 119))	('lowering plasma concentrations', 'Phenotype', 'HP:0020171', (125, 155))	('insulin', 'Gene', (168, 175))	('lipids', 'Chemical', 'MESH:D008055', (177, 183))	('regulation', 'MPA', (44, 54))	('insulin', 'Gene', '3630', (168, 175))	('adaptations', 'Var', (20, 31))	('inflammatory cytokines', 'MPA', (188, 210))	('plasma concentrations of glucose', 'MPA', (134, 166))	('lipids', 'MPA', (177, 183))
51038	25963309	Research concerning potential long-term consequences of the condition for the offspring, is limited, but lack of nutrition in-utero has been associated with chronic disease in adulthood, including some cancers.	('lack', 'Var', (105, 109))	('chronic disease', 'Disease', 'MESH:D002908', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('associated', 'Reg', (141, 151))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('chronic disease', 'Disease', (157, 172))
51050	25963309	Previous research has primarily focused on short-term outcomes associated with hyperemesis, with inconsistent associations demonstrated for preterm birth, low birth weight and risk of offspring small for gestational age.	('small for gestational age', 'Phenotype', 'HP:0001518', (194, 219))	('low birth weight', 'Phenotype', 'HP:0001518', (155, 171))	('preterm birth', 'Phenotype', 'HP:0001622', (140, 153))	('hyperemesis', 'Disease', (79, 90))	('low birth', 'Var', (155, 164))	('hyperemesis', 'Disease', 'MESH:D006939', (79, 90))
51057	25963309	Only a small percentage of these cancers are caused by an inherited genetic mutation, suggesting that cancer risk in this group is under influence of many modifiable risk factors.	('caused', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('genetic mutation', 'Var', (68, 84))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
51067	25963309	Our study included the twelve most common types of cancer in childhood and adolescence, defined according to the 10th edition of the International Classification of Disease (ICD-10); leukemias (C91-95), lymphomas (C81-C85), tumors of the brain and nervous system (C70-72 and D42-43), breast, females only (C50), bone (C40-C41), testis (C62), ovary (C56), thyroid gland (C73), adrenal gland (C74), retinoblastoma (C69.2), Wilms' tumor (C64.9) and hepatoblastoma (C22).	('leukemias', 'Phenotype', 'HP:0001909', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('C40', 'Gene', (318, 321))	('retinoblastoma', 'Disease', (397, 411))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (446, 460))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (428, 433))	('ovary', 'Disease', (342, 347))	('ovary', 'Disease', 'MESH:D010051', (342, 347))	('lymphomas', 'Disease', 'MESH:D008223', (203, 212))	('leukemias', 'Disease', (183, 192))	('adrenal gland', 'Disease', (376, 389))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (421, 433))	('lymphomas', 'Phenotype', 'HP:0002665', (203, 212))	('C64.9', 'Var', (435, 440))	('tumors of the brain', 'Disease', 'MESH:D001932', (224, 243))	('retinoblastoma', 'Phenotype', 'HP:0009919', (397, 411))	('tumors of the brain', 'Phenotype', 'HP:0030692', (224, 243))	('C70-72', 'Var', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumors of the brain', 'Disease', (224, 243))	('C73', 'Var', (370, 373))	('hepatoblastoma', 'Disease', (446, 460))	('retinoblastoma', 'Disease', 'MESH:D012175', (397, 411))	('C69.2', 'Var', (413, 418))	('C64.9', 'CellLine', 'CVCL:1573', (435, 440))	('lymphomas', 'Disease', (203, 212))	('hepatoblastoma', 'Disease', 'MESH:D018197', (446, 460))	("Wilms' tumor", 'Disease', 'MESH:D009396', (421, 433))	("Wilms' tumor", 'Disease', (421, 433))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('C62', 'Var', (336, 339))	('C40', 'Gene', '55571', (318, 321))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('leukemias', 'Disease', 'MESH:D007938', (183, 192))	('lymphoma', 'Phenotype', 'HP:0002665', (203, 211))	('thyroid gland', 'Disease', (355, 368))	('cancer', 'Disease', (51, 57))
51072	25963309	In Sweden, hyperemesis was defined through ICD-8 codes 638.0 and 638.9 until 1987, ICD-9 code 643 until 1997 and subsequently with ICD-10 code O21, O21.1 and O21.9, gathered from the MBR and supplemented from the National Patient Registry (NPR) to increase the validity of the diagnosis.	('O21', 'Var', (143, 146))	('hyperemesis', 'Disease', (11, 22))	('hyperemesis', 'Disease', 'MESH:D006939', (11, 22))	('men', 'Species', '9606', (197, 200))	('MBR', 'Gene', '706', (183, 186))	('O21.1', 'Var', (148, 153))	('MBR', 'Gene', (183, 186))	('Patient', 'Species', '9606', (222, 229))	('O21.9', 'Var', (158, 163))
51095	25963309	However, according to the hypothesis of fetal programming, adverse exposure in-utero may increase an individual's vulnerability for disease in adulthood, co-acting with environmental exposures.	('men', 'Species', '9606', (176, 179))	('adverse', 'Var', (59, 66))	('increase', 'PosReg', (89, 97))
51111	25963309	DNA methylations have been observed in several steps of carcinogenesis.	('methylations', 'Var', (4, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('carcinogenesis', 'Disease', (56, 70))	('observed', 'Reg', (27, 35))
51112	25963309	It has also been suggested that nutritional restriction may cause changes to the fetal blood circulation, sparing the brain at the expense of other organs and tissues during a "window of vulnerability" in fetal development.	('men', 'Species', '9606', (218, 221))	('nutritional restriction', 'Var', (32, 55))	('changes', 'Reg', (66, 73))	('sparing', 'NegReg', (106, 113))
51200	25859847	In conclusion, we identified specific and global methylation differences between GCT subtypes, providing insight into their developmental timing and underlying developmental biology.	('differences', 'Reg', (61, 72))	('men', 'Species', '9606', (131, 134))	('methylation', 'Var', (49, 60))	('GCT', 'Phenotype', 'HP:0100728', (81, 84))	('men', 'Species', '9606', (167, 170))
51233	25859847	The transcription regulatory region upstream of the TSS (TSSAssociated, TSS200) was generally hypomethylated in all tumor types as were regions annotated as first exon, 5'UTR and CpG islands.	('SS', 'Chemical', '-', (53, 55))	('hypomethylated', 'Var', (94, 108))	('SS', 'Phenotype', 'HP:0100617', (73, 75))	('SS', 'Phenotype', 'HP:0100617', (53, 55))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SS', 'Chemical', '-', (58, 60))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SS', 'Chemical', '-', (73, 75))	('tumor', 'Disease', (116, 121))	('SS', 'Phenotype', 'HP:0100617', (58, 60))
51234	25859847	The gene body, 3'-UTR, micro-RNAs and LINE/SINE elements were generally hypermethylated except in SS, which show a bimodal pattern (Fig 2A and S2A Fig).	('men', 'Species', '9606', (51, 54))	('SS', 'Chemical', '-', (98, 100))	('SINE', 'Disease', (43, 47))	('SINE', 'Disease', 'None', (43, 47))	('SS', 'Phenotype', 'HP:0100617', (98, 100))	('hypermethylated', 'Var', (72, 87))
51248	25859847	The 61 DMPs hypermethylated in SE/DG relative to type I TE were concentrated at three specific genes: NCOR2, ALOX12 and ECEL1P2 (Table 1, S3 Table, S4A Fig).	('NCOR2', 'Gene', (102, 107))	('ALOX12', 'Gene', (109, 115))	('ALOX12', 'Gene', '239', (109, 115))	('ECEL1P2', 'Gene', (120, 127))	('ECEL1P2', 'Gene', '347694', (120, 127))	('SE/DG', 'Var', (31, 36))	('TE', 'Phenotype', 'HP:0009792', (56, 58))	('EC', 'Phenotype', 'HP:0002898', (120, 122))	('DMPs', 'Chemical', '-', (7, 11))	('NCOR2', 'Gene', '9612', (102, 107))
51255	25859847	DMRs hypermethylated in SE/DG predominantly included recurrent DMRs and DMRs within genes associated with germ cell and testis development (Table 1 and S3 Table).	('SE/DG', 'Gene', (24, 29))	('DMRs', 'Chemical', '-', (0, 4))	('DMRs', 'Chemical', '-', (63, 67))	('hypermethylated', 'Var', (5, 20))	('DMRs', 'Chemical', '-', (72, 76))	('men', 'Species', '9606', (134, 137))
51257	25859847	DMRs hypermethylated in SS also included genes associated with male germ cell determination, fertility and GCTs, enforcing the epigenetic relation between GCT cells and their cell of origin (Table 1 and S3 Table).	('SS', 'Phenotype', 'HP:0100617', (24, 26))	('DMRs', 'Chemical', '-', (0, 4))	('GCT', 'Phenotype', 'HP:0100728', (155, 158))	('GCT', 'Phenotype', 'HP:0100728', (107, 110))	('hypermethylated', 'Var', (5, 20))	('male germ cell determination', 'CPA', (63, 91))	('SS', 'Chemical', '-', (24, 26))	('associated', 'Reg', (47, 57))	('GCTs', 'Phenotype', 'HP:0100728', (107, 111))
51259	25859847	For most genes their methylation profile was non discriminative between the GCT subtypes, the exceptions being TEX14 which was also independently identified as a DMR[SE/DG-ss] (Fig 4D) and BAX1, which also contained a DMR[se/dg-SS] (all SNP related genes: S5B Table).	('S5B', 'Gene', (256, 259))	('methylation', 'MPA', (21, 32))	('SS', 'Phenotype', 'HP:0100617', (228, 230))	('TEX14', 'Gene', (111, 116))	('GCT', 'Phenotype', 'HP:0100728', (76, 79))	('DMR', 'Chemical', '-', (162, 165))	('DMR[se/dg-SS]', 'Var', (218, 231))	('DMR', 'Chemical', '-', (218, 221))	('TEX14', 'Gene', '56155', (111, 116))	('TE', 'Phenotype', 'HP:0009792', (111, 113))	('S5B', 'Gene', '5711', (256, 259))	('SS', 'Chemical', '-', (228, 230))
51261	25859847	Regarding imprinting controlled regions (Fig 1C and S4 Table) in the tumor groups probes covering regions that are regulating paternally expressed genes (ICR_P) showed somatic methylation in type I and II GCTs with a trend towards hypermethylation in DC (Fig 6A).	('methylation', 'Var', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GCTs', 'Phenotype', 'HP:0100728', (205, 209))	('tumor', 'Disease', (69, 74))	('GCT', 'Phenotype', 'HP:0100728', (205, 208))	('hypermethylation', 'Var', (231, 247))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
51262	25859847	SS and the cell lines showed hypomethylation of ICR_Ps, a distinction also visible in the PCA plots.	('ICR_Ps', 'Gene', (48, 54))	('SS', 'Phenotype', 'HP:0100617', (0, 2))	('hypomethylation', 'Var', (29, 44))	('SS', 'Chemical', '-', (0, 2))
51272	25859847	In the ICR_Ps which constitute the majority of the validated ICRs, the dominating pattern is: (1) somatic methylation in the type II tumors (2) hypomethylation in the type I testicular TEs and SS and (3) a trend towards hypermethylation in DC and ovarian TE.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('hypomethylation', 'Var', (144, 159))	('type II tumors', 'Disease', 'MESH:D009369', (125, 139))	('TE', 'Phenotype', 'HP:0009792', (255, 257))	('TE', 'Phenotype', 'HP:0009792', (185, 187))	('SS', 'Phenotype', 'HP:0100617', (193, 195))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ovarian TE', 'Disease', 'MESH:D010051', (247, 257))	('hypermethylation', 'MPA', (220, 236))	('type II tumors', 'Disease', (125, 139))	('ovarian TE', 'Disease', (247, 257))	('SS', 'Chemical', '-', (193, 195))
51277	25859847	The largest methylation differences were detected between the hypermethylated EC/mNS + type I TE and hypomethylated SS + SE/DG clusters, in line with previous reports (Fig 2A).	('methylation differences', 'MPA', (12, 35))	('mNS', 'Gene', (81, 84))	('SS', 'Chemical', '-', (116, 118))	('TE', 'Phenotype', 'HP:0009792', (94, 96))	('mNS', 'Gene', '2996', (81, 84))	('SS', 'Phenotype', 'HP:0100617', (116, 118))	('EC', 'Phenotype', 'HP:0002898', (78, 80))	('hypermethylated', 'Var', (62, 77))
51279	25859847	Hypermethylation in EC/mNS and type I TE is concentrated at non-transcription related regions when compared to SE/DG, pointing to a global difference in methylation status rather than differential methylation of specific regulatory elements.	('mNS', 'Gene', (23, 26))	('TE', 'Phenotype', 'HP:0009792', (38, 40))	('Hypermethylation', 'Var', (0, 16))	('mNS', 'Gene', '2996', (23, 26))	('EC', 'Phenotype', 'HP:0002898', (20, 22))	('men', 'Species', '9606', (235, 238))
51281	25859847	Regarding type III tumors, differential hypomethylation in SS relative to SE/DG is enriched for paternally expressed imprinting associated regions and DMRs cover male germ cell related genes (Figs 3, 4 and 5, Tables 1 and 2).	('type III tumors', 'Disease', 'MESH:D009369', (10, 25))	('type III tumors', 'Disease', (10, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SS', 'Chemical', '-', (59, 61))	('hypomethylation', 'Var', (40, 55))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DMRs', 'Chemical', '-', (151, 155))	('SS', 'Phenotype', 'HP:0100617', (59, 61))
51283	25859847	Testicular type I TE shows a trend towards imprinting erasure and type II GCTS (SE/DG/EC/mNS) showed somatic imprinting status (Figs 6 and 7).	('mNS', 'Gene', (89, 92))	('GCT', 'Phenotype', 'HP:0100728', (74, 77))	('TE', 'Phenotype', 'HP:0009792', (18, 20))	('imprinting', 'Var', (43, 53))	('mNS', 'Gene', '2996', (89, 92))	('EC', 'Phenotype', 'HP:0002898', (86, 88))
51299	25859847	Our limited series of SS show a consistent pattern of distinct hypomethylation and loss of imprinting at the paternally expressed ICRs (ICR_M: heterogeneous >= 50%, Fig 2B).	('SS', 'Chemical', '-', (22, 24))	('imprinting', 'MPA', (91, 101))	('hypomethylation', 'Var', (63, 78))	('SS', 'Phenotype', 'HP:0100617', (22, 24))	('loss', 'NegReg', (83, 87))
51304	25859847	SE/DG/SS were globally hypomethylated, in line with previous reports and the demethylated state of their precursor.	('hypomethylated', 'Var', (23, 37))	('SS', 'Phenotype', 'HP:0100617', (6, 8))	('SE/DG/SS', 'Var', (0, 8))	('SS', 'Chemical', '-', (6, 8))
51352	24586637	In a previous study, we have also demonstrated an association between the presence of LVI and poor prognosis in upper urinary tract urothelial carcinoma.	('LVI', 'Protein', (86, 89))	('presence', 'Var', (74, 82))	('upper urinary tract urothelial carcinoma', 'Disease', (112, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('upper urinary tract urothelial carcinoma', 'Disease', 'MESH:D014552', (112, 152))
51433	24369132	Maternal cigarette smoking during pregnancy and reproductive health in children: a review of epidemiological studies Maternal cigarette smoking may affect the intrauterine hormonal environment during pregnancy and this early fetal exposure may have detrimental effects on the future trajectory of reproductive health.	('smoking during pregnancy', 'Phenotype', 'HP:0031437', (19, 43))	('men', 'Species', '9606', (254, 257))	('affect', 'Reg', (148, 154))	('fetal exposure', 'Phenotype', 'HP:0031437', (225, 239))	('Maternal', 'Var', (117, 125))	('children', 'Species', '9606', (71, 79))	('intrauterine hormonal environment', 'MPA', (159, 192))	('men', 'Species', '9606', (188, 191))
51482	24369132	in which daughters exposed to <10 cigarettes per day and >=10 cigarettes per day experienced AOM 4.0 and 6.5 months earlier than nonexposed, respectively.	('AOM', 'Disease', 'MESH:C537492', (93, 96))	('AOM', 'Disease', (93, 96))	('>=10 cigarettes', 'Var', (57, 72))
51576	24369132	The significant negative effect of maternal smoking was dose-dependent and was consistent after adjusting for alcohol and coffee consumption.	('maternal smoking', 'Var', (35, 51))	('negative', 'NegReg', (16, 24))	('alcohol', 'Chemical', 'MESH:D000438', (110, 117))
51592	20543847	Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer We conducted a genome-wide association study for testicular germ cell tumor genotyping 298,782 SNPs in 979 cases and 4,947 controls from the UK and replicating associations in a further 664 cases and 3,456 controls.	('DMRT1', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('Variants', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('ATF7IP', 'Gene', '55729', (30, 36))	('TERT', 'Gene', (21, 25))	('cancer', 'Disease', (78, 84))	('tumor', 'Disease', (155, 160))	('TERT', 'Gene', '7015', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('DMRT1', 'Gene', '1761', (14, 19))	('germ cell tumor', 'Phenotype', 'HP:0100728', (145, 160))	('germ cell cancer', 'Phenotype', 'HP:0100728', (68, 84))	('ATF7IP', 'Gene', (30, 36))
51593	20543847	We identified two independent signals within the TERT-CLPTM1L locus on chromosome 5 which has been associated with multiple other cancers (rs4635969, OR=1.54 (95%CI 1.33-1.79), P=1.14x10-23 and rs2736100, OR 1.33 (1.18-1.50) P=7.55 x10-15).	('CLPTM1L', 'Gene', (54, 61))	('associated with', 'Reg', (99, 114))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('rs4635969', 'Mutation', 'rs4635969', (139, 148))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('rs2736100', 'Var', (194, 203))	('rs4635969', 'Var', (139, 148))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs2736100', 'Mutation', 'rs2736100', (194, 203))	('CLPTM1L', 'Gene', '81037', (54, 61))
51594	20543847	We also identified a locus on chromosome 12 (rs2900333, OR=1.27 (95%CI 1.12-1.44), P=6.16x10-10) that contains ATF7IP, a regulator of TERT expression.	('ATF7IP', 'Gene', (111, 117))	('rs2900333', 'Mutation', 'rs2900333', (45, 54))	('TERT', 'Gene', (134, 138))	('TERT', 'Gene', '7015', (134, 138))	('ATF7IP', 'Gene', '55729', (111, 117))	('rs2900333', 'Var', (45, 54))
51595	20543847	Finally we identified a locus on chromosome 9 (rs755383, OR=1.37 (95%CI 1.21-1.55), P=1.12x10-23) containing the sex determination gene DMRT1, which has been linked with teratoma susceptibility in mice.	('rs755383', 'Mutation', 'rs755383', (47, 55))	('rs755383', 'Var', (47, 55))	('teratoma', 'Phenotype', 'HP:0009792', (170, 178))	('teratoma', 'Disease', 'MESH:D013724', (170, 178))	('DMRT1', 'Gene', (136, 141))	('mice', 'Species', '10090', (197, 201))	('teratoma', 'Disease', (170, 178))
51604	20543847	Following multiple logistic regression to test for independence of effects, four SNPs were selected for follow up: rs2736100 and rs4635969 at 5p15, rs755383 at 9p24 and rs2900333 at 12p13.	('p15', 'Gene', (143, 146))	('rs2900333', 'Var', (169, 178))	('rs4635969', 'Mutation', 'rs4635969', (129, 138))	('p15', 'Gene', '1030', (143, 146))	('rs2900333', 'Mutation', 'rs2900333', (169, 178))	('rs2736100', 'Var', (115, 124))	('rs755383', 'Mutation', 'rs755383', (148, 156))	('rs755383', 'Var', (148, 156))	('p13', 'Gene', (184, 187))	('rs2736100', 'Mutation', 'rs2736100', (115, 124))	('rs4635969', 'Var', (129, 138))	('p13', 'Gene', '440926', (184, 187))
51605	20543847	We identified two SNPs on 5p15, rs2736100 and rs4635969, associated with TGCT susceptibility.	('rs4635969', 'Mutation', 'rs4635969', (46, 55))	('rs2736100', 'Mutation', 'rs2736100', (32, 41))	('p15', 'Gene', (27, 30))	('TGCT', 'Disease', (73, 77))	('p15', 'Gene', '1030', (27, 30))	('rs2736100', 'Var', (32, 41))	('rs4635969', 'Var', (46, 55))	('associated', 'Reg', (57, 67))
51606	20543847	The effects of rs2736100 and rs4635969 are maintained when corrected for each other by logistic regression (OR=1.26 (1.17-1.36), P=8.71x10-9 and OR=1.46 (1.34-1.60), P=2.22x10-16 respectively).	('rs4635969', 'Mutation', 'rs4635969', (29, 38))	('rs2736100', 'Mutation', 'rs2736100', (15, 24))	('rs4635969', 'Var', (29, 38))	('rs2736100', 'Var', (15, 24))
51607	20543847	Furthermore correlation between rs2736100 and rs4635969 is poor (D'=0.019, r2=0 in HapMAp CEU samples, D'=0.41, r2=0.04 in our GWAS control data) and comparison of haplotype frequencies provided evidence of two haplotypes differing in frequency between cases and controls (Supplementary Table 2).	('rs4635969', 'Mutation', 'rs4635969', (46, 55))	('rs2736100', 'Mutation', 'rs2736100', (32, 41))	('men', 'Species', '9606', (279, 282))	('rs2736100', 'Var', (32, 41))	('rs4635969', 'Var', (46, 55))
51608	20543847	Taken together, these data strongly suggest that rs2736100 and rs4635969 are independently associated with TGCT.	('rs4635969', 'Var', (63, 72))	('rs2736100', 'Var', (49, 58))	('TGCT', 'Disease', (107, 111))	('rs2736100', 'Mutation', 'rs2736100', (49, 58))	('rs4635969', 'Mutation', 'rs4635969', (63, 72))	('associated', 'Reg', (91, 101))
51609	20543847	rs2736100 and rs4635969 lie within a 103kB region on 5p15 (1,306Kb-1,409Kb) that comprises a 41kB region of recombination overlying TERT (human telomerase reverse transcriptase) followed by a 62kB LD block overlying the 3' end of TERT and CLPTM1L (cisplatin resistance related protein CRR9p).	('rs2736100', 'Var', (0, 9))	('cisplatin resistance related protein CRR9p', 'Gene', (248, 290))	('p15', 'Gene', '1030', (54, 57))	('CLPTM1L', 'Gene', '81037', (239, 246))	('telomerase reverse transcriptase', 'Gene', (144, 176))	('CLPTM1L', 'Gene', (239, 246))	('rs4635969', 'Var', (14, 23))	('rs2736100', 'Mutation', 'rs2736100', (0, 9))	('telomerase reverse transcriptase', 'Gene', '7015', (144, 176))	('human', 'Species', '9606', (138, 143))	('TERT', 'Gene', (230, 234))	('TERT', 'Gene', '7015', (230, 234))	('cisplatin resistance related protein CRR9p', 'Gene', '81037', (248, 290))	('TERT', 'Gene', '7015', (132, 136))	('TERT', 'Gene', (132, 136))	('rs4635969', 'Mutation', 'rs4635969', (14, 23))	('p15', 'Gene', (54, 57))
51610	20543847	rs2736100 lies in intron 2 of TERT in the upstream recombination region whilst rs4635969 lies 5' of CLPTM1L in the block of LD (see Fig 1).	('rs2736100', 'Var', (0, 9))	('TERT', 'Gene', (30, 34))	('rs4635969', 'Var', (79, 88))	('rs2736100', 'Mutation', 'rs2736100', (0, 9))	('CLPTM1L', 'Gene', '81037', (100, 107))	('TERT', 'Gene', '7015', (30, 34))	('CLPTM1L', 'Gene', (100, 107))	('rs4635969', 'Mutation', 'rs4635969', (79, 88))
51612	20543847	Associations of SNPs in the 5p15 upstream region of recombination have been reported in lung cancer (rs2736100, rs2736098), specifically adenocarcinoma of the lung (rs2736100), glioma (rs2736100, rs2853676), basal cell carcinoma and carcinomas of the urinary bladder and prostate (rs2736098).	('p15', 'Gene', '1030', (29, 32))	('rs2736100', 'Var', (185, 194))	('lung cancer', 'Disease', (88, 99))	('rs2736098', 'Mutation', 'rs2736098', (281, 290))	('rs2736098', 'Var', (112, 121))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (137, 163))	('basal cell carcinoma', 'Disease', (208, 228))	('rs2853676', 'Var', (196, 205))	('rs2853676', 'Mutation', 'rs2853676', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('rs2736098', 'Mutation', 'rs2736098', (112, 121))	('Associations', 'Reg', (0, 12))	('rs2736100', 'Mutation', 'rs2736100', (185, 194))	('glioma', 'Disease', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('rs2736100', 'Var', (165, 174))	('rs2736100', 'Var', (101, 110))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (208, 228))	('adenocarcinoma of the lung', 'Disease', (137, 163))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('p15', 'Gene', (29, 32))	('carcinomas of the urinary bladder', 'Disease', 'MESH:D001749', (233, 266))	('rs2736100', 'Mutation', 'rs2736100', (165, 174))	('rs2736098', 'Var', (281, 290))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (208, 228))	('prostate', 'Disease', (271, 279))	('rs2736100', 'Mutation', 'rs2736100', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('carcinomas of the urinary bladder', 'Disease', (233, 266))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))
51613	20543847	Associations of SNPs in the downstream LD block have been reported in basal cell carcinoma, cutaneous melanoma and carcinomas of the urinary bladder, cervix, prostate (rs401681), lung (rs401681, rs402710, rs4635969), and pancreas (rs401681, rs4635969).	('Associations', 'Interaction', (0, 12))	('rs402710', 'Var', (195, 203))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (70, 90))	('rs401681', 'Var', (231, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('rs4635969', 'Var', (205, 214))	('rs402710', 'Mutation', 'rs402710', (195, 203))	('rs401681', 'Var', (168, 176))	('pancreas', 'Disease', 'MESH:D010190', (221, 229))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (70, 90))	('rs4635969', 'Mutation', 'rs4635969', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('cutaneous melanoma', 'Disease', (92, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (92, 110))	('prostate', 'Disease', (158, 166))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (92, 110))	('rs401681', 'Mutation', 'rs401681', (185, 193))	('carcinomas of the urinary bladder', 'Disease', 'MESH:D001749', (115, 148))	('basal cell carcinoma', 'Disease', (70, 90))	('rs401681', 'Mutation', 'rs401681', (231, 239))	('cervix', 'Disease', (150, 156))	('rs4635969', 'Mutation', 'rs4635969', (241, 250))	('lung', 'Disease', (179, 183))	('rs401681', 'Mutation', 'rs401681', (168, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas of the urinary bladder', 'Disease', (115, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('pancreas', 'Disease', (221, 229))	('rs401681', 'Var', (185, 193))
51614	20543847	Associations with TGCT of rs401681 (P=1.17x10-6) and rs402710 (P=1.38 x10-4) were evident in our GWAS data.	('TGCT', 'Gene', (18, 22))	('rs402710', 'Mutation', 'rs402710', (53, 61))	('rs402710', 'Var', (53, 61))	('rs401681', 'Mutation', 'rs401681', (26, 34))	('rs401681', 'Var', (26, 34))
51615	20543847	However, these SNPs are both correlated with rs4635969 and the associations at rs401681 and rs402710 disappeared with correction for rs4635969, suggesting a single signal driving the association in our data which is best represented by rs4635969 (Supplementary Table 3, 4 and 5).	('rs4635969', 'Mutation', 'rs4635969', (45, 54))	('rs401681', 'Mutation', 'rs401681', (79, 87))	('rs401681', 'Var', (79, 87))	('rs4635969', 'Var', (45, 54))	('rs4635969', 'Mutation', 'rs4635969', (133, 142))	('rs4635969', 'Mutation', 'rs4635969', (236, 245))	('rs402710', 'Mutation', 'rs402710', (92, 100))	('men', 'Species', '9606', (253, 256))	('rs402710', 'Var', (92, 100))
51616	20543847	We also identified a strong association for rs2853676 (P=8.70x10-7); this association remained significant when corrected for either rs2736100 or rs4635969 but disappeared with simultaneous correction for both rs2736100 and rs4635969.	('rs4635969', 'Var', (224, 233))	('rs4635969', 'Mutation', 'rs4635969', (146, 155))	('rs2736100', 'Mutation', 'rs2736100', (133, 142))	('rs4635969', 'Var', (146, 155))	('rs2853676', 'Var', (44, 53))	('rs2853676', 'Mutation', 'rs2853676', (44, 53))	('rs4635969', 'Mutation', 'rs4635969', (224, 233))	('rs2736100', 'Mutation', 'rs2736100', (210, 219))	('rs2736100', 'Var', (133, 142))
51617	20543847	Since neither rs2736100 nor rs4635969 alone can fully account for the association observed between TGCT and sequence variants in this region, it is plausible that a unique causal variant in LD with, and capturing the effects of both rs2736100[T] and rs4635969[T] may exist.	('rs2736100[T]', 'Var', (233, 245))	('rs2736100', 'Mutation', 'rs2736100', (14, 23))	('rs4635969', 'Mutation', 'rs4635969', (250, 259))	('rs4635969[T', 'Var', (250, 261))	('rs2736100', 'Mutation', 'rs2736100', (233, 242))	('rs4635969', 'Mutation', 'rs4635969', (28, 37))
51626	20543847	Consistent with this, amplification of the 5p15 region has been reported in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('p15', 'Gene', (44, 47))	('p15', 'Gene', '1030', (44, 47))	('cancer', 'Disease', (84, 90))	('amplification', 'Var', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('reported', 'Reg', (64, 72))
51630	20543847	There is some reflection of this dichotomy in our data as the association of rs2736100 is stronger with seminomas (OR 1.48 (1.32-1.66) than non-seminomas (1.26(1.12-1.42), (P=0.04)) (see Methods and Supplementary Tables 7 and 8).	('seminomas', 'Disease', 'MESH:D018239', (144, 153))	('seminomas', 'Disease', (144, 153))	('rs2736100', 'Mutation', 'rs2736100', (77, 86))	('association', 'Interaction', (62, 73))	('seminomas', 'Disease', 'MESH:D018239', (104, 113))	('seminomas', 'Disease', (104, 113))	('non-seminomas', 'Disease', 'MESH:D018239', (140, 153))	('men', 'Species', '9606', (205, 208))	('rs2736100', 'Var', (77, 86))	('non-seminomas', 'Disease', (140, 153))
51632	20543847	Here rs2900333 lies in a 181kB LD block containing a single gene, ATF7IP (Homo sapiens activating transcription factor 7 interacting protein) which is also known as MCAF1 (MBD1-containing chromatin-associated factor 1).	('MBD1-containing chromatin-associated factor 1', 'Gene', (172, 217))	('ATF7IP', 'Gene', (66, 72))	('MBD1-containing chromatin-associated factor 1', 'Gene', '55729', (172, 217))	('activating transcription factor 7 interacting protein', 'Gene', '55729', (87, 140))	('rs2900333', 'Var', (5, 14))	('rs2900333', 'Mutation', 'rs2900333', (5, 14))	('Homo sapiens', 'Species', '9606', (74, 86))	('ATF7IP', 'Gene', '55729', (66, 72))	('MCAF1', 'Gene', (165, 170))	('MCAF1', 'Gene', '55729', (165, 170))
51638	20543847	The strongest evidence comes from mouse studies which demonstrated that DMRT1 deficiency is associated with testicular cancer: 90% of Dmrt1 -/- 129Sv mice developed teratomas compared to <1% of Dmrt1+/+ mice.	('mice', 'Species', '10090', (150, 154))	('teratomas', 'Phenotype', 'HP:0009792', (165, 174))	('testicular cancer', 'Disease', (108, 125))	('Dmrt1', 'Gene', (134, 139))	('teratoma', 'Phenotype', 'HP:0009792', (165, 173))	('testicular cancer', 'Phenotype', 'HP:0010788', (108, 125))	('deficiency', 'Var', (78, 88))	('teratomas', 'Disease', 'MESH:D013724', (165, 174))	('mice', 'Species', '10090', (203, 207))	('129Sv', 'Species', '10090', (144, 149))	('Dmrt1', 'Gene', '50796', (134, 139))	('associated', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('teratomas', 'Disease', (165, 174))	('developed', 'PosReg', (155, 164))	('Dmrt1', 'Gene', (194, 199))	('testicular cancer', 'Disease', 'MESH:D013736', (108, 125))	('DMRT1', 'Gene', (72, 77))	('mouse', 'Species', '10090', (34, 39))	('Dmrt1', 'Gene', '50796', (194, 199))
51639	20543847	DMRT1 has further been implicated in human sex differentiation as abnormal male gonadal development is associated with deletions of the 9p24.3 region that contains DMRT1, Furthermore, germ cell tumors arise in a significant proportion of these deletion cases.	('DMRT1', 'Gene', (164, 169))	('deletions', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('men', 'Species', '9606', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('germ cell tumors', 'Phenotype', 'HP:0100728', (184, 200))	('human', 'Species', '9606', (37, 42))	('abnormal male gonadal development', 'CPA', (66, 99))	('germ cell tumor', 'Phenotype', 'HP:0100728', (184, 199))	('tumors', 'Disease', (194, 200))	('arise', 'Reg', (201, 206))
51640	20543847	In this GWAS we have identified rs2736100 and rs4635969 at the TERT-CLPTM1L locus on 5p15, rs2900333 at the ATF7IP locus on 12p13 and rs755383 at the DMRT1 locus on 9p24, whilst in our previous GWAS we identified rs995030 and rs1508595 at the KITLG locus on 12q21, rs4624820 at the SPRY4 locus on 5q31 and rs210138 at the BAK1 locus on 6p21.	('rs4635969', 'Mutation', 'rs4635969', (46, 55))	('BAK1', 'Gene', (322, 326))	('ATF7IP', 'Gene', (108, 114))	('p13', 'Gene', '440926', (126, 129))	('rs210138', 'Var', (306, 314))	('rs2900333', 'Mutation', 'rs2900333', (91, 100))	('rs4624820', 'Var', (265, 274))	('rs995030', 'Var', (213, 221))	('SPRY4', 'Gene', (282, 287))	('p15', 'Gene', (86, 89))	('ATF7IP', 'Gene', '55729', (108, 114))	('rs995030', 'Mutation', 'rs995030', (213, 221))	('rs2736100', 'Var', (32, 41))	('KITLG', 'Gene', (243, 248))	('CLPTM1L', 'Gene', '81037', (68, 75))	('rs755383', 'Mutation', 'rs755383', (134, 142))	('rs755383', 'Var', (134, 142))	('rs1508595', 'Mutation', 'rs1508595', (226, 235))	('KITLG', 'Gene', '4254', (243, 248))	('rs210138', 'Mutation', 'rs210138', (306, 314))	('p15', 'Gene', '1030', (86, 89))	('rs1508595', 'Var', (226, 235))	('SPRY4', 'Gene', '81848', (282, 287))	('p13', 'Gene', (126, 129))	('rs2736100', 'Mutation', 'rs2736100', (32, 41))	('CLPTM1L', 'Gene', (68, 75))	('rs4624820', 'Mutation', 'rs4624820', (265, 274))	('TERT', 'Gene', (63, 67))	('rs2900333', 'Var', (91, 100))	('TERT', 'Gene', '7015', (63, 67))	('rs4635969', 'Var', (46, 55))	('BAK1', 'Gene', '578', (322, 326))
51647	20543847	The power to detect these new loci on chromosome 5p15 (rs2736100, rs46359699), 9p24 and 12p13 was 49%, 95%, 69% and 17% respectively.	('p13', 'Gene', (90, 93))	('p15', 'Gene', '1030', (50, 53))	('rs46359699', 'Var', (66, 76))	('p13', 'Gene', '440926', (90, 93))	('rs2736100', 'Var', (55, 64))	('rs2736100', 'Mutation', 'rs2736100', (55, 64))	('p15', 'Gene', (50, 53))	('rs46359699', 'Mutation', 'rs46359699', (66, 76))
51667	32648412	Even if the components of TDS alone did not contain poor prognostic features for TGCT, the presence of TDS was found as the most important independent predictive factor for oncological outcomes in both seminomas and nonseminomas as well as all patients with TGCT.	('seminomas and nonseminomas', 'Disease', 'MESH:D018239', (202, 228))	('TDS', 'Gene', (103, 106))	('predictive factor', 'Reg', (151, 168))	('presence', 'Var', (91, 99))	('patients', 'Species', '9606', (244, 252))
51706	32648412	Animal models and epidemiological researches have revealed that deficiencies in the production of androgens, disorders of androgen receptor expression, disturbance in androgen levels, exposure to anti-androgenic or estrogenic disruptors were attributed to the pathogenesis of TDS.	('expression', 'MPA', (140, 150))	('deficiencies', 'NegReg', (64, 76))	('androgen receptor', 'Gene', '367', (122, 139))	('disorders', 'Var', (109, 118))	('androgen receptor', 'Gene', (122, 139))	('production', 'MPA', (84, 94))	('disturbance', 'Var', (152, 163))	('androgen', 'MPA', (167, 175))	('TDS', 'Disease', (276, 279))
51716	32648412	Although the presence of TM alone is not an indication for further investigation, the presence of other risk factors carries risk for TGCT development.	('TGCT', 'Disease', (134, 138))	('presence', 'Var', (86, 94))	('men', 'Species', '9606', (146, 149))	('risk', 'Reg', (125, 129))	('TM', 'Phenotype', 'HP:0012215', (25, 27))
51747	32648412	When we evaluated two different tumor types separately, in the presence of TDS, the rate of local recurrence (88.9% vs. 57.1%) was higher in non-seminomas; whereas distant metastasis (100% vs. 88.9%) and cancer-specific mortality rates (100% vs. 77.8%) were higher in seminomas.	('presence', 'Var', (63, 71))	('local recurrence', 'CPA', (92, 108))	('cancer', 'Disease', (204, 210))	('seminomas', 'Disease', (268, 277))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('seminomas', 'Disease', 'MESH:D018239', (268, 277))	('mortality', 'Disease', (220, 229))	('mortality', 'Disease', 'MESH:D003643', (220, 229))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('non-seminomas', 'Disease', (141, 154))	('seminomas', 'Disease', 'MESH:D018239', (145, 154))	('seminomas', 'Disease', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('distant metastasis', 'CPA', (164, 182))	('tumor', 'Disease', (32, 37))	('non-seminomas', 'Disease', 'MESH:D018239', (141, 154))	('higher', 'PosReg', (131, 137))
51752	32648412	Moreover, we have seen a significant increase in the rates of local recurrence, distant metastasis and cancer specific mortality in the presence of TDS.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TDS', 'Var', (148, 151))	('mortality', 'Disease', 'MESH:D003643', (119, 128))	('local recurrence', 'CPA', (62, 78))	('increase', 'PosReg', (37, 45))	('mortality', 'Disease', (119, 128))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('presence', 'Var', (136, 144))	('distant metastasis', 'CPA', (80, 98))
51757	20415751	Birthweight was not associated with the OR of Tanner stage 2+ among girls; however, boys who were low birthweight (<2500 g) and boys born higher than average birthweight (3500-3999 g) were more likely to be Tanner stage 2+ than 1.	('boys', 'Species', '9606', (128, 132))	('girls', 'Species', '9606', (68, 73))	('low birthweight', 'Phenotype', 'HP:0001518', (98, 113))	('<2500 g', 'Var', (115, 122))	('boys', 'Species', '9606', (84, 88))	('3500-3999 g', 'Var', (171, 182))	('higher than average birthweight', 'Phenotype', 'HP:0001520', (138, 169))	('Tanner stage 2+', 'Disease', (207, 222))
51759	20415751	In an analysis of asynchronous maturation, girls born at high birthweight (>4000 g) were more likely to have breast development 3+ than girls of normal birthweight, OR = 3.18 [95% CI 1.39, 8.25].	('breast development', 'CPA', (109, 127))	('normal birthweight', 'Phenotype', 'HP:0001518', (145, 163))	('men', 'Species', '9606', (123, 126))	('high birthweight', 'Phenotype', 'HP:0001520', (57, 73))	('girls', 'Species', '9606', (43, 48))	('>4000 g', 'Var', (75, 82))	('girls', 'Species', '9606', (136, 141))
51761	20415751	Birthweight has been associated with risk of chronic diseases, including coronary heart disease, diabetes, hypertension and cancer.	('hypertension', 'Phenotype', 'HP:0000822', (107, 119))	('cancer', 'Disease', (124, 130))	('coronary heart disease', 'Disease', (73, 95))	('coronary heart disease', 'Phenotype', 'HP:0001677', (73, 95))	('coronary heart disease', 'Disease', 'MESH:D003324', (73, 95))	('associated', 'Reg', (21, 31))	('diabetes', 'Disease', (97, 105))	('hypertension', 'Disease', 'MESH:D006973', (107, 119))	('Birthweight', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('diabetes', 'Disease', 'MESH:D003920', (97, 105))	('chronic diseases', 'Disease', (45, 61))	('chronic diseases', 'Disease', 'MESH:D002908', (45, 61))	('hypertension', 'Disease', (107, 119))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
51762	20415751	Specifically, low birthweight and subsequent catch-up in weight gain before 2 years of age is associated with increased risk of diabetes, coronary heart disease and insulin resistance.	('diabetes', 'Disease', (128, 136))	('weight gain', 'Phenotype', 'HP:0004324', (57, 68))	('weight gain', 'Disease', (57, 68))	('low birthweight', 'Var', (14, 29))	('diabetes', 'Disease', 'MESH:D003920', (128, 136))	('low birthweight', 'Phenotype', 'HP:0001518', (14, 29))	('insulin', 'Gene', (165, 172))	('coronary heart disease', 'Disease', (138, 160))	('insulin resistance', 'Phenotype', 'HP:0000855', (165, 183))	('insulin', 'Gene', '3630', (165, 172))	('coronary heart disease', 'Phenotype', 'HP:0001677', (138, 160))	('weight gain', 'Disease', 'MESH:D015430', (57, 68))	('coronary heart disease', 'Disease', 'MESH:D003324', (138, 160))
51777	20415751	This interest initially arose from the associations between high birthweight and increased breast cancer risk, and earlier pubertal onset and increased breast cancer risk Although the biological mechanisms underlying these associations are unknown, it has been hypothesised that increased exposure to hormones, such as oestrogen, occurs in utero.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('high birthweight', 'Var', (60, 76))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('associations', 'Interaction', (39, 51))	('breast cancer', 'Disease', (152, 165))	('high birthweight', 'Phenotype', 'HP:0001520', (60, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
51825	20415751	Girls who were in the highest category of birthweight (>=4000 g) were significantly more likely to be B3+ than girls who were born between 3000 and 3499 g, with an OR of 3.18 [95% CI = 1.39, 8.25].	('Girls', 'Species', '9606', (0, 5))	('B3+', 'Var', (102, 105))	('girls', 'Species', '9606', (111, 116))	('>=4000 g', 'Var', (55, 63))
51839	20415751	We observed that girls of high birthweight (>=4000 g) were more likely to be at a higher stage of breast development than girls with a birthweight between 3000 and 3499 g. Biro described a paradigm in which the majority of girls undergo puberty in an asynchronous manner, with breast development (thelarche) appearing before pubic hair development (adrenarche).	('men', 'Species', '9606', (112, 115))	('girls', 'Species', '9606', (223, 228))	('girls', 'Species', '9606', (17, 22))	('adrenarche', 'Disease', (349, 359))	('adrenarche', 'Disease', 'None', (349, 359))	('high birthweight', 'Phenotype', 'HP:0001520', (26, 42))	('breast', 'Disease', (277, 283))	('men', 'Species', '9606', (343, 346))	('men', 'Species', '9606', (291, 294))	('>=4000 g', 'Var', (44, 52))	('girls', 'Species', '9606', (122, 127))
51842	20415751	Our data show that high birthweight was associated with breast development of girls.	('high birthweight', 'Var', (19, 35))	('men', 'Species', '9606', (70, 73))	('breast development', 'CPA', (56, 74))	('high birthweight', 'Phenotype', 'HP:0001520', (19, 35))	('girls', 'Species', '9606', (78, 83))	('associated', 'Reg', (40, 50))
51843	20415751	Therefore, high birthweight, or factors associated with high birthweight, may lead to a growth trajectory in childhood that results in earlier pubertal breast maturation.	('lead to', 'Reg', (78, 85))	('high birthweight', 'Phenotype', 'HP:0001520', (11, 27))	('high birthweight', 'Phenotype', 'HP:0001520', (56, 72))	('growth trajectory', 'CPA', (88, 105))	('child', 'Species', '9606', (109, 114))	('high birthweight', 'Var', (11, 27))	('earlier pubertal breast maturation', 'CPA', (135, 169))
51854	20415751	Low birthweight has been associated with chronic diseases such as coronary heart disease, hypertension and diabetes in men.	('coronary heart disease', 'Disease', 'MESH:D003324', (66, 88))	('hypertension', 'Disease', (90, 102))	('associated', 'Reg', (25, 35))	('Low birthweight', 'Var', (0, 15))	('diabetes', 'Disease', (107, 115))	('diabetes', 'Disease', 'MESH:D003920', (107, 115))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('men', 'Species', '9606', (119, 122))	('chronic diseases', 'Disease', 'MESH:D002908', (41, 57))	('chronic diseases', 'Disease', (41, 57))	('coronary heart disease', 'Disease', (66, 88))	('coronary heart disease', 'Phenotype', 'HP:0001677', (66, 88))	('Low birthweight', 'Phenotype', 'HP:0001518', (0, 15))
51856	20415751	Therefore, although it appears that low birthweight conveys risk of certain chronic diseases, little is known regarding the role of all three factors, notably birthweight, puberty and cancer risk in men, in the same study.	('cancer', 'Disease', (184, 190))	('men', 'Species', '9606', (199, 202))	('low birthweight', 'Phenotype', 'HP:0001518', (36, 51))	('chronic diseases', 'Disease', (76, 92))	('chronic diseases', 'Disease', 'MESH:D002908', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('low birthweight', 'Var', (36, 51))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
51870	20415751	Previous research has documented associations between high birthweight and increased risk of breast cancer as well as early puberty onset and increased breast cancer risk.	('high birthweight', 'Var', (54, 70))	('puberty onset', 'Phenotype', 'HP:0000826', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('early puberty', 'Phenotype', 'HP:0000826', (118, 131))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Disease', (152, 165))	('men', 'Species', '9606', (26, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high birthweight', 'Phenotype', 'HP:0001520', (54, 70))
51875	31583820	The antineoplastic and antiangiogenic effects of animacroxam on TGCT in vivo were assessed through exploratory animal studies and a modified chorioallantoic membrane assay, revealing that animacroxam has significant antitumor activity in TGCT.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('chorioallantoic membrane', 'Gene', '71817', (141, 165))	('chorioallantoic membrane', 'Gene', (141, 165))	('animacroxam', 'Var', (188, 199))	('TGCT', 'Disease', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
51877	31583820	Furthermore, the observed antiangiogenic effects of animacroxam were related to its ability to inhibit endothelial cell-cell communication, as the expression of gap junction-forming connexin 43 was strongly suppressed, and gap-junctional intercellular mass transport was reduced.	('connexin 43', 'Gene', (182, 193))	('connexin 43', 'Gene', '2697', (182, 193))	('reduced', 'NegReg', (271, 278))	('animacroxam', 'Var', (52, 63))	('expression', 'MPA', (147, 157))	('antiangiogenic effects', 'CPA', (26, 48))	('inhibit', 'NegReg', (95, 102))	('gap-junctional intercellular mass transport', 'MPA', (223, 266))	('gap', 'Protein', (161, 164))	('suppressed', 'NegReg', (207, 217))	('endothelial cell-cell communication', 'MPA', (103, 138))
51878	31583820	Our data suggest that the chimeric HDAC inhibitor animacroxam may become a promising candidate for the treatment of solid cancers and may serve as an interesting alternative to platinum-based therapies.	('HDAC', 'Gene', (35, 39))	('animacroxam', 'Var', (50, 61))	('HDAC', 'Gene', '9734', (35, 39))	('platinum', 'Chemical', 'MESH:D010984', (177, 185))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
51892	31583820	Animacroxam did not cause unspecific cytotoxicity and, most notably, was shown to exert its effects irrespective of the cisplatin sensitivity of the investigated cancer cell models.	('cytotoxicity', 'Disease', (37, 49))	('Animacroxam', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
51930	31583820	For immunohistochemistry, sections were dewaxed and subjected to a heat-induced epitope retrieval step prior to incubation with either anti-Ki67 (clone MIB-1; Agilent Technologies, Santa Clara, CA, USA) or anti-desmin (clone D33; Agilent Technologies).	('desmin', 'Gene', '1674', (211, 217))	('anti-Ki67', 'Var', (135, 144))	('MIB-1', 'Gene', (152, 157))	('desmin', 'Gene', (211, 217))	('MIB-1', 'Gene', '57534', (152, 157))
51936	31583820	Then, the relative number of Ki67- or desmin-expressing cells compared to the control-treated tumors was calculated.	('desmin', 'Gene', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('desmin', 'Gene', '1674', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('Ki67-', 'Var', (29, 34))
51958	31583820	Additionally, animacroxam exerted a good biotolerability as no changes in behavior, weight, or food and water consumption of the mice were observed.	('mice', 'Species', '10090', (129, 133))	('animacroxam', 'Var', (14, 25))	('biotolerability', 'MPA', (41, 56))
51969	31583820	This reduction in tumor volume by animacroxam was statistically significant when compared to the volume of control tumors after 7 days (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('reduction', 'NegReg', (5, 14))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('animacroxam', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
51976	31583820	Interestingly, the 'necrotic cap' seen in the animacroxam-treated tumor plaques did not show any 18F-FDG signal, supporting the idea that the tumor capping of animacroxam-treated tumors reflects an accumulation of protein-rich fluid and cellular debris of necrotic cells and does not consist of metabolically active tumor cells.	('necrotic', 'Disease', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('necrotic', 'Disease', 'MESH:D009336', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('18F-FDG', 'Chemical', 'MESH:D019788', (97, 104))	('necrotic', 'Disease', (256, 264))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (179, 184))	('necrotic', 'Disease', 'MESH:D009336', (256, 264))	('tumor', 'Disease', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('accumulation', 'PosReg', (198, 210))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (179, 185))	('tumor', 'Disease', (316, 321))	('animacroxam-treated', 'Var', (159, 178))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
51980	31583820	Moreover, the formation of G-6-P enables glucose to enter glycolysis.	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('glucose', 'MPA', (41, 48))	('G-6-P', 'Var', (27, 32))
51981	31583820	Treatment with animacroxam led to a significantly decreased HK activity in TGCT tumor cells in a concentration- and time-dependent manner leading to reduction of HK activity of > 85% after 48 h (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('reduction', 'NegReg', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HK', 'Gene', '3098', (162, 164))	('tumor', 'Disease', (80, 85))	('animacroxam', 'Var', (15, 26))	('decreased', 'NegReg', (50, 59))	('HK', 'Gene', '3098', (60, 62))
51987	31583820	As GLUT1 expression showed no significant inhibition by animacroxam, we checked whether animacroxam might rather affect intracellular glucose utilization to impair glycolysis by substrate limitation.	('substrate limitation', 'MPA', (178, 198))	('impair', 'NegReg', (157, 163))	('GLUT1', 'Gene', (3, 8))	('GLUT1', 'Gene', '6513', (3, 8))	('animacroxam', 'Var', (88, 99))	('glucose', 'Chemical', 'MESH:D005947', (134, 141))	('glycolysis', 'MPA', (164, 174))	('affect', 'Reg', (113, 119))	('intracellular glucose utilization', 'MPA', (120, 153))
51988	31583820	Hence, we determined changes in the glycolytic flux by measuring lactate levels in the supernatant of 2102EP cells after incubation with animacroxam and vorinostat which showed that the high glycolytic activity of untreated TGCT cells was dose-dependently inhibited by animacroxam by up to almost 100% (Fig.	('inhibited', 'NegReg', (256, 265))	('animacroxam', 'Var', (269, 280))	('vorinostat', 'Chemical', 'MESH:C111237', (153, 163))	('high glycolytic activity', 'MPA', (186, 210))	('lactate', 'Chemical', 'MESH:D019344', (65, 72))
51993	31583820	However, since animacroxam, but not vorinostat, strongly increased cytoplasmic ROS, this ROS increase may not be due to an HDAC-inhibitory effect but rather be connected to the cytoskeleton-interfering imidazole moiety of the chimeric compound animacroxam.	('animacroxam', 'Var', (15, 26))	('imidazole', 'Chemical', 'MESH:C029899', (202, 211))	('vorinostat', 'Chemical', 'MESH:C111237', (36, 46))	('HDAC', 'Gene', (123, 127))	('ROS increase', 'Phenotype', 'HP:0025464', (89, 101))	('increased', 'PosReg', (57, 66))	('HDAC', 'Gene', '9734', (123, 127))	('cytoplasmic ROS', 'MPA', (67, 82))
51994	31583820	Performing ROS experiments with brimamin reflecting the imidazole part of the chimeric inhibitor animacroxam revealed that brimamin induced a pronounced increase in cytoplasmic ROS of TGCT cells (Fig.	('increase', 'PosReg', (153, 161))	('imidazole', 'Chemical', 'MESH:C029899', (56, 65))	('cytoplasmic ROS', 'MPA', (165, 180))	('brimamin', 'Var', (123, 131))
51997	31583820	As the CAM is a fast-developing structure, topical treatment with animacroxam for 48 h led to a marked reduction in microvascular perfusion of the treated area as compared to an untreated control area of the same CAM (Fig.	('CAM', 'Gene', '71817', (7, 10))	('CAM', 'Gene', (213, 216))	('microvascular perfusion', 'MPA', (116, 139))	('CAM', 'Gene', (7, 10))	('reduction', 'NegReg', (103, 112))	('CAM', 'Gene', '71817', (213, 216))	('animacroxam', 'Var', (66, 77))
52007	31583820	For quantification, desmin-positive cells were counted in 10 randomly chosen HPF per sample section, which revealed a 22% reduction in microvessel density of animacroxam-treated tumors.	('desmin', 'Gene', (20, 26))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('microvessel density', 'CPA', (135, 154))	('animacroxam-treated', 'Var', (158, 177))	('desmin', 'Gene', '1674', (20, 26))	('reduction', 'NegReg', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
52010	31583820	Treatment of endothelial EA.hy926 cells with animacroxam resulted in a significant and dose-dependent reduction in the formation of capillary-like tube structures of up to 73.2% after 16 h (Fig.	('reduction', 'NegReg', (102, 111))	('animacroxam', 'Var', (45, 56))	('formation of capillary-like tube structures', 'CPA', (119, 162))	('EA.hy926', 'CellLine', 'CVCL:3901', (25, 33))
52018	31583820	The effect of animacroxam was in the range of that of Cbx, a well-known gap junction/Cx43 uncoupling agent, which served as a positive control (Sagar and Larson, 2006).	('animacroxam', 'Var', (14, 25))	('Cx43', 'Gene', (85, 89))	('Cx43', 'Gene', '2697', (85, 89))
52040	31583820	Interestingly, we observed increased ROS formation in tumors treated with animacroxam.	('increased', 'PosReg', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ROS', 'MPA', (37, 40))	('animacroxam', 'Var', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
52041	31583820	Hence, we propose that animacroxam may also influence endothelial permeability, which has not been observed for cisplatin or the HDACi vorinostat, respectively.	('vorinostat', 'Chemical', 'MESH:C111237', (135, 145))	('endothelial permeability', 'MPA', (54, 78))	('HDAC', 'Gene', (129, 133))	('influence', 'Reg', (44, 53))	('HDAC', 'Gene', '9734', (129, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('animacroxam', 'Var', (23, 34))
52045	31583820	Furthermore, we observed that animacroxam caused downregulation of the glycolytic enzyme BPGM.	('BPGM', 'Gene', '669', (89, 93))	('BPGM', 'Gene', (89, 93))	('animacroxam', 'Var', (30, 41))	('downregulation', 'NegReg', (49, 63))	('glycolytic enzyme', 'MPA', (71, 88))
52048	31583820	BPGM reduction was seen after treatment with the animacroxam and the HDAC-inhibiting vorinostat, but not after treatment with the DNA-damaging agent cisplatin.	('BPGM', 'Gene', '669', (0, 4))	('HDAC', 'Gene', (69, 73))	('animacroxam', 'Var', (49, 60))	('reduction', 'NegReg', (5, 14))	('HDAC', 'Gene', '9734', (69, 73))	('BPGM', 'Gene', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('vorinostat', 'Chemical', 'MESH:C111237', (85, 95))
52049	31583820	Thus, it is feasible that BPGM inhibition by animacroxam might be an HDACi-driven effect.	('inhibition', 'NegReg', (31, 41))	('HDAC', 'Gene', (69, 73))	('HDAC', 'Gene', '9734', (69, 73))	('BPGM', 'Gene', (26, 30))	('animacroxam', 'Var', (45, 56))	('BPGM', 'Gene', '669', (26, 30))
52061	31583820	The mechanism by which animacroxam exerts its effects on endothelial vessel formation and maintenance may be explained by its HDAC-inhibitory potency, including a proposed specificity for the cytoplasmic HDAC6 (Mahal, Schruefer, et al., 2015).	('endothelial vessel formation', 'CPA', (57, 85))	('HDAC', 'Gene', (204, 208))	('HDAC', 'Gene', '9734', (204, 208))	('animacroxam', 'Var', (23, 34))	('HDAC6', 'Gene', '10013', (204, 209))	('HDAC6', 'Gene', (204, 209))	('HDAC', 'Gene', (126, 130))	('HDAC', 'Gene', '9734', (126, 130))
52066	31583820	Avascular effects of animacroxam may also be related to the additional involvement of the cytoskeleton-interfering imidazole moiety which has already shown to disrupt blood vessels (Mahal, Biersack, et al., 2015).	('Avascular effects', 'MPA', (0, 17))	('blood', 'MPA', (167, 172))	('imidazole', 'Chemical', 'MESH:C029899', (115, 124))	('animacroxam', 'Var', (21, 32))
52088	31744479	GCNIS originates from fetal gonocytes (POU5F1+/MAGE-A4-), which fail to differentiate to pre-spermatogonia (POU5F1-/MAGE-A4+) and undergo malignant transformation.	('undergo', 'Reg', (130, 137))	('MAGE-A4+', 'Gene', '4103', (116, 124))	('POU5F1+/MAGE-A4-', 'Var', (39, 55))	('malignant transformation', 'CPA', (138, 162))	('GCNIS', 'Chemical', '-', (0, 5))	('MAGE-A4+', 'Gene', (116, 124))
52092	31744479	Functional analysis was performed in-vitro by siRNA knock-down of Gankyrin in the NTera2 cells (derived from embryonal carcinoma).	('Gankyrin', 'Gene', (66, 74))	('NTera2', 'CellLine', 'CVCL:0034', (82, 88))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (109, 128))	('knock-down', 'Var', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (109, 128))	('embryonal carcinoma', 'Disease', (109, 128))
52096	31744479	Gankyrin knock-down in NTera2 cells resulted in an increase in apoptosis mediated via the TP53 pathway, whilst POU5F1 expression was unaffected.	('increase', 'PosReg', (51, 59))	('NTera2', 'CellLine', 'CVCL:0034', (23, 29))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('knock-down', 'Var', (9, 19))	('apoptosis', 'CPA', (63, 72))
52097	31744479	Furthermore, Gankyrin knock-down in NTera2 cells increased cisplatin sensitivity with an increase in cell death (13%, p < 0.05) following Gankyrin knock-down, when compared to cisplatin treatment alone, likely via BAX and FAS.	('knock-down', 'Var', (22, 32))	('BAX', 'Gene', (214, 217))	('BAX', 'Gene', '581', (214, 217))	('NTera2', 'CellLine', 'CVCL:0034', (36, 42))	('death', 'Disease', 'MESH:D003643', (106, 111))	('cisplatin sensitivity', 'MPA', (59, 80))	('death', 'Disease', (106, 111))	('increased', 'PosReg', (49, 58))	('Gankyrin', 'Var', (138, 146))	('knock-down', 'Var', (147, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('men', 'Species', '9606', (191, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
52100	31744479	These results suggest that manipulation of Gankyrin expression may reduce the cisplatin dose required for the treatment of TGCC, with benefits in reducing dose-dependent side effects of chemotherapy.	('reduce', 'NegReg', (67, 73))	('TGCC', 'Disease', (123, 127))	('cisplatin dose', 'MPA', (78, 92))	('men', 'Species', '9606', (115, 118))	('manipulation', 'Var', (27, 39))	('dose-dependent side effects', 'MPA', (155, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('Gankyrin expression', 'Protein', (43, 62))
52108	31744479	We have previously shown that MAGE-A4- GCNIS cells proliferate more frequently than the MAGE-A4+ population, suggesting that MAGE-A4 might have an anti-proliferative effect when expressed in GCNIS cells.	('GCNIS', 'Chemical', '-', (39, 44))	('proliferate', 'CPA', (51, 62))	('MAGE-A4', 'Var', (125, 132))	('anti-proliferative effect', 'CPA', (147, 172))	('MAGE-A4+', 'Gene', (88, 96))	('MAGE-A4+', 'Gene', '4103', (88, 96))	('GCNIS', 'Chemical', '-', (191, 196))
52166	31744479	The dose to be used in further experiments was 4 muM of cisplatin for 24 h which corresponded to ~ 50% cell death.	('muM', 'Gene', '56925', (49, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('muM', 'Gene', (49, 52))	('men', 'Species', '9606', (37, 40))	('cisplatin', 'Var', (56, 65))	('death', 'Disease', 'MESH:D003643', (108, 113))	('death', 'Disease', (108, 113))
52186	31744479	An increased proportion of nuclear Gankyrin expression was observed in POU5F1+/MAGE-A4- GCNIS compared to POU5F1+/MAGE-A4+ GCNIS (Fig.	('increased', 'PosReg', (3, 12))	('POU5F1+/MAGE-A4- GCNIS', 'Var', (71, 93))	('expression', 'MPA', (44, 54))	('MAGE-A4+', 'Gene', (114, 122))	('GCNIS', 'Chemical', '-', (123, 128))	('MAGE-A4+', 'Gene', '4103', (114, 122))	('nuclear Gankyrin', 'Protein', (27, 43))	('GCNIS', 'Chemical', '-', (88, 93))
52188	31744479	To investigate the role of Gankyrin in malignant germ cells, we used the embryonal carcinoma cell line (NTera2) to perform Gankyrin knock-down in vitro using an siRNA approach.	('embryonal carcinoma', 'Disease', 'MESH:D018236', (73, 92))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (73, 92))	('embryonal carcinoma', 'Disease', (73, 92))	('NTera2', 'CellLine', 'CVCL:0034', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('knock-down', 'Var', (132, 142))
52189	31744479	Knock-down of Gankyrin expression resulted in a significant reduction in the number of NTera2 cells (32%; p < 0.01, Fig.	('reduction', 'NegReg', (60, 69))	('NTera2', 'CellLine', 'CVCL:0034', (87, 93))	('Knock-down', 'Var', (0, 10))	('Gankyrin', 'Gene', (14, 22))
52193	31744479	Knock-down of Gankyrin expression resulted in a significant increase in TP53 expression (Fig.	('expression', 'MPA', (77, 87))	('Gankyrin', 'Gene', (14, 22))	('TP53', 'Gene', '7157', (72, 76))	('Knock-down', 'Var', (0, 10))	('increase', 'PosReg', (60, 68))	('TP53', 'Gene', (72, 76))
52195	31744479	Functional image-based analysis using a cell-permeable fluorescent caspase biosensor revealed knockdown of Gankyrin resulted in activation of Cleaved Caspase 3 (CC3) mediated apoptosis, whilst no apoptotic cells were identified in controls (Fig.	('activation', 'PosReg', (128, 138))	('knockdown', 'Var', (94, 103))	('caspase', 'Gene', (67, 74))	('Gankyrin', 'Gene', (107, 115))	('apoptosis', 'CPA', (175, 184))	('Cleaved Caspase', 'MPA', (142, 157))	('caspase', 'Gene', '842', (67, 74))
52197	31744479	We confirmed the siRNA mediated knock-down of Gankyrin expression in cisplatin exposed NTera2 cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('Gankyrin', 'Protein', (46, 54))	('expression', 'MPA', (55, 65))	('NTera2', 'CellLine', 'CVCL:0034', (87, 93))	('knock-down', 'Var', (32, 42))
52199	31744479	There was no effect of Gankyrin knock-down on TP53 mRNA or protein expression (Fig.	('protein expression', 'MPA', (59, 77))	('TP53', 'Gene', (46, 50))	('knock-down', 'Var', (32, 42))	('TP53', 'Gene', '7157', (46, 50))
52203	31744479	GCNIS is believed to result from failure of differentiation from gonocyte (POU5F1+) to (pre) spermatogonia (POU5F1-).	('GCNIS', 'Disease', (0, 5))	('POU5F1+', 'Var', (75, 82))	('GCNIS', 'Chemical', '-', (0, 5))
52204	31744479	Our observation that nuclear Gankyrin is not expressed in gonocytes (POU5F1+/Gankyrin-) but expressed in gonocytes from samples with maturation delay and pre-GCNIS (POU5F1+/Gankyrin+) indicates that Gankyrin expression is associated with the early stage of TGCC development.	('men', 'Species', '9606', (269, 272))	('maturation delay', 'Phenotype', 'HP:0002750', (133, 149))	('GCNIS', 'Chemical', '-', (158, 163))	('POU5F1+/Gankyrin+', 'Var', (165, 182))	('TGCC', 'Disease', (257, 261))	('associated', 'Reg', (222, 232))
52205	31744479	Furthermore, within the GCNIS cell populations, Gankyrin expression is present in a higher proportion of POU5F1+/MAGE-A4- compared with POU5F1+/MAGE-A4+cells, which may reflect an increased oncogenic potential in the in the more proliferative POU5F1+/MAGE-A4- population.	('Gankyrin', 'Protein', (48, 56))	('expression', 'MPA', (57, 67))	('POU5F1+/MAGE-A4-', 'Var', (105, 121))	('MAGE-A4+', 'Gene', '4103', (144, 152))	('increased', 'PosReg', (180, 189))	('GCNIS', 'Chemical', '-', (24, 29))	('oncogenic potential', 'CPA', (190, 209))	('MAGE-A4+', 'Gene', (144, 152))	('higher', 'PosReg', (84, 90))
52206	31744479	Previous studies have demonstrated that Gankyrin prevents POU5F1 degradation in HCC and loss of Gankyrin can reduce the oncogenic potential of tumour cells through interaction with MAGE-A4.	('POU5F1', 'Gene', (58, 64))	('interaction', 'Interaction', (164, 175))	('degradation', 'MPA', (65, 76))	('HCC', 'Gene', '619501', (80, 83))	('reduce', 'NegReg', (109, 115))	('MAGE-A4', 'Protein', (181, 188))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('loss', 'Var', (88, 92))	('tumour', 'Disease', (143, 149))	('HCC', 'Gene', (80, 83))	('Gankyrin', 'Protein', (96, 104))
52208	31744479	Therefore, we investigated the effects of Gankyrin knock-down in NTera2 cells, an established embryonal carcinoma cell line which is widely used in studies relating to TGCC.	('embryonal carcinoma', 'Disease', 'MESH:D018236', (94, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (94, 113))	('embryonal carcinoma', 'Disease', (94, 113))	('knock-down', 'Var', (51, 61))	('NTera2', 'CellLine', 'CVCL:0034', (65, 71))
52211	31744479	A number of pro-apoptotic genes are located downstream of TP53 and we found that TP53 expression is upregulated following knock-down of Gankyrin in NTera2 cells, which is in keeping with the results of a previous study.	('knock-down', 'Var', (122, 132))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('expression', 'MPA', (86, 96))	('upregulated', 'PosReg', (100, 111))	('NTera2', 'CellLine', 'CVCL:0034', (148, 154))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
52212	31744479	Furthermore, we have demonstrated that Gankyrin knock-down results in an increased expression of apoptosis genes BAX and FAS, both of which are downstream of TP53.	('TP53', 'Gene', '7157', (158, 162))	('increased', 'PosReg', (73, 82))	('TP53', 'Gene', (158, 162))	('BAX', 'Gene', '581', (113, 116))	('FAS', 'Gene', (121, 124))	('knock-down', 'Var', (48, 58))	('expression', 'MPA', (83, 93))	('BAX', 'Gene', (113, 116))
52213	31744479	Down-regulation of Gankyrin also induces apoptosis in hepatocellular carcinoma cells with wild type TP53 whilst increased expression of Gankyrin inhibits apoptosis by causing degradation of TP53 protein and reduced transcription of its downstream apoptotic genes.	('TP53', 'Gene', (100, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('Gankyrin', 'Gene', (136, 144))	('transcription', 'MPA', (215, 228))	('apoptotic', 'Gene', (247, 256))	('expression', 'Var', (122, 132))	('TP53', 'Gene', '7157', (190, 194))	('Down-regulation', 'NegReg', (0, 15))	('reduced', 'NegReg', (207, 214))	('hepatocellular carcinoma', 'Disease', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('TP53', 'Gene', '7157', (100, 104))	('apoptosis', 'CPA', (154, 163))	('increased', 'PosReg', (112, 121))	('protein', 'Protein', (195, 202))	('TP53', 'Gene', (190, 194))	('inhibits', 'NegReg', (145, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('apoptosis', 'CPA', (41, 50))	('induces', 'Reg', (33, 40))	('degradation', 'MPA', (175, 186))
52214	31744479	Taken together these results suggest that following Gankyrin knock-down in NTera2 cells the reduction in cell number is likely to be mediated by an increase in apoptosis mediated through the TP53 signalling pathway leading to increased expression of the apoptotic genes BAX and FAS.	('FAS', 'Gene', (278, 281))	('apoptosis', 'CPA', (160, 169))	('knock-down', 'Var', (61, 71))	('increase', 'PosReg', (148, 156))	('cell number', 'CPA', (105, 116))	('NTera2', 'CellLine', 'CVCL:0034', (75, 81))	('Gankyrin knock-down', 'Var', (52, 71))	('TP53', 'Gene', '7157', (191, 195))	('reduction', 'NegReg', (92, 101))	('TP53', 'Gene', (191, 195))	('NTera2', 'Gene', (75, 81))	('increased', 'PosReg', (226, 235))	('BAX', 'Gene', (270, 273))	('expression', 'MPA', (236, 246))	('BAX', 'Gene', '581', (270, 273))
52217	31744479	Previous studies have reported that TP53 mutations did not occur in TGCC, however recent studies have shown that 10 out of 148 patients with seminoma (7%) have a TP53 mutation.	('TP53', 'Gene', '7157', (162, 166))	('mutation', 'Var', (167, 175))	('TP53', 'Gene', (162, 166))	('TP53', 'Gene', '7157', (36, 40))	('seminoma', 'Disease', 'MESH:D018239', (141, 149))	('patients', 'Species', '9606', (127, 135))	('TP53', 'Gene', (36, 40))	('seminoma', 'Disease', (141, 149))
52219	31744479	Recent studies have demonstrated that knockdown of TP53 in NTera2 cells resulted in reduced cisplatin mediated apoptosis.	('cisplatin mediated', 'MPA', (92, 110))	('TP53', 'Gene', (51, 55))	('reduced', 'NegReg', (84, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('NTera2', 'CellLine', 'CVCL:0034', (59, 65))	('knockdown', 'Var', (38, 47))	('TP53', 'Gene', '7157', (51, 55))
52220	31744479	Therefore, given that we identified an effect of Gankyrin knock-down on the TP53 and BAX/FAS apoptosis pathway, we speculated that manipulation of Gankyrin might modulate the effect of cisplatin in TGCC.	('modulate', 'Reg', (162, 170))	('BAX', 'Gene', '581', (85, 88))	('TP53', 'Gene', '7157', (76, 80))	('knock-down', 'Var', (58, 68))	('TP53', 'Gene', (76, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('BAX', 'Gene', (85, 88))
52222	31744479	We showed that Gankyrin knock-down enhances the reduction in cell number caused by cisplatin treatment by 13% (p < 0.05), compared to cisplatin treatment alone.	('cell number', 'CPA', (61, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('Gankyrin', 'Protein', (15, 23))	('men', 'Species', '9606', (149, 152))	('knock-down', 'Var', (24, 34))	('men', 'Species', '9606', (98, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('enhances', 'PosReg', (35, 43))	('reduction', 'NegReg', (48, 57))
52225	31744479	We have also demonstrated that repression of Gankyrin in NTera2 cells results in a reduction in total cell number and enhances the cytotoxic effect of cisplatin in this TGCC cell line.	('enhances', 'PosReg', (118, 126))	('repression', 'Var', (31, 41))	('NTera2', 'CellLine', 'CVCL:0034', (57, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('reduction', 'NegReg', (83, 92))	('cytotoxic', 'CPA', (131, 140))	('total cell number', 'CPA', (96, 113))	('Gankyrin', 'Protein', (45, 53))
52228	31744479	Conceived and designed the experiments: M.E.C-M, A. J, R.T.M.	('A. J', 'Var', (49, 53))	('M.E.C-M', 'Var', (40, 47))	('men', 'Species', '9606', (33, 36))
52379	29670653	This study does not explicitly describe which variables or the number of patients that were included in the multivariable model; however, they found that tumour size >= 3 cm (hazard ratio 1.87, 95% confidence interval 1.15 to 3.06) was associated with relapse, but rete testis invasion was not (hazard ratio 1.36, 95% confidence interval 0.81 to 2.28).	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('relapse', 'CPA', (252, 259))	('>= 3', 'Var', (166, 170))	('tumour', 'Disease', (154, 160))	('patients', 'Species', '9606', (73, 81))
52459	29670653	CT scans, on the other hand, are associated with significant radiation exposure, and every scan increases the lifetime attributable risk for secondary malignancy, which is a particularly important concern in testicular cancer patients, given the relatively young age of diagnosis.	('testicular cancer', 'Phenotype', 'HP:0010788', (208, 225))	('testicular cancer', 'Disease', 'MESH:D013736', (208, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('increases', 'PosReg', (96, 105))	('malignancy', 'Disease', (151, 161))	('testicular cancer', 'Disease', (208, 225))	('patients', 'Species', '9606', (226, 234))	('scan', 'Var', (91, 95))
52586	29482183	EDCs are able to cross the placenta and may adversely affect placental functioning and/or fetal development.	('placental functioning', 'CPA', (61, 82))	('fetal development', 'CPA', (90, 107))	('men', 'Species', '9606', (103, 106))	('EDCs', 'Var', (0, 4))	('affect', 'Reg', (54, 60))
52646	24120139	A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('Cancer', 'Disease', (60, 66))	('Influences', 'Reg', (49, 59))	('tumor', 'Disease', (168, 173))	('p53', 'Gene', '7157', (14, 17))	('KIT Ligand', 'Gene', (38, 48))	('polymorphisms', 'Var', (213, 226))	('transcription', 'MPA', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('p53', 'Gene', '7157', (123, 126))	('KIT Ligand', 'Gene', '4254', (38, 48))	('p53', 'Gene', '7157', (241, 244))	('cancer', 'Disease', (275, 281))	('p53', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('p53', 'Gene', (123, 126))	('influence', 'Reg', (265, 274))	('Polymorphic', 'Var', (2, 13))	('p53', 'Gene', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
52651	24120139	Genome-wide association studies (GWASs) have identified almost 900 single-nucleotide polymorphisms (SNPs) significantly associated with cancer susceptibility traits.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('single-nucleotide polymorphisms', 'Var', (67, 98))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
52652	24120139	Interestingly, many cancer-associated SNPs identified in GWASs are significantly enriched in noncoding functional DNA elements as defined by the ENCODE project.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('noncoding functional', 'MPA', (93, 113))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('SNPs', 'Var', (38, 42))	('cancer', 'Disease', (20, 26))
52653	24120139	Indeed, single locus and gene-specific studies have presented strong data to support the role of polymorphic transcriptional regulatory elements in influencing the risk of cancers of the breast, kidney, colon, and connective tissues.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('kidney', 'Disease', (195, 201))	('cancers of the breast', 'Phenotype', 'HP:0100013', (172, 193))	('colon', 'Disease', (203, 208))	('breast', 'Disease', (187, 193))	('polymorphic', 'Var', (97, 108))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))
52659	24120139	A reflection of this lies in the fact that approximately 50% of human cancers carry somatic mutations of the p53 gene over 80% of which are missense mutations spanning the highly conserved DBD.	('human', 'Species', '9606', (64, 69))	('missense mutations', 'Var', (140, 158))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (92, 101))	('p53', 'Gene', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
52660	24120139	Moreover, many of the same somatic DBD mutations can be found as inherited, cancer-causing mutations in extremely cancer-prone families belonging to the Li-Fraumeni syndrome.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (153, 173))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Li-Fraumeni syndrome', 'Disease', (153, 173))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (114, 120))
52661	24120139	Together, these observations suggest the possibility that SNPs in key bases of functional p53-REs (p53-RE SNPs) could influence the ability of p53 to regulate transcription and result in differences in cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('SNPs', 'Var', (58, 62))	('cancer', 'Disease', (202, 208))	('result in differences', 'Reg', (177, 198))	('regulate transcription', 'MPA', (150, 172))	('ability', 'MPA', (132, 139))	('influence', 'Reg', (118, 127))
52662	24120139	In this report, we identify and describe a SNP in a functional p53-RE that affects the ability of p53 to regulate transcription and influence cancer susceptibility and has undergone positive natural selection throughout human evolution.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('affects', 'Reg', (75, 82))	('cancer', 'Disease', (142, 148))	('p53-RE', 'Gene', (63, 69))	('human', 'Species', '9606', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ability', 'MPA', (87, 94))	('regulate transcription', 'MPA', (105, 127))	('SNP', 'Var', (43, 46))	('influence', 'Reg', (132, 141))
52663	24120139	Our data indicate that polymorphisms in functional p53 response elements are primarily detrimental but in rare instances can impart selective benefits, rising to substantial frequencies in populations and resulting in differences in cancer susceptibility among individuals.	('polymorphisms', 'Var', (23, 36))	('p53', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('differences', 'Reg', (218, 229))	('resulting', 'Reg', (205, 214))	('rising', 'PosReg', (152, 158))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))
52664	24120139	We reasoned that if SNPs in key nucleotides of functional p53-REs can lead to differential cancer risk, then at least one cancer GWAS SNP or proxy (a SNP in linkage disequilibrium [LD]) should reside in a genomic region occupied by p53, containing a strong p53-RE and in a key nucleotide of the element.	('cancer GWAS SNP', 'Disease', 'MESH:D009369', (122, 137))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer GWAS SNP', 'Disease', (122, 137))	('SNPs', 'Var', (20, 24))	('lead to', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
52671	24120139	The SNP, KITLG p53-RE SNP, rs4590952 (G/A), is in LD with rs995030, rs3782181, and rs4474514 (Figure 2B), which have been shown in three GWASs to associate with differential risk for developing testicular cancer in Caucasians with a per allele odds ratio (OR) of up to 3.07 (p = 1.0 x 10-31, Table S4).	('rs4474514', 'Var', (83, 92))	('testicular cancer', 'Phenotype', 'HP:0010788', (194, 211))	('testicular cancer', 'Disease', 'MESH:D013736', (194, 211))	('rs4590952', 'Var', (27, 36))	('testicular cancer', 'Disease', (194, 211))	('rs995030', 'Mutation', 'rs995030', (58, 66))	('rs4474514', 'Mutation', 'rs4474514', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('rs3782181', 'Mutation', 'rs3782181', (68, 77))	('rs4590952', 'Mutation', 'rs4590952', (27, 36))	('rs3782181', 'Var', (68, 77))	('rs995030', 'Var', (58, 66))
52682	24120139	First, we irradiated WT pups at postnatal day 2 (P2) with a melanoma-inducing 5.6 kJ/m2 of ultraviolet (UV) light and observed an up to 16-fold increase in epidermal melanocyte numbers after UVR compared to nontreated mice (Figure S2A).	('epidermal melanocyte numbers', 'CPA', (156, 184))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('mice', 'Species', '10090', (218, 222))	('UVR', 'Var', (191, 194))	('increase', 'PosReg', (144, 152))
52686	24120139	These data provide strong evidence that in its natural setting, the action of p53-Kitlg signaling results in a measurable effect on a cancer-related process such as cellular proliferation.	('p53-Kitlg', 'Var', (78, 87))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('effect', 'Reg', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cellular proliferation', 'CPA', (165, 187))
52687	24120139	One of the studies incorporated heterozygous cell lines, two HapMap CEU LCL (GM06993 and GM11992), which were treated with doxorubicin.	('GM06993', 'Var', (77, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (123, 134))	('GM11992', 'Var', (89, 96))
52689	24120139	To test p53 dependence, we transfected each of these constructs into the colorectal cancer wild-type p53 cell line (HCT116 p53+/+) and its isogenic p53 null form (HCT116 p53-/-).	('HCT116', 'CellLine', 'CVCL:0291', (116, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('HCT116 p53-/-', 'Var', (163, 176))	('HCT116', 'CellLine', 'CVCL:0291', (163, 169))
52692	24120139	To extend this study to cells derived from other cancers and, importantly, to cells derived from testicular cancers, we transfected the reporter plasmids into four p53 wild-type cell lines (GH, testicular; Tera1, testicular; Tera2, testicular; and MCF7, breast) and three p53 mutant or null cell lines (CRL-2073, germ cell tumor; H1299, lung; and Soas2, osteosarcoma).	('testicular cancers', 'Disease', 'MESH:D013736', (97, 115))	('testicular cancers', 'Phenotype', 'HP:0010788', (97, 115))	('osteosarcoma', 'Disease', (354, 366))	('osteosarcoma', 'Disease', 'MESH:D012516', (354, 366))	('germ cell tumor', 'Phenotype', 'HP:0100728', (313, 328))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('testicular cancers', 'Disease', (97, 115))	('cancers', 'Disease', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('testicular cancer', 'Phenotype', 'HP:0010788', (97, 114))	('MCF7', 'CellLine', 'CVCL:0031', (248, 252))	('H1299', 'CellLine', 'CVCL:0060', (330, 335))	('Tera2', 'CellLine', 'CVCL:2777', (225, 230))	('osteosarcoma', 'Phenotype', 'HP:0002669', (354, 366))	('mutant', 'Var', (276, 282))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancers', 'Disease', (108, 115))	('tumor', 'Disease', (323, 328))	('lung', 'Disease', (337, 341))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Tera1', 'CellLine', 'CVCL:2776', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
52693	24120139	Consistent with the results obtained in the HCT116 p53-/- cells, we measured, on average, a nonsignificant 1.5-fold increase in luciferase activity from the G allele reporter relative to the A allele when tested in the three p53 mutant or null cell lines, ranging from 1.1 to 2.1.	('HCT116', 'CellLine', 'CVCL:0291', (44, 50))	('p53', 'Gene', (225, 228))	('activity', 'MPA', (139, 147))	('increase', 'PosReg', (116, 124))	('mutant', 'Var', (229, 235))	('luciferase', 'Enzyme', (128, 138))
52704	24120139	Thus far, our genomic analyses and subsequent experimental validation have supported the assertion that a functional SNP in a functional p53-RE in the KITLG gene resides among the 62,567 cancer GWAS SNPs.	('KITLG', 'Gene', (151, 156))	('cancer GWAS SNP', 'Disease', 'MESH:D009369', (187, 202))	('SNP', 'Var', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer GWAS SNP', 'Disease', (187, 202))
52705	24120139	To assess the likelihood that the KITLG p53-RE SNP's association with the pool of cancer GWAS SNPs was by chance, we determined the frequency of similar SNPs in the genome (Figure 7A).	('p53-RE', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer GWAS SNP', 'Disease', (82, 97))	('cancer GWAS SNP', 'Disease', 'MESH:D009369', (82, 97))
52708	24120139	In this report, we present strong evidence supporting the hypothesis that well-placed polymorphisms in functional p53-binding sites can result in differential p53-dependent transcriptional regulation and cancer risk, through the identification and characterization of the KITLG p53-RE SNP.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('p53-dependent transcriptional regulation', 'MPA', (159, 199))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('result in', 'Reg', (136, 145))	('polymorphisms', 'Var', (86, 99))	('KITLG', 'Gene', (272, 277))
52709	24120139	The KITLG p53-RE SNP is strongly linked to three SNPs shown, in three independent GWASs, to associate with differential risk for developing seminomatous and nonseminomatous testicular cancer, with a per allele odds ratio of up to 3.07 (p value = 1.0 x 10-31), one of the highest and most significant findings among all cancer GWASs.	('cancer', 'Disease', (184, 190))	('testicular cancer', 'Phenotype', 'HP:0010788', (173, 190))	('p53-RE', 'Var', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('KITLG', 'Gene', (4, 9))	('seminomatous and nonseminomatous testicular cancer', 'Disease', 'MESH:D013736', (140, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
52712	24120139	Indeed, activating mutations of the KIT receptor have been shown to promote tumor formation and the receptor is currently targeted by many therapeutic agents in cancer treatments.	('activating mutations', 'Var', (8, 28))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('promote', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('KIT', 'Gene', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
52713	24120139	In testicular cancer, the KIT pathway is central to its molecular pathology, and many components of this pathway are somatically mutated to activate KIT signaling.	('activate', 'PosReg', (140, 148))	('testicular cancer', 'Disease', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutated', 'Var', (129, 136))	('testicular cancer', 'Phenotype', 'HP:0010788', (3, 20))	('testicular cancer', 'Disease', 'MESH:D013736', (3, 20))	('KIT signaling', 'MPA', (149, 162))
52715	24120139	Although p53 is the most commonly mutated gene in human cancer, whereby 50% of all cancers have mutant p53, less than 3% of testicular cancers do.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('human', 'Species', '9606', (50, 55))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', (135, 141))	('mutant', 'Var', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('p53', 'Gene', (103, 106))	('testicular cancers', 'Disease', 'MESH:D013736', (124, 142))	('cancers', 'Disease', (135, 142))	('testicular cancers', 'Phenotype', 'HP:0010788', (124, 142))	('testicular cancers', 'Disease', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancers', 'Disease', (83, 90))	('testicular cancer', 'Phenotype', 'HP:0010788', (124, 141))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', (83, 89))
52725	24120139	Interestingly, in Caucasians, variation in all other pigmentation genes that we know about results in impaired melanogenic function and concomitant reduced pigmentation.	('variation', 'Var', (30, 39))	('impaired melanogenic function', 'Disease', (102, 131))	('reduced', 'NegReg', (148, 155))	('pigmentation', 'Disease', 'MESH:D010859', (156, 168))	('pigmentation', 'Disease', (156, 168))	('pigmentation', 'Disease', 'MESH:D010859', (53, 65))	('pigmentation', 'Disease', (53, 65))	('impaired melanogenic function', 'Disease', 'MESH:D003072', (102, 131))
52792	24263066	We have found that moderate dose infradiaphragmatic RT for stage I seminoma was associated with an increased risk of developing a second (non-testicular germ cell) cancer, with an SIR of 1.53 (95% CI: 1.39-1.68).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('stage I seminoma', 'Disease', (59, 75))	('infradiaphragmatic RT', 'Var', (33, 54))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('stage I seminoma', 'Disease', 'MESH:D018239', (59, 75))
52793	24263066	A weakness of our analysis of the impact of reducing radiation dose and field size is that follow-up was shorter in men with these modifications.	('modifications', 'Var', (131, 144))	('weakness', 'Disease', (2, 10))	('weakness', 'Disease', 'MESH:D018908', (2, 10))	('shorter', 'NegReg', (105, 112))	('men', 'Species', '9606', (116, 119))
52806	24263066	Similarly, in a nationwide cohort of testicular cancers from The Netherlands, subdiaphragmatic radiotherapy was associated with a 2.6-fold increase in second cancers, whereas there were no significant excesses in patients treated only by surgery.	('cancers', 'Disease', (48, 55))	('testicular cancer', 'Phenotype', 'HP:0010788', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('testicular cancers', 'Disease', 'MESH:D013736', (37, 55))	('increase', 'PosReg', (139, 147))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('testicular cancers', 'Phenotype', 'HP:0010788', (37, 55))	('patients', 'Species', '9606', (213, 221))	('subdiaphragmatic radiotherapy', 'Var', (78, 107))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('testicular cancers', 'Disease', (37, 55))
52865	24056494	Tumours were classified as seminomas (N=167, 62.8%), including seminoma not other specified (ICD-O, M9061: n=160), anaplastic seminoma (M9062: n=4) or non-seminomas (N=99, 37.2%), including embryonal carcinoma (M9070: n=26), yolk sac tumour (M9071: n=1), malignant teratoma not other specified (M9080: n=2), teratocarcinoma (M9081: n=15), malignant teratoma, intermediate (M9083: n=5), mixed germ cell tumour (M9085: n=49) and choriocarcinoma (M9100: n=1) according to Parkin et al.	('M9061', 'CellLine', 'CVCL:E765', (100, 105))	('tumour', 'Phenotype', 'HP:0002664', (402, 408))	('seminoma', 'Disease', 'MESH:D018239', (63, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('M9085:', 'Var', (410, 416))	('tumour', 'Disease', 'MESH:D009369', (402, 408))	('seminoma', 'Disease', (126, 134))	('germ cell tumour', 'Phenotype', 'HP:0100728', (392, 408))	('M9081', 'Var', (325, 330))	('tumour', 'Disease', (402, 408))	('seminoma', 'Disease', (155, 163))	('malignant teratoma', 'Disease', (255, 273))	('seminoma', 'Disease', 'MESH:D018239', (126, 134))	('malignant teratoma', 'Disease', 'MESH:D013724', (255, 273))	('seminoma', 'Disease', 'MESH:D018239', (155, 163))	('anaplastic seminoma', 'Disease', (115, 134))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('seminoma', 'Disease', (27, 35))	('teratocarcinoma', 'Disease', 'MESH:D018243', (308, 323))	('tumour', 'Disease', (234, 240))	('teratoma', 'Phenotype', 'HP:0009792', (265, 273))	('M9071', 'Var', (242, 247))	('seminoma', 'Disease', 'MESH:D018239', (27, 35))	('teratocarcinoma', 'Disease', (308, 323))	('seminomas', 'Disease', 'MESH:D018239', (155, 164))	('seminomas', 'Disease', (155, 164))	('choriocarcinoma', 'Disease', 'MESH:D002822', (427, 442))	('choriocarcinoma', 'Disease', (427, 442))	('malignant teratoma', 'Disease', (339, 357))	('malignant teratoma', 'Disease', 'MESH:D013724', (339, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (433, 442))	('seminomas', 'Disease', 'MESH:D018239', (27, 36))	('seminomas', 'Disease', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (190, 209))	('non-seminomas', 'Disease', (151, 164))	('M9080', 'Var', (295, 300))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (190, 209))	('seminoma', 'Disease', (63, 71))	('non-seminomas', 'Disease', 'MESH:D018239', (151, 164))	('embryonal carcinoma', 'Disease', (190, 209))	('teratoma', 'Phenotype', 'HP:0009792', (349, 357))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (427, 442))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('anaplastic seminoma', 'Disease', 'MESH:D018239', (115, 134))
53010	33368789	Testosterone therapy is known to elevate cardiovascular risk factors (blood pressure, polycythemia, lipid changes, and insulin resistance), but mortality and morbidity do not appear to exceed that of cis men (Seal, 2019; Streed et al., 2017).	('lipid changes', 'MPA', (100, 113))	('polycythemia', 'Disease', 'MESH:D011086', (86, 98))	('mortality', 'Disease', 'MESH:D003643', (144, 153))	('cardiovascular', 'MPA', (41, 55))	('insulin', 'Gene', (119, 126))	('lipid', 'Chemical', 'MESH:D008055', (100, 105))	('Testosterone', 'Chemical', 'MESH:D013739', (0, 12))	('insulin resistance', 'Phenotype', 'HP:0000855', (119, 137))	('insulin', 'Gene', '3630', (119, 126))	('elevate cardiovascular risk', 'Phenotype', 'HP:0001626', (33, 60))	('men', 'Species', '9606', (204, 207))	('mortality', 'Disease', (144, 153))	('polycythemia', 'Disease', (86, 98))	('elevate', 'PosReg', (33, 40))	('polycythemia', 'Phenotype', 'HP:0001901', (86, 98))	('therapy', 'Var', (13, 20))
53027	33368789	Additionally, discomfort with gender-specific screening programs leads to patient delay, and transmasculine people are also more likely to have inadequate or abnormal Papanicolaou smears than cisgender women (Gatos, 2018; Peitzmeier et al., 2014).	('Papanicolaou', 'Chemical', '-', (167, 179))	('patient', 'Species', '9606', (74, 81))	('people', 'Species', '9606', (108, 114))	('patient delay', 'CPA', (74, 87))	('transmasculine', 'Var', (93, 107))	('women', 'Species', '9606', (202, 207))
53030	33368789	On the other hand, testosterone often causes substantial (if not total) atrophy of the endometrium, which would lower risk (Braun et al., 2017; Dizon et al., 2006).	('risk', 'MPA', (118, 122))	('atrophy', 'Disease', 'MESH:D001284', (72, 79))	('testosterone', 'Var', (19, 31))	('atrophy', 'Disease', (72, 79))	('testosterone', 'Chemical', 'MESH:D013739', (19, 31))
53062	33368789	Mitigating this discomfort by normalizing dysmorphic traits appears to be effective, although more research is needed (Steel et al., 2014).	('dysmorphic traits', 'Disease', 'MESH:C567520', (42, 59))	('normalizing', 'Var', (30, 41))	('dysmorphic traits', 'Disease', (42, 59))
53105	31842336	Abnormalities in their expression or function contribute to the development of multiple disorders, including cancer.	('function', 'MPA', (37, 45))	('contribute to', 'Reg', (46, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Abnormalities', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('multiple disorders', 'Disease', 'MESH:D009105', (79, 97))	('cancer', 'Disease', (109, 115))	('men', 'Species', '9606', (71, 74))	('multiple disorders', 'Disease', (79, 97))	('expression', 'MPA', (23, 33))
53124	31842336	The key molecular alteration in ccRCC is von Hippel-Lindau (VHL) gene mutation, which leads to uncontrolled hypoxia-induced factor (HIF) expression, followed by the activation of several growth factor pathways, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others.	('von Hippel-Lindau', 'Gene', (41, 58))	('VHL', 'Gene', (60, 63))	('rat', 'Species', '10116', (22, 25))	('VEGF', 'Gene', '7422', (257, 261))	('growth factor pathways', 'Pathway', (187, 209))	('von Hippel-Lindau', 'Gene', '7428', (41, 58))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('VHL', 'Gene', '7428', (60, 63))	('mutation', 'Var', (70, 78))	('uncontrolled', 'MPA', (95, 107))	('VEGF', 'Gene', (257, 261))	('hypoxia', 'Disease', (108, 115))	('vascular endothelial growth factor', 'Gene', (221, 255))	('vascular endothelial growth factor', 'Gene', '7422', (221, 255))	('activation', 'PosReg', (165, 175))	('RCC', 'Disease', 'MESH:D002292', (34, 37))	('RCC', 'Disease', (34, 37))
53201	31842336	In patients with a good response (PSA level after 7 months of ADT <0.2 ng/mL), it is 75 months while in patients with a poor response (PSA > 4.0 ng/mL), it is 13 months.	('PSA', 'Gene', (34, 37))	('PSA', 'Gene', '354', (34, 37))	('<0.2 ng/mL', 'Var', (66, 76))	('PSA', 'Gene', (135, 138))	('patients', 'Species', '9606', (3, 11))	('PSA', 'Gene', '354', (135, 138))	('patients', 'Species', '9606', (104, 112))
53213	31842336	The relieved domain is translocated to the nucleus where it interacts with various molecules and activates multiple signaling pathways, including these involving Ras, RHOA (Ras homolog family member A), PI3K (phosphoinositide 3-kinase), PP2A (protein phosphatase 2A), MAPK (mitogen-activated protein kinase), TAKI1 (TGF-beta-activated kinase), ERK1/2 (extracellular signal-regulated kinase 1/2), and JNK (c-Jun N-terminal kinase).	('c-Jun N-terminal kinase', 'Gene', (405, 428))	('activates', 'PosReg', (97, 106))	('ERK1/2', 'Gene', (344, 350))	('PI3K', 'Var', (203, 207))	('JNK', 'Gene', (400, 403))	('c-Jun N-terminal kinase', 'Gene', '5599', (405, 428))	('RHOA', 'Gene', '387', (167, 171))	('TGF-beta-activated kinase', 'Gene', '56911', (316, 341))	('PP2A', 'Gene', '5524', (237, 241))	('TGF-beta-activated kinase', 'Gene', (316, 341))	('MAPK', 'Gene', (268, 272))	('ERK1/2', 'Gene', '5595;5594', (344, 350))	('extracellular signal-regulated kinase 1/2', 'Gene', '5595', (352, 393))	('JNK', 'Gene', '5599', (400, 403))	('extracellular signal-regulated kinase 1/2', 'Gene', (352, 393))	('RHOA', 'Gene', (167, 171))	('PP2A', 'Gene', (237, 241))
53218	31842336	It appears that as tumors progress, cancer cells tend to acquire resistance to TGF-beta growth inhibitory effects due to mutations and/or functional inactivation of TGF-beta pathway elements.	('TGF-beta', 'Gene', (79, 87))	('TGF-beta', 'Gene', (165, 173))	('tumors', 'Disease', (19, 25))	('men', 'Species', '9606', (185, 188))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('growth inhibitory effects', 'MPA', (88, 113))	('cancer', 'Disease', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('resistance', 'MPA', (65, 75))
53219	31842336	The most commonly mutated genes of the TGF-beta signaling pathway include TGFBR1, TGFBR2, SMAD4, and SMAD2.	('TGFBR1', 'Gene', (74, 80))	('TGFBR2', 'Gene', '7048', (82, 88))	('TGFBR2', 'Gene', (82, 88))	('mutated', 'Var', (18, 25))
53223	31842336	The same study also showed that miRNAs contribute to the transcriptional activity of the TGF-beta pathway, indicating functional links between short-non-coding RNAs and transforming growth factor effects in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('links', 'Interaction', (129, 134))	('cancer', 'Disease', (207, 213))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('TGF-beta pathway', 'Pathway', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('short-non-coding RNAs', 'Var', (143, 164))	('transcriptional activity', 'MPA', (57, 81))
53226	31842336	Activin A and TGFB2 are involved in the formation of the ureteric bud while TGFB2 knock-out results in kidney agenesis in mice.	('mice', 'Species', '10090', (122, 126))	('knock-out', 'Var', (82, 91))	('results in', 'Reg', (92, 102))	('TGFB2', 'Gene', '21808', (14, 19))	('kidney agenesis', 'Phenotype', 'HP:0000104', (103, 118))	('TGFB2', 'Gene', (14, 19))	('kidney agenesis', 'Disease', 'MESH:D007674', (103, 118))	('kidney agenesis', 'Disease', (103, 118))	('TGFB2', 'Gene', (76, 81))	('TGFB2', 'Gene', '21808', (76, 81))
53239	31842336	Moreover, an analysis of 151 cases of urinary system cancers provided evidence that an intronic variant of TGFBR1, Int7G24A (rs334354), was associated with a higher risk of RCC development.	('TGFBR1', 'Gene', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('associated with', 'Reg', (140, 155))	('RCC', 'Disease', (173, 176))	('cancers', 'Disease', (53, 60))	('rs334354', 'Mutation', 'rs334354', (125, 133))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('RCC', 'Disease', 'MESH:D002292', (173, 176))	('rs334354', 'Var', (125, 133))	('men', 'Species', '9606', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
53246	31842336	Recently, downregulation of TGFBR3 expression in advanced ccRCC tumor samples was confirmed by an independent study in which the loss of this receptor led to the stimulation of cell migration and formation of lung metastasis.	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('tumor', 'Disease', (64, 69))	('TGFBR3', 'Gene', (28, 34))	('RCC', 'Disease', (60, 63))	('lung metastasis', 'CPA', (209, 224))	('loss', 'Var', (129, 133))	('RCC', 'Disease', 'MESH:D002292', (60, 63))	('cell migration', 'CPA', (177, 191))	('downregulation', 'NegReg', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('stimulation', 'PosReg', (162, 173))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
53252	31842336	VHL inactivation is the key molecular aberration associated with ccRCC and several studies demonstrated regulation of TGF-beta signaling by VHL status.	('inactivation', 'Var', (4, 16))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('TGF-beta signaling', 'MPA', (118, 136))	('RCC', 'Disease', (67, 70))	('rat', 'Species', '10116', (98, 101))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', (140, 143))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (140, 143))	('rat', 'Species', '10116', (42, 45))
53255	31842336	Pro-cancerous TGF-beta effects were confirmed by antibody-mediated neutralization of TGF-beta1, which led to tumor regression and inhibition of angiogenesis in a xenograft athymic mouse model.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('neutralization', 'Var', (67, 81))	('mouse', 'Species', '10090', (180, 185))	('inhibition', 'NegReg', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('angiogenesis', 'CPA', (144, 156))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('TGF-beta1', 'Gene', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', (4, 10))	('tumor', 'Disease', (109, 114))
53272	31842336	The silencing of FAK and PINCH1 inhibited cooperation between TGF-beta1 and RGD.	('PINCH1', 'Gene', (25, 31))	('inhibited', 'NegReg', (32, 41))	('rat', 'Species', '10116', (47, 50))	('FAK', 'Gene', (17, 20))	('FAK', 'Gene', '5747', (17, 20))	('cooperation', 'Interaction', (42, 53))	('silencing', 'Var', (4, 13))	('PINCH1', 'Gene', '3987', (25, 31))
53277	31842336	Inhibition of TGF-beta1 signaling attenuates tumor growth and osteolysis in mice with ccRCC xenografts.	('attenuates', 'NegReg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TGF-beta1', 'Gene', (14, 23))	('osteolysis', 'Disease', 'MESH:D010014', (62, 72))	('tumor', 'Disease', (45, 50))	('RCC', 'Disease', 'MESH:D002292', (88, 91))	('RCC', 'Disease', (88, 91))	('osteolysis', 'Phenotype', 'HP:0002797', (62, 72))	('mice', 'Species', '10090', (76, 80))	('Inhibition', 'Var', (0, 10))	('osteolysis', 'Disease', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
53283	31842336	These alterations included multiple copy number losses or gains (e.g., of TGFB1, TGFB3, TGFBR2, BMPR1B, ACVR2B, SMAD4, SMAD2, SMAD1, SMAD7, PITX2) as well as mutations of TGFRB2 (R522X, S320X, S320X).	('TGFBR2', 'Gene', '7048', (88, 94))	('SMAD7', 'Gene', '4092', (133, 138))	('PITX2', 'Gene', '5308', (140, 145))	('S320X', 'Var', (186, 191))	('ACVR2B', 'Gene', (104, 110))	('SMAD1', 'Gene', '4086', (126, 131))	('BMPR1B', 'Gene', '658', (96, 102))	('S320X', 'Mutation', 'p.S320X', (186, 191))	('TGFRB2', 'Gene', (171, 177))	('TGFBR2', 'Gene', (88, 94))	('TGFB1', 'Gene', '7040', (74, 79))	('mutations', 'Var', (158, 167))	('TGFB1', 'Gene', (74, 79))	('losses', 'NegReg', (48, 54))	('S320X', 'Var', (193, 198))	('R522X', 'Var', (179, 184))	('S320X', 'Mutation', 'p.S320X', (193, 198))	('TGFB3', 'Gene', '7043', (81, 86))	('gains', 'PosReg', (58, 63))	('PITX2', 'Gene', (140, 145))	('SMAD7', 'Gene', (133, 138))	('BMPR1B', 'Gene', (96, 102))	('ACVR2B', 'Gene', '93', (104, 110))	('TGFB3', 'Gene', (81, 86))	('SMAD1', 'Gene', (126, 131))	('rat', 'Species', '10116', (10, 13))	('R522X', 'Mutation', 'rs863223852', (179, 184))
53284	31842336	The functional significance of these alterations, as well as their influence on penile cancer progression, await future analyses.	('penile cancer', 'Disease', 'MESH:D009369', (80, 93))	('penile cancer', 'Disease', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rat', 'Species', '10116', (41, 44))	('alterations', 'Var', (37, 48))
53289	31842336	In fetal testis, TGF-beta attenuates proliferation, indicating that aberrances of the TGF-beta pathway may lead to tumor development.	('lead to', 'Reg', (107, 114))	('TGF-beta', 'Gene', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('men', 'Species', '9606', (128, 131))	('tumor', 'Disease', (115, 120))	('rat', 'Species', '10116', (44, 47))	('proliferation', 'CPA', (37, 50))	('attenuates', 'NegReg', (26, 36))	('aberrances', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
53290	31842336	Indeed, alpha-inhibin acts as a tumor suppressor and its knock-out results in the development of mixed or incompletely differentiated gonadal tumors, including intratubular, focally invasive gonadal stromal tumors in testis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('gonadal tumors', 'Phenotype', 'HP:0010785', (134, 148))	('results in', 'Reg', (67, 77))	('alpha-inhibin', 'Protein', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('intratubular', 'Disease', (160, 172))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('men', 'Species', '9606', (89, 92))	('knock-out', 'Var', (57, 66))	('invasive gonadal stromal tumors', 'Disease', 'MESH:D018312', (182, 213))	('gonadal tumors', 'Disease', 'MESH:D006058', (134, 148))	('gonadal tumors', 'Disease', (134, 148))	('rat', 'Species', '10116', (163, 166))	('mixed', 'Disease', (97, 102))	('tumor', 'Disease', (142, 147))	('invasive gonadal stromal tumors', 'Disease', (182, 213))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
53297	31842336	In a study involving 577 tumor cases and > 700 controls, the TGFB1 Ex5-73C > T variant was positively associated with TGCT risk while Ex1-282G and 509C > T variants were linked with increased risks of seminoma and non-seminoma, respectively (Purdue at al., 2007).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('509C > T', 'Mutation', 'rs1800469', (147, 155))	('associated', 'Reg', (102, 112))	('Ex1', 'Gene', (134, 137))	('Ex1', 'Gene', '122786', (134, 137))	('tumor', 'Disease', (25, 30))	('seminoma and non-seminoma', 'Disease', 'MESH:D018239', (201, 226))	('Ex5-73C > T', 'Var', (67, 78))	('TGFB1', 'Gene', '7040', (61, 66))	('TGCT', 'Disease', (118, 122))	('Ex5-73C > T', 'Mutation', 'rs1800472', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('TGFB1', 'Gene', (61, 66))
53298	31842336	In the TGF-beta1 protein sequence, the Ex5-73C > T (rs1800472) variant results in a substitution of threonine with isoleucine (T263I) while Ex1-282G > C (rs1800471) changes the arginine to proline (P25R).	('Ex5-73C > T', 'Mutation', 'rs1800472', (39, 50))	('TGF-beta1', 'Gene', (7, 16))	('arginine', 'Chemical', 'MESH:D001127', (177, 185))	('P25R', 'Mutation', 'rs1800471', (198, 202))	('rs1800472', 'Mutation', 'rs1800472', (52, 61))	('results in', 'Reg', (71, 81))	('proline', 'Chemical', 'MESH:C489032', (189, 196))	('T263I', 'Mutation', 'rs1800472', (127, 132))	('changes', 'Reg', (165, 172))	('isoleucine', 'Chemical', 'MESH:C043801', (115, 125))	('threonine', 'Chemical', 'MESH:C061951', (100, 109))	('Ex1-282G > C (rs1800471', 'Var', (140, 163))	('arginine to proline', 'MPA', (177, 196))	('Ex5-73C > T', 'Var', (39, 50))	('rs1800471', 'Mutation', 'rs1800471', (154, 163))
53299	31842336	The functional consequences of these alterations are unknown, although it was suggested they could influence TGF-beta expression, with Ex5-73T causing a decrease, and Ex1-282G > C resulting in an increase of TGF-beta protein levels.	('Ex5-73T', 'Var', (135, 142))	('TGF-beta protein levels', 'MPA', (208, 231))	('increase', 'PosReg', (196, 204))	('influence', 'Reg', (99, 108))	('Ex1-282G > C', 'Var', (167, 179))	('TGF-beta', 'Gene', (109, 117))	('rat', 'Species', '10116', (41, 44))	('expression', 'MPA', (118, 128))	('decrease', 'NegReg', (153, 161))
53300	31842336	The -509C > T (rs1800469) variant does not change the TGF-beta1 amino acid sequence; however, it was linked with elevated plasma concentrations of TGF-beta1.	('-509C > T', 'Mutation', 'rs1800469', (4, 13))	('plasma concentrations', 'MPA', (122, 143))	('elevated', 'PosReg', (113, 121))	('elevated plasma concentrations', 'Phenotype', 'HP:0020170', (113, 143))	('rat', 'Species', '10116', (136, 139))	('rs1800469', 'Mutation', 'rs1800469', (15, 24))	('rs1800469', 'Var', (15, 24))
53301	31842336	The exact mechanism by which altered TGF-beta functioning could affect the development of TGCT is currently unknown.	('development', 'CPA', (75, 86))	('TGCT', 'Disease', (90, 94))	('altered', 'Var', (29, 36))	('affect', 'Reg', (64, 70))	('men', 'Species', '9606', (82, 85))	('TGF-beta', 'Protein', (37, 45))
53307	31842336	The associations between bladder cancer's clinical course and genetic variants of TGF-beta1 and its receptors has been confirmed by several studies.	('associations', 'Interaction', (4, 16))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('genetic variants', 'Var', (62, 78))	('TGF-beta1', 'Gene', (82, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))
53308	31842336	TGFB1 c.29C > T substitution (rs1800470) correlates with an increased risk of bladder cancer.	('c.29C > T', 'Mutation', 'rs1800470', (6, 15))	('TGFB1', 'Gene', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('c.29C > T', 'Var', (6, 15))	('bladder cancer', 'Disease', (78, 92))	('rs1800470', 'Mutation', 'rs1800470', (30, 39))	('rs1800470', 'Var', (30, 39))	('TGFB1', 'Gene', '7040', (0, 5))
53309	31842336	This SNP (Single Nucleotide Polymorphism) is located in a region encoding the hydrophobic core of the TGF-beta1 signal peptide and results in a substitution of proline with leucine in the 10th position of the amino acid sequence.	('results in a', 'Reg', (131, 143))	('leucine', 'Chemical', 'MESH:C038361', (173, 180))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('proline', 'MPA', (160, 167))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('leucine', 'MPA', (173, 180))	('substitution', 'Var', (144, 156))	('proline', 'Chemical', 'MESH:C489032', (160, 167))
53310	31842336	found Int7G24A (rs334354) intronic variant of the TGFBR1 gene frequently associates with transitional cell carcinoma (TCC) of the bladder as well as renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cell carcinoma', 'Disease', 'MESH:D002292', (102, 116))	('renal cell carcinoma', 'Disease', (149, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (149, 169))	('cell carcinoma', 'Disease', (102, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('TC', 'Disease', 'MESH:D013736', (118, 120))	('rs334354', 'Mutation', 'rs334354', (16, 24))	('TGFBR1', 'Gene', (50, 56))	('rs334354', 'Var', (16, 24))	('cell carcinoma', 'Disease', 'MESH:D002292', (155, 169))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (89, 116))	('associates with', 'Reg', (73, 88))
53313	31842336	Interestingly, the Int7G24A SNP is also associated with increased risks of osteosarcoma, colorectal, and breast cancer, suggestive of its general involvement in cancer predisposition.	('osteosarcoma', 'Disease', (75, 87))	('Int7G24A', 'Var', (19, 27))	('osteosarcoma', 'Disease', 'MESH:D012516', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('colorectal', 'Disease', 'MESH:D015179', (89, 99))	('colorectal', 'Disease', (89, 99))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('men', 'Species', '9606', (153, 156))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (75, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
53318	31842336	However, it was also shown that a loss of TGFBR1 expression correlates with poor prognoses of bladder cancer patients while loss of TGFBR1 and TGFBR2 correlated with increased bladder tumor grades, which agrees with the decreased TGFBR2 expression in invasive tumors compared with superficial transitional cell carcinomas.	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (293, 320))	('patients', 'Species', '9606', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('cell carcinoma', 'Disease', 'MESH:D002292', (306, 320))	('invasive tumors', 'Disease', (251, 266))	('carcinomas', 'Phenotype', 'HP:0030731', (311, 321))	('carcinomas', 'Disease', 'MESH:D002277', (311, 321))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('bladder tumor', 'Phenotype', 'HP:0009725', (176, 189))	('loss', 'Var', (124, 128))	('TGFBR2', 'Gene', '7048', (143, 149))	('TGFBR2', 'Gene', '7048', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('loss', 'NegReg', (34, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('TGFBR1', 'Gene', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('bladder tumor', 'Disease', (176, 189))	('carcinomas', 'Disease', (311, 321))	('transitional cell carcinomas', 'Phenotype', 'HP:0006740', (293, 321))	('TGFBR1', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TGFBR2', 'Gene', (143, 149))	('TGFBR2', 'Gene', (230, 236))	('bladder tumor', 'Disease', 'MESH:D001749', (176, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('increased', 'PosReg', (166, 175))	('cell carcinoma', 'Disease', (306, 320))	('invasive tumors', 'Disease', 'MESH:D009361', (251, 266))
53333	31842336	Loss of the IQGAP1 tumor suppressor leads to increased expression of TGFBR2 and activated the TGF-beta1 signaling pathway, thereby stimulating growth of human bladder cancer cells.	('IQGAP1', 'Gene', (12, 18))	('TGFBR2', 'Gene', (69, 75))	('human', 'Species', '9606', (153, 158))	('tumor', 'Disease', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bladder cancer', 'Disease', 'MESH:D001749', (159, 173))	('bladder cancer', 'Disease', (159, 173))	('increased', 'PosReg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('bladder cancer', 'Phenotype', 'HP:0009725', (159, 173))	('growth', 'CPA', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('expression', 'MPA', (55, 65))	('IQGAP1', 'Gene', '8826', (12, 18))	('TGFBR2', 'Gene', '7048', (69, 75))	('Loss', 'Var', (0, 4))	('TGF-beta1 signaling pathway', 'Pathway', (94, 121))	('activated', 'PosReg', (80, 89))	('stimulating', 'PosReg', (131, 142))
53338	31842336	Blockade of Shh activity inhibits TGF-beta1-induced migration, invasion, and clonogenic growth of bladder cancer cells.	('clonogenic growth', 'CPA', (77, 94))	('Shh', 'Gene', (12, 15))	('TGF-beta1-induced', 'Gene', (34, 51))	('inhibits', 'NegReg', (25, 33))	('Blockade', 'Var', (0, 8))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('bladder cancer', 'Disease', (98, 112))	('invasion', 'CPA', (63, 71))	('Shh', 'Gene', '6469', (12, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('rat', 'Species', '10116', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
53342	31842336	These effects are mediated by TGFBR1, as silencing of this receptor attenuates the migration and invasiveness of T24 cells, with concomitant downregulation of pro-invasive MMP9, as well as integrins alpha2, alpha3, and beta1.	('attenuates', 'NegReg', (68, 78))	('silencing', 'Var', (41, 50))	('MMP9', 'Gene', '4318', (172, 176))	('MMP9', 'Gene', (172, 176))	('alpha2, alpha3, and beta1', 'Gene', '170589;28883;28881', (199, 224))	('invasiveness of T24 cells', 'CPA', (97, 122))	('pro-invasive', 'CPA', (159, 171))	('downregulation', 'NegReg', (141, 155))	('TGFBR1', 'Gene', (30, 36))	('rat', 'Species', '10116', (86, 89))
53350	31842336	Loss of PPM1A promotes TGF-beta1-induced EMT in vitro and correlates with bladder cancer progression and poor prognosis for patients.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TGF-beta1-induced', 'Protein', (23, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('PPM1A', 'Gene', (8, 13))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('promotes', 'PosReg', (14, 22))	('PPM1A', 'Gene', '5494', (8, 13))	('bladder cancer', 'Disease', (74, 88))	('Loss', 'Var', (0, 4))	('patients', 'Species', '9606', (124, 132))
53354	31842336	Silencing of Malat1 attenuates TGF-beta1-induced migration and invasion of bladder cancer cells and inhibits progression of tumor xenografts in mice.	('attenuates', 'NegReg', (20, 30))	('rat', 'Species', '10116', (52, 55))	('inhibits', 'NegReg', (100, 108))	('invasion of bladder cancer', 'Disease', (63, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Malat1', 'Gene', (13, 19))	('mice', 'Species', '10090', (144, 148))	('migration', 'CPA', (49, 58))	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (124, 129))	('TGF-beta1-induced', 'Gene', (31, 48))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
53366	31842336	COL6A3 silencing resulted in reduced expression of TGF-beta as well as phosphorylation of SMAD2 and SMAD3.	('phosphorylation', 'MPA', (71, 86))	('COL6A3', 'Gene', (0, 6))	('TGF-beta', 'Protein', (51, 59))	('SMAD3', 'Gene', '4088', (100, 105))	('COL6A3', 'Gene', '1293', (0, 6))	('reduced', 'NegReg', (29, 36))	('SMAD3', 'Gene', (100, 105))	('SMAD2', 'Protein', (90, 95))	('expression', 'MPA', (37, 47))	('silencing', 'Var', (7, 16))
53368	31842336	Silencing of Trim59 attenuates migration and invasion of bladder cancer cells while the presence of TGF-beta1 relieves the suppressive effect of Trim59 knock-out.	('attenuates', 'NegReg', (20, 30))	('Trim59', 'Gene', '286827', (145, 151))	('Trim59', 'Gene', '286827', (13, 19))	('invasion of bladder cancer', 'Disease', (45, 71))	('TGF-beta1', 'Gene', (100, 109))	('Trim59', 'Gene', (13, 19))	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('rat', 'Species', '10116', (34, 37))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('Trim59', 'Gene', (145, 151))
53372	31842336	It is thus difficult to conclude to what extent the silencing of both genes contributed to the attenuation of MSC tumor growth stimulatory effects.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('silencing', 'Var', (52, 61))	('attenuation', 'NegReg', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MSC', 'Disease', (110, 113))	('tumor', 'Disease', (114, 119))
53382	31842336	The importance of TGF-beta receptors in bladder cancer is underscored by studies that demonstrated that Tgfbr2 knock-out or Tgfbr1 inhibition attenuates growth and progression of chemically-induced bladder tumors in mice while TGFBR3 knock-down in a human T24 bladder cancer cell line results in reduced viability, colony formation, migration, and invasion.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('Tgfbr1', 'Gene', (124, 130))	('bladder tumors', 'Disease', (198, 212))	('migration', 'CPA', (333, 342))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder tumors', 'Phenotype', 'HP:0009725', (198, 212))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('colony formation', 'CPA', (315, 331))	('knock-out', 'Var', (111, 120))	('rat', 'Species', '10116', (93, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('progression', 'CPA', (164, 175))	('mice', 'Species', '10090', (216, 220))	('bladder tumor', 'Phenotype', 'HP:0009725', (198, 211))	('bladder cancer', 'Disease', 'MESH:D001749', (260, 274))	('bladder cancer', 'Disease', (260, 274))	('inhibition attenuates', 'NegReg', (131, 152))	('invasion', 'CPA', (348, 356))	('Tgfbr1', 'Gene', '21812', (124, 130))	('bladder tumors', 'Disease', 'MESH:D001749', (198, 212))	('bladder cancer', 'Phenotype', 'HP:0009725', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('rat', 'Species', '10116', (336, 339))	('human', 'Species', '9606', (250, 255))	('Tgfbr2', 'Gene', (104, 110))
53383	31842336	Deletion of Tgfbr2 decreased the population of cancer stem cells, attenuated proliferation, and induced apoptosis of bladder cancer cells in vivo.	('decreased', 'NegReg', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('attenuated', 'NegReg', (66, 76))	('rat', 'Species', '10116', (84, 87))	('Tgfbr2', 'Gene', (12, 18))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (117, 131))	('induced', 'Reg', (96, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (125, 131))	('apoptosis', 'CPA', (104, 113))	('bladder cancer', 'Disease', (117, 131))	('proliferation', 'CPA', (77, 90))	('Deletion', 'Var', (0, 8))
53384	31842336	Furthermore, conditional knock-out of Tgfbr2 decreased EMT as indicated by lowered expression of mesenchymal markers, including vimentin, Slug, Snai1, Twist, and Zeb1, with concomitant upregulation of epithelial E-cadherin.	('vimentin', 'Gene', '7431', (128, 136))	('lowered', 'NegReg', (75, 82))	('EMT', 'CPA', (55, 58))	('vimentin', 'Gene', (128, 136))	('Snai1', 'Gene', (144, 149))	('Twist', 'Gene', '7291', (151, 156))	('Zeb1', 'Gene', (162, 166))	('decreased', 'NegReg', (45, 54))	('Zeb1', 'Gene', '6935', (162, 166))	('decreased EMT', 'Phenotype', 'HP:0032198', (45, 58))	('Twist', 'Gene', (151, 156))	('E-cadherin', 'Gene', (212, 222))	('expression', 'MPA', (83, 93))	('upregulation', 'PosReg', (185, 197))	('E-cadherin', 'Gene', '999', (212, 222))	('Tgfbr2', 'Gene', (38, 44))	('Snai1', 'Gene', '6615', (144, 149))	('knock-out', 'Var', (25, 34))
53385	31842336	Notably, TGFBR2 mutations are frequently found in bladder cancer patients.	('found', 'Reg', (41, 46))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('mutations', 'Var', (16, 25))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TGFBR2', 'Gene', (9, 15))	('bladder cancer', 'Disease', (50, 64))	('patients', 'Species', '9606', (65, 73))	('TGFBR2', 'Gene', '7048', (9, 15))
53386	31842336	Glu269 to Lys mutation (G A) facilitates TGF-beta1-induced invasion of bladder cancer cells.	('invasion of bladder cancer', 'Disease', 'MESH:D001749', (59, 85))	('TGF-beta1-induced', 'Gene', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Glu269 to Lys', 'Mutation', 'p.E269K', (0, 13))	('Glu269 to Lys mutation', 'Var', (0, 22))	('facilitates', 'PosReg', (29, 40))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('invasion of bladder cancer', 'Disease', (59, 85))
53395	31842336	Specifically, ectopic expression of GDF-9 in bladder cancer cell lines attenuated cell growth, and reduced migration and adhesion.	('rat', 'Species', '10116', (110, 113))	('GDF-9', 'Gene', '2661', (36, 41))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('ectopic expression', 'Var', (14, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('attenuated', 'NegReg', (71, 81))	('cell growth', 'CPA', (82, 93))	('GDF-9', 'Gene', (36, 41))	('reduced', 'NegReg', (99, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
53398	31842336	Remarkably, GDF-15 knock-out resulted in reverse effects.	('GDF-15', 'Gene', '9518', (12, 18))	('GDF-15', 'Gene', (12, 18))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('knock-out', 'Var', (19, 28))
53400	31842336	The GDF-15 evaluation in bladder cancer cell lines suggested that its expression could be reduced in bladder tumors, possibly due to DNA hypermethylation as well p53 inactivation in bladder cancer cells.	('reduced', 'NegReg', (90, 97))	('p53', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (25, 39))	('bladder cancer', 'Disease', (25, 39))	('bladder tumors', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Phenotype', 'HP:0009725', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('GDF-15', 'Gene', '9518', (4, 10))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('bladder tumors', 'Disease', (101, 115))	('expression', 'MPA', (70, 80))	('bladder tumors', 'Phenotype', 'HP:0009725', (101, 115))	('GDF-15', 'Gene', (4, 10))	('bladder tumor', 'Phenotype', 'HP:0009725', (101, 114))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('p53', 'Gene', '7157', (162, 165))	('inactivation', 'Var', (166, 178))	('hypermethylation', 'Var', (137, 153))
53410	31842336	Contrarily, earlier research reported a lack of promoter methylation and mutations in the TGFBR2 gene.	('TGFBR2', 'Gene', '7048', (90, 96))	('TGFBR2', 'Gene', (90, 96))	('mutations', 'Var', (73, 82))
53417	31842336	Furthermore, the expression of TGFBR2 is suppressed by DHT, which attenuates the binding of Sp1 to its promoter.	('TGFBR2', 'Gene', (31, 37))	('expression', 'MPA', (17, 27))	('suppressed', 'NegReg', (41, 51))	('TGFBR2', 'Gene', '7048', (31, 37))	('DHT', 'Var', (55, 58))	('binding', 'Interaction', (81, 88))	('DHT', 'Chemical', 'MESH:D013196', (55, 58))
53419	31842336	AR mutations or loss, which lead to androgen resistance in differentiated prostate cancers, contribute to TGF-beta overexpression, stimulation of growth, viability, and aggressiveness of prostate cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('androgen resistance', 'MPA', (36, 55))	('overexpression', 'PosReg', (115, 129))	('aggressiveness of prostate cancer', 'Disease', (169, 202))	('prostate cancers', 'Phenotype', 'HP:0012125', (74, 90))	('aggressiveness', 'Phenotype', 'HP:0000718', (169, 183))	('prostate cancers', 'Disease', (74, 90))	('aggressiveness of prostate cancer', 'Disease', 'MESH:D011471', (169, 202))	('androgen resistance', 'Phenotype', 'HP:0008226', (36, 55))	('TGF-beta', 'Gene', (106, 114))	('growth', 'MPA', (146, 152))	('AR', 'Gene', '367', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('viability', 'CPA', (154, 163))	('androgen', 'Chemical', 'MESH:D000728', (36, 44))	('loss', 'NegReg', (16, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('prostate cancers', 'Disease', 'MESH:D011471', (74, 90))	('mutations', 'Var', (3, 12))	('stimulation', 'PosReg', (131, 142))
53430	31842336	Specifically, PI3K/AKT inhibition attenuates TGF-beta-induced expression of vimentin, downregulation of keratin, and increased cell motility.	('attenuates', 'NegReg', (34, 44))	('vimentin', 'Gene', '7431', (76, 84))	('TGF-beta-induced', 'Gene', (45, 61))	('increased', 'PosReg', (117, 126))	('inhibition', 'Var', (23, 33))	('rat', 'Species', '10116', (106, 109))	('expression', 'MPA', (62, 72))	('AKT', 'Gene', '207', (19, 22))	('vimentin', 'Gene', (76, 84))	('cell motility', 'CPA', (127, 140))	('downregulation', 'NegReg', (86, 100))	('AKT', 'Gene', (19, 22))	('keratin', 'Protein', (104, 111))
53433	31842336	Inhibition of either TGF-beta or NF-kappabeta suppressed the invasion of cancer cells and the EMT process.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('TGF-beta', 'Protein', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('NF-kappabeta', 'Gene', (33, 45))	('EMT process', 'CPA', (94, 105))	('NF-kappabeta', 'Gene', '4790', (33, 45))	('Inhibition', 'Var', (0, 10))	('suppressed', 'NegReg', (46, 56))
53440	31842336	It was therefore suggested that blocking of TGF-beta signaling in the prostate tumor microenvironment could inhibit cancer progression.	('prostate tumor', 'Phenotype', 'HP:0100787', (70, 84))	('cancer', 'Disease', (116, 122))	('men', 'Species', '9606', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('inhibit', 'NegReg', (108, 115))	('prostate tumor', 'Disease', 'MESH:D011471', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TGF-beta', 'Protein', (44, 52))	('blocking', 'Var', (32, 40))	('prostate tumor', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
53447	31842336	Remarkably, PMEAP1 knock-out induces TGF-beta signaling and the formation of bone metastases, indicating negative feedback regulation between the two genes.	('bone metastases', 'Disease', (77, 92))	('PMEAP1', 'Gene', (12, 18))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('knock-out', 'Var', (19, 28))	('TGF-beta signaling', 'MPA', (37, 55))	('induces', 'PosReg', (29, 36))	('bone metastases', 'Disease', 'MESH:D009362', (77, 92))
53469	31842336	Inhibition of miR-629 results in suppression of TGF-beta-dependent induction of SMAD2/3 and SMAD4 through upregulation of TRIM33 expression.	('miR-629', 'Gene', '693214', (14, 21))	('induction', 'MPA', (67, 76))	('expression', 'MPA', (129, 139))	('SMAD4', 'Gene', (92, 97))	('miR-629', 'Gene', (14, 21))	('SMAD2/3', 'Gene', (80, 87))	('suppression', 'NegReg', (33, 44))	('TGF-beta-dependent', 'Protein', (48, 66))	('Inhibition', 'Var', (0, 10))	('upregulation', 'PosReg', (106, 118))	('TRIM33', 'Gene', '51592', (122, 128))	('TRIM33', 'Gene', (122, 128))
53474	31842336	Remarkably, induced expression of TAK1 leads to stimulation of tumor growth, which can be inhibited by overexpression of miR-486-5p.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('TAK1', 'Gene', (34, 38))	('expression', 'Var', (20, 30))	('stimulation', 'PosReg', (48, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('TAK1', 'Gene', '6885', (34, 38))
53475	31842336	miRNAs can also interfere with TGF-beta-induced signaling in renal cancer cells.	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('interfere', 'NegReg', (16, 25))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('TGF-beta-induced', 'Pathway', (31, 47))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('miRNAs', 'Var', (0, 6))	('renal cancer', 'Disease', (61, 73))
53485	31842336	Inhibition of miR-25-3p potentiates the TGF-beta1-stimulatory effect on the expression of adhesion proteins, indicating its interference with the cellular effects of transforming growth factor.	('adhesion proteins', 'Protein', (90, 107))	('expression', 'MPA', (76, 86))	('Inhibition', 'Var', (0, 10))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('TGF-beta1-stimulatory', 'Gene', (40, 61))	('potentiates', 'PosReg', (24, 35))
53495	31842336	The global analysis of 782 miRNAs in germ-cell tumors revealed that TGF-beta signaling was one of the two predicted pathways most highly targeted by miRNAs that were differentially expressed in yolk sack tumors (YSTs) compared with germinomatous tumors (GERs).	('germinomatous tumors', 'Disease', (232, 252))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('TGF-beta', 'Gene', (68, 76))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('yolk sack tumors', 'Disease', (194, 210))	('tumors', 'Disease', (204, 210))	('GERs', 'Disease', (254, 258))	('yolk sack tumors', 'Disease', 'MESH:D018240', (194, 210))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('miRNAs', 'Var', (149, 155))	('GERs', 'Disease', 'MESH:D009369', (254, 258))	('germinomatous tumors', 'Disease', 'MESH:D009369', (232, 252))	('germinomatous tumors', 'Phenotype', 'HP:0100620', (232, 252))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('YSTs', 'Disease', (212, 216))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('YSTs', 'Disease', 'MESH:D018240', (212, 216))
53496	31842336	The expressions of 34 genes of the TGF-beta/BMP signaling pathway (including ligands, receptors, SMAD proteins, key target genes) were altered in YST compared with GER.	('BMP', 'Gene', '649;650;2658', (44, 47))	('expressions', 'MPA', (4, 15))	('altered', 'Reg', (135, 142))	('BMP', 'Gene', (44, 47))	('YST', 'Var', (146, 149))
53505	31842336	Induced ZEB1-AS1 expression inhibits apoptosis, promotes the cell cycle, and activates proliferation, as well as stimulates the growth of bladder cancer xenografts in mice.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('rat', 'Species', '10116', (94, 97))	('apoptosis', 'CPA', (37, 46))	('inhibits', 'NegReg', (28, 36))	('ZEB1-AS1', 'Gene', (8, 16))	('proliferation', 'CPA', (87, 100))	('stimulates', 'PosReg', (113, 123))	('growth', 'CPA', (128, 134))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('promotes', 'PosReg', (48, 56))	('activates', 'PosReg', (77, 86))	('expression', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cell cycle', 'CPA', (61, 71))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (8, 16))	('mice', 'Species', '10090', (167, 171))
53506	31842336	According to another study, miR-200b targets and inhibits the expression of MMP16.	('inhibits', 'NegReg', (49, 57))	('expression', 'MPA', (62, 72))	('MMP16', 'Gene', (76, 81))	('miR-200b', 'Var', (28, 36))	('MMP16', 'Gene', '4325', (76, 81))
53507	31842336	TGF-beta1-mediated repression miR-200b leads to activation of MMP16 expression and stimulation of the migration of bladder cancer cells.	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('expression', 'MPA', (68, 78))	('rat', 'Species', '10116', (105, 108))	('MMP16', 'Gene', (62, 67))	('miR-200b', 'Var', (30, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('stimulation', 'PosReg', (83, 94))	('activation', 'PosReg', (48, 58))	('migration', 'CPA', (102, 111))	('MMP16', 'Gene', '4325', (62, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
53511	31842336	The miRNA-TGF-beta interference also contributes to the chemoresistance of bladder cancer cells (further discussed in Chapter 6).	('miRNA-TGF-beta interference', 'Var', (4, 31))	('contributes', 'Reg', (37, 48))	('chemoresistance', 'CPA', (56, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
53520	31842336	Inoculation of mice with prostate cancer cells overexpressing both miR-373-3p and TR4 results in the development of metastases, suggesting that silencing of miR-373-3p and/or TR4 might be used in prostate cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('miR', 'Gene', (157, 160))	('miR', 'Gene', (67, 70))	('men', 'Species', '9606', (217, 220))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('development', 'CPA', (101, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('miR', 'Gene', '220972', (157, 160))	('men', 'Species', '9606', (108, 111))	('prostate cancer', 'Disease', (196, 211))	('metastases', 'Disease', (116, 126))	('silencing', 'Var', (144, 153))	('mice', 'Species', '10090', (15, 19))	('miR', 'Gene', '220972', (67, 70))	('TR4', 'Gene', (82, 85))
53524	31842336	Transfection of prostate cancer cell lines with miR-93 mimics stimulates their proliferation, migration, and invasion.	('proliferation', 'CPA', (79, 92))	('invasion', 'CPA', (109, 117))	('miR-93', 'Gene', '407051', (48, 54))	('rat', 'Species', '10116', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('miR-93', 'Gene', (48, 54))	('migration', 'CPA', (94, 103))	('Transfection of prostate cancer', 'Disease', 'MESH:D011471', (0, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (16, 31))	('mimics', 'Var', (55, 61))	('Transfection of prostate cancer', 'Disease', (0, 31))	('stimulates', 'PosReg', (62, 72))	('rat', 'Species', '10116', (86, 89))
53540	31842336	Re-introduction of miR-539 into prostate cancer cells inhibits expression of DLX1, leading to attenuation of TGF-beta signaling, inhibition of proliferation, migration, and invasion, as well as growth of prostate cancer xenografts in mice.	('invasion', 'CPA', (173, 181))	('rat', 'Species', '10116', (150, 153))	('TGF-beta signaling', 'MPA', (109, 127))	('inhibits', 'NegReg', (54, 62))	('migration', 'CPA', (158, 167))	('Re', 'Chemical', 'MESH:D012211', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mice', 'Species', '10090', (234, 238))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('prostate cancer', 'Disease', (32, 47))	('miR-539', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (204, 219))	('expression', 'MPA', (63, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (204, 219))	('prostate cancer', 'Disease', (204, 219))	('DLX1', 'Gene', (77, 81))	('growth', 'CPA', (194, 200))	('inhibition', 'NegReg', (129, 139))	('rat', 'Species', '10116', (161, 164))	('attenuation', 'NegReg', (94, 105))	('proliferation', 'CPA', (143, 156))
53558	31842336	Loss of miR-15 and miR-16 in prostate cancer cells potentiates TGF-beta signaling by upregulating USP9X (a gene encoding an enzyme deubiquitinating SMAD4), as well as activin RIIA, an activin receptor, contributing to the survival of cancer cells in bone marrow and the formation of bone metastasis.	('TGF-beta signaling', 'MPA', (63, 81))	('contributing', 'Reg', (202, 214))	('prostate cancer', 'Disease', (29, 44))	('miR-1', 'Gene', '79187', (19, 24))	('upregulating', 'PosReg', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('miR-1', 'Gene', (8, 13))	('survival', 'CPA', (222, 230))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (38, 44))	('activin', 'Gene', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('miR-1', 'Gene', '79187', (8, 13))	('activin', 'Gene', (167, 174))	('USP9X', 'Gene', '8239', (98, 103))	('miR-1', 'Gene', (19, 24))	('Loss', 'Var', (0, 4))	('USP9X', 'Gene', (98, 103))	('potentiates', 'PosReg', (51, 62))	('activin', 'Gene', '83729', (184, 191))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (29, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (29, 44))	('cancer', 'Disease', (234, 240))	('activin', 'Gene', '83729', (167, 174))
53574	31842336	In that study, antisense oligonucleotides attenuated TGF-beta secretion by bladder cancer cells, reduced colony growth in soft agar, and inhibited the growth of tumors inoculated in mice.	('attenuated', 'NegReg', (42, 52))	('inhibited', 'NegReg', (137, 146))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (182, 186))	('reduced', 'NegReg', (97, 104))	('secretion', 'MPA', (62, 71))	('antisense oligonucleotides', 'Var', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors inoculated', 'Disease', (161, 178))	('tumors inoculated', 'Disease', 'MESH:D002372', (161, 178))	('TGF-beta', 'Protein', (53, 61))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('colony growth in', 'CPA', (105, 121))
53577	31842336	An example of such an approach is M7824, a bi-functional fusion protein consisting of avemulab, a monoclonal antibody directed against PD-L1 (programmed death-ligand 1) and the extracellular domain of TGFBR2.	('PD-L1', 'Gene', (135, 140))	('TGFBR2', 'Gene', '7048', (201, 207))	('programmed death-ligand 1', 'Gene', (142, 167))	('programmed death-ligand 1', 'Gene', '29126', (142, 167))	('TGFBR2', 'Gene', (201, 207))	('M7824', 'Var', (34, 39))
53580	31842336	The study demonstrated that the TGFBR2 component of M7824 increased the sensitivity of urothelial transitional cell carcinoma cells towards TRAIL-mediated lysis.	('TRAIL', 'Gene', (140, 145))	('increased', 'PosReg', (58, 67))	('TGFBR2', 'Gene', '7048', (32, 38))	('urothelial transitional cell carcinoma', 'Disease', (87, 125))	('urothelial transitional cell carcinoma', 'Disease', 'MESH:D002295', (87, 125))	('sensitivity', 'MPA', (72, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (98, 125))	('rat', 'Species', '10116', (17, 20))	('TGFBR2', 'Gene', (32, 38))	('TRAIL', 'Gene', '8743', (140, 145))	('M7824', 'Var', (52, 57))
53581	31842336	Compared to the sole PD-L1 blockade, M7824 also stimulated antigen-specific CD8+-mediated tumor cell lysis.	('M7824', 'Var', (37, 42))	('antigen-specific CD8+-mediated', 'MPA', (59, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('stimulated', 'PosReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
53582	31842336	Mechanistically, treatment of bladder cancer cells with M7824 altered the expression of genes involved in the angiogenesis process, remodeling of the extracellular matrix, EMT, as well as extracellular markers involved in immunogenic modulation.	('expression', 'MPA', (74, 84))	('altered', 'Reg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('men', 'Species', '9606', (22, 25))	('M7824', 'Var', (56, 61))	('angiogenesis', 'CPA', (110, 122))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
53584	31842336	TGF-beta +C28.>T polymorphism (in other studies described as c.-1347C > T, -509C > T, and rs1800469) was linked with patients' outcome to BCG (Bacillus Calmette-Guerin) immunotherapy.	('linked with', 'Reg', (105, 116))	('rs1800469', 'Mutation', 'rs1800469', (90, 99))	('c.-1347C > T', 'Var', (61, 73))	('Bacillus Calmette-Guerin', 'Species', '33892', (143, 167))	('-509C > T', 'Mutation', 'rs1800469', (75, 84))	('rs1800469', 'Var', (90, 99))	('patients', 'Species', '9606', (117, 125))	('c.-1347C > T', 'Mutation', 'rs1800469', (61, 73))	('BCG', 'Species', '33892', (138, 141))	('TGF-beta +C28.', 'Gene', (0, 14))
53586	31842336	Interestingly, this genotype is associated with increased TGF-beta expression when compared with CC homozygotes, and individuals with T substitution have twice higher TGF-beta1 plasma concentrations when compared with CC carriers.	('increased', 'PosReg', (48, 57))	('higher', 'PosReg', (160, 166))	('rat', 'Species', '10116', (191, 194))	('T substitution', 'Var', (134, 148))	('TGF-beta', 'Protein', (58, 66))	('expression', 'MPA', (67, 77))	('increased TGF-beta', 'Phenotype', 'HP:0030269', (48, 66))	('TGF-beta1 plasma concentrations', 'MPA', (167, 198))
53630	30297773	Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy.	('diabetes', 'Disease', (105, 113))	('increased', 'PosReg', (95, 104))	('para-aortic radiotherapy', 'Var', (18, 42))	('diabetes', 'Disease', 'MESH:D003920', (105, 113))
53637	30297773	PAO-RT for TC will generally result in irradiation of the head and body of the pancreas, which contains part of the insulin-producing beta-cells.	('result in', 'Reg', (29, 38))	('PAO-RT', 'Var', (0, 6))	('insulin', 'Gene', (116, 123))	('irradiation', 'CPA', (39, 50))	('insulin', 'Gene', '3630', (116, 123))	('TC', 'Phenotype', 'HP:0010788', (11, 13))
53698	30297773	Adjusted for age, para-aortic RT was associated with a 1.66-fold (95% CI: 1.05-2.62; Table 2) increased diabetes risk compared to no radiotherapy.	('increased', 'PosReg', (94, 103))	('diabetes', 'Disease', (104, 112))	('para-aortic', 'Var', (18, 29))	('diabetes', 'Disease', 'MESH:D003920', (104, 112))
53710	30297773	In particular, high diabetes risks were observed after treatment with radiotherapy, total body irradiation, alkylating agents and treatment at ages <4 years.	('diabetes', 'Disease', (20, 28))	('alkylating', 'Var', (108, 118))	('diabetes', 'Disease', 'MESH:D003920', (20, 28))
53714	30297773	Although para-aortic radiotherapy for TC does not include the pancreatic tail and generally lower para-aortic doses are used compared to treatment of childhood cancer and HL patients, infradiaphragmatic radiotherapy was associated with an elevated diabetes risk in TC survivors.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('diabetes', 'Disease', (248, 256))	('cancer', 'Disease', (160, 166))	('diabetes', 'Disease', 'MESH:D003920', (248, 256))	('infradiaphragmatic radiotherapy', 'Var', (184, 215))	('patients', 'Species', '9606', (174, 182))	('HL', 'Disease', 'MESH:C538324', (171, 173))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('TC', 'Phenotype', 'HP:0010788', (38, 40))	('TC', 'Phenotype', 'HP:0010788', (265, 267))
53718	30297773	A study in primates showed that pancreatic radiotherapy induced degranulation, vacuolisation, mitochondrial destruction and impaired insulin secretion shortly after treatment.	('mitochondrial destruction', 'CPA', (94, 119))	('impaired insulin secretion', 'Disease', (124, 150))	('pancreatic radiotherapy', 'Var', (32, 55))	('impaired insulin secretion', 'Disease', 'MESH:D007333', (124, 150))	('vacuolisation', 'CPA', (79, 92))	('degranulation', 'MPA', (64, 77))
53719	30297773	Adjuvant radiotherapy has also been shown to reduce beta-cell function and insulin secretion capacity of the pancreas in 1-year gastric cancer survivors.	('radiotherapy', 'Var', (9, 21))	('gastric cancer', 'Disease', (128, 142))	('insulin', 'Gene', (75, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('insulin', 'Gene', '3630', (75, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('reduce', 'NegReg', (45, 51))	('beta-cell function', 'CPA', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
53747	30297773	Provision of study materials or patients: B.M.P.A., A.W.v.d.B.-D., L.I., R.d.W., J.A.W., A.C.M.v.d.B., G.G., P.d.B., H.A.v.d.B., M.C.C.M.H., O.W.M.M., T.J.S., M.J.A., B.G.L.V., S.H., J.M.K., J.A.G., F.E.v.L.	('J.M.K.', 'Var', (183, 189))	('J.A.G.', 'Var', (191, 197))	('patients', 'Species', '9606', (32, 40))
53854	31676840	Median residual tumor diameter was 20 mm in the L-RRRTM versus 42 mm in the C-RRRTM group (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (16, 21))	('L-RRRTM', 'Var', (48, 55))
53892	31676840	The most common residual tumor location was para-aortic (86, 57%); 69% in the L-RRRTM group versus 41% in the C-RRRTM group (p = 0.001).	('L-RRRTM', 'Var', (78, 85))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
53925	31676840	In contrast to the short hospital stay for the laparoscopy patients in this series, the median hospital stay in other studies was longer after L-RRRTM, ranging from 3-7 days (Table 5).	('longer', 'PosReg', (130, 136))	('L-RRRTM', 'Var', (143, 150))	('patients', 'Species', '9606', (59, 67))
53931	31676840	L-RRRTM meets or exceeds the results from most open conventional surgeries and should always be considered as a viable alternative in the resection of residual tumor mass after cisplatin-containing chemotherapy for locally advanced testicular cancer, offering less morbidity, a favorable cosmetic outcome for the patient, and a shorter hospital stay.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('testicular cancer', 'Phenotype', 'HP:0010788', (232, 249))	('testicular cancer', 'Disease', 'MESH:D013736', (232, 249))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('patient', 'Species', '9606', (313, 320))	('testicular cancer', 'Disease', (232, 249))	('L-RRRTM', 'Var', (0, 7))	('tumor', 'Disease', (160, 165))
53934	31676840	A multidisciplinary expert testicular cancer team with an experienced (oncological) laparoscopist is essential to achieve these peri-operative and longterm results and this has to be taken into account in the discussion of treatment options, L-RRRTM vs. C-RRRTM, with the testicular cancer patient.	('testicular cancer', 'Disease', 'MESH:D013736', (27, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patient', 'Species', '9606', (290, 297))	('testicular cancer', 'Disease', (272, 289))	('L-RRRTM', 'Var', (242, 249))	('testicular cancer', 'Phenotype', 'HP:0010788', (27, 44))	('testicular cancer', 'Disease', 'MESH:D013736', (272, 289))	('testicular cancer', 'Phenotype', 'HP:0010788', (272, 289))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('multidisciplinary expert testicular cancer', 'Disease', 'MESH:D013736', (2, 44))	('multidisciplinary expert testicular cancer', 'Disease', (2, 44))
53942	26631610	Familial germline whole genome sequencing (WGS) was performed for these families, and analytical methods were utilized to identify de novo alterations, including mutations, recombinations, and structural rearrangements in the pre- and post-exposure offspring.	('structural rearrangements', 'Var', (193, 218))	('mutations', 'Var', (162, 171))	('men', 'Species', '9606', (213, 216))	('recombinations', 'Var', (173, 187))
53950	26631610	As a result of the effect these toxic agents can have on reproduction, patients exposed to chemotherapy express concern about whether these treatments may induce germ cell mutations that lead to transmissible genetic damage in post-treatment offspring.	('mutations', 'Var', (172, 181))	('men', 'Species', '9606', (145, 148))	('patients', 'Species', '9606', (71, 79))	('genetic damage', 'Disease', 'MESH:D030342', (209, 223))	('induce', 'Reg', (155, 161))	('genetic damage', 'Disease', (209, 223))	('lead to', 'Reg', (187, 194))	('men', 'Species', '9606', (237, 240))
53958	26631610	We hypothesized that if there were a transmissible genomic effect of chemotherapy exposure in the offspring of cancer survivors, it would manifest through increased de novo mutations across the entire genome.	('increased', 'PosReg', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (173, 182))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
54000	26631610	The majority of mutations for all children occurred in intergenic regions (Table S4), and there were no recurrent de novo events observed at the base pair level.	('occurred', 'Reg', (43, 51))	('children', 'Species', '9606', (34, 42))	('mutations', 'Var', (16, 25))
54010	26631610	In addition, non-genetic effects, such as epigenetic changes or transcription-based alternative splicing not observable with whole genome sequencing, may identify transmissible mutagenic effects in humans and warrant further evaluation.	('transcription-based alternative splicing', 'Var', (64, 104))	('epigenetic changes', 'Var', (42, 60))	('humans', 'Species', '9606', (198, 204))
54040	29765521	In testicular cancer patients, low levels of 25-OHvitD have been correlated to low bone density and higher risk of fracture.	('bone density', 'CPA', (83, 95))	('25-OHvitD', 'Var', (45, 54))	('testicular cancer', 'Disease', (3, 20))	('25-OHvitD', 'Chemical', '-', (45, 54))	('low bone density', 'Phenotype', 'HP:0004349', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('fracture', 'Disease', 'MESH:D050723', (115, 123))	('patients', 'Species', '9606', (21, 29))	('low', 'NegReg', (79, 82))	('fracture', 'Disease', (115, 123))	('testicular cancer', 'Phenotype', 'HP:0010788', (3, 20))	('testicular cancer', 'Disease', 'MESH:D013736', (3, 20))	('low', 'Var', (31, 34))
54101	29765521	Low levels of 25-OHvitD are correlated to low bone densitometry, high risk of vertebral fractures, to an increased infertility and cardiovascular risk.	('vertebral fractures', 'Disease', 'MESH:D050723', (78, 97))	('25-OHvitD', 'Var', (14, 23))	('25-OHvitD', 'Chemical', '-', (14, 23))	('bone densitometry', 'CPA', (46, 63))	('vertebral fractures', 'Phenotype', 'HP:0002953', (78, 97))	('vertebral fractures', 'Disease', (78, 97))	('infertility', 'Phenotype', 'HP:0000789', (115, 126))	('infertility', 'Disease', 'MESH:D007247', (115, 126))	('infertility', 'Disease', (115, 126))	('low', 'NegReg', (42, 45))
54102	29765521	In addition, low levels of 25-OHvitD correlate to a bad prognosis in the afro-american patients with testicular and prostate cancer.	('25-OHvitD', 'Chemical', '-', (27, 36))	('25-OHvitD', 'Var', (27, 36))	('low', 'NegReg', (13, 16))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('prostate cancer', 'Disease', (116, 131))	('testicular', 'Disease', (101, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
54111	29765521	The patients were defined to have sufficient (>= 30 ng/ml), insufficient (< 30 - >= 20 ng/ml), mildly deficient (< 20 ng/ml - >= 10 ng/ml) or severe deficient (< 10 ng/ml) 25-OHvitD according to the Endocrine Society guidelines and Institute of Medicine's standards.	('insufficient', 'Disease', (60, 72))	('25-OHvitD', 'Chemical', '-', (172, 181))	('deficient', 'NegReg', (102, 111))	('< 10 ng/ml', 'Var', (160, 170))	('patients', 'Species', '9606', (4, 12))	('deficient', 'NegReg', (149, 158))	('insufficient', 'Disease', 'MESH:D000309', (60, 72))
54149	29475970	Cases included in this analysis were diagnosed with testicular germ cell cancer (International Classification of Childhood Cancer, 3rd edition recode 103; International Classification of Diseases for Oncology, 3rd edition [ICD-O-3], morphology codes 9060-9065 [germ cell tumors] 9070-9072 [embryonal carcinoma] 9080-9085 [teratomas] 9100, 9101, 9105 [choriocarcinoma]; topography codes C62.0, C62.1, C62.9).	('Oncology', 'Phenotype', 'HP:0002664', (200, 208))	('choriocarcinoma', 'Disease', (351, 366))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (290, 309))	('embryonal carcinoma', 'Disease', (290, 309))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (290, 309))	('teratomas', 'Phenotype', 'HP:0009792', (322, 331))	('cancer', 'Disease', (73, 79))	('germ cell tumors', 'Phenotype', 'HP:0100728', (261, 277))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (351, 366))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Childhood Cancer', 'Disease', 'MESH:C536928', (113, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('teratomas', 'Disease', 'MESH:D013724', (322, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('germ cell cancer', 'Phenotype', 'HP:0100728', (63, 79))	('germ cell tumor', 'Phenotype', 'HP:0100728', (261, 276))	('teratomas', 'Disease', (322, 331))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('9060-9065 [', 'Var', (250, 261))	('Childhood Cancer', 'Disease', (113, 129))	('choriocarcinoma', 'Disease', 'MESH:D002822', (351, 366))
54193	29475970	In models mutually adjusting for each hormone (androstenedione and testosterone), the observed association with androstenedione among adolescents remained (Q4 vs Q1 OR: 2.2; 95% CI: 1.25-3.91), while the association with testosterone was attenuated (Q4 vs Q1 OR: 1.28; 95% CI: 0.71-2.33).	('testosterone', 'Chemical', 'MESH:D013739', (67, 79))	('androstenedione', 'MPA', (112, 127))	('androstenedione', 'Chemical', 'MESH:D000735', (112, 127))	('testosterone', 'Chemical', 'MESH:D013739', (221, 233))	('androstenedione', 'Chemical', 'MESH:D000735', (47, 62))	('Q4', 'Var', (156, 158))
54194	29475970	The associations between high androstenedione and adolescent TGCT appeared to be stronger among non-Hispanic whites (Q4 vs. Q1 OR: 3.29; 95% CI: 1.33-8.12 vs. 1.95; 95% CI: 0.97-3.94 in Hispanics; p-value for interaction = 0.15).	('adolescent', 'Disease', (50, 60))	('high', 'Var', (25, 29))	('androstenedione', 'Chemical', 'MESH:D000735', (30, 45))	('TGCT', 'Gene', (61, 65))	('high androstenedione', 'Phenotype', 'HP:0025380', (25, 45))	('associations', 'Interaction', (4, 16))
54207	29475970	Male reproductive disorders thought to be related to TGCT, including undescended testes, hypospadias, and poor semen quality, have been induced in rodents after perinatal exposure to EDCs, and exposure to EDCs has been associated with shortened anogenital distance, a sensitive marker of androgen action in utero among male newborns.	('hypospadias', 'Disease', (89, 100))	('induced', 'Reg', (136, 143))	('reproductive disorders', 'Phenotype', 'HP:0000078', (5, 27))	('hypospadias', 'Phenotype', 'HP:0000047', (89, 100))	('undescended testes', 'Phenotype', 'HP:0000028', (69, 87))	('shortened anogenital distance', 'CPA', (235, 264))	('men', 'Species', '9606', (113, 116))	('perinatal exposure', 'Phenotype', 'HP:0031437', (161, 179))	('Male reproductive disorders', 'Disease', (0, 27))	('EDCs', 'Gene', (205, 209))	('hypospadias', 'Disease', 'MESH:D007021', (89, 100))	('undescended testes', 'Disease', (69, 87))	('exposure', 'Var', (193, 201))
54226	23623693	Reports suggest that digit ratio is not affected by pubertal growth and not related to adult sex hormone levels, but may be associated with male infertility, namely low sperm count .	('digit', 'Var', (21, 26))	('infertility', 'Phenotype', 'HP:0000789', (145, 156))	('male infertility', 'Phenotype', 'HP:0003251', (140, 156))	('male infertility', 'Disease', (140, 156))	('associated', 'Reg', (124, 134))	('low', 'NegReg', (165, 168))	('male infertility', 'Disease', 'MESH:D007248', (140, 156))	('low sperm count', 'Phenotype', 'HP:0000798', (165, 180))
54231	23623693	Using existing data from the U. S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study, we evaluated the association between 2D:4D digit ratio, DeltaR-L, left hand dominance and TGCT.	('DeltaR-L', 'Var', (177, 185))	('Tumor', 'Phenotype', 'HP:0002664', (59, 64))	('men', 'Species', '9606', (42, 45))	('men', 'Species', '9606', (72, 75))	('association', 'Interaction', (138, 149))	('Testicular Tumor', 'Phenotype', 'HP:0010788', (48, 64))	('TGCT', 'Disease', (211, 215))
54245	23623693	Studies evaluating digit ratio and cancer risk using larger sample sizes have reported that osteoarthritis and prostate cancer were inversely associated with right hand 2D:4D  and breast cancer was positively associated with left hand 2D:4D and inversely associated with DeltaR-L.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('right hand 2D:4D', 'Var', (158, 174))	('cancer', 'Disease', (120, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('osteoarthritis', 'Disease', 'MESH:D010003', (92, 106))	('inversely', 'NegReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Interaction', (209, 219))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('breast cancer', 'Disease', (180, 193))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('osteoarthritis', 'Phenotype', 'HP:0002758', (92, 106))	('osteoarthritis', 'Disease', (92, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('left hand 2D:4D', 'Var', (225, 240))	('prostate cancer', 'Disease', (111, 126))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (35, 41))	('associated', 'Interaction', (142, 152))
54296	23230429	The strongest association for TGCC susceptibility is for single nucleotide polymorphisms (SNPs) at the 12q22 within the kit-ligand gene.	('kit-ligand', 'Gene', (120, 130))	('TGCC', 'Disease', (30, 34))	('kit-ligand', 'Gene', '4254', (120, 130))	('single nucleotide polymorphisms', 'Var', (57, 88))	('TGCC', 'Chemical', '-', (30, 34))
54298	23230429	These impacts might rely on the downstream target KRAS which then activate the p110 catalytic subunit of the PI3K pathway which in turn through AKT pathways will act on proliferation, survival, and migration.	('AKT', 'Gene', (144, 147))	('act', 'Reg', (162, 165))	('migration', 'CPA', (198, 207))	('KRAS', 'Gene', (50, 54))	('activate', 'PosReg', (66, 74))	('PI3K pathway', 'Pathway', (109, 121))	('proliferation', 'CPA', (169, 182))	('KRAS', 'Gene', '3845', (50, 54))	('AKT', 'Gene', '207', (144, 147))	('p110', 'Var', (79, 83))	('survival', 'CPA', (184, 192))
54300	23230429	Next to this, as testicular physiology is under the control of the endocrine functions mainly through the activity of androgen and estrogen receptors, it was deeply studied if polymorphisms of genes involved in hormonal metabolism could be associated with a higher risk of TCs.	('TCs', 'Disease', (273, 276))	('TCs', 'Chemical', 'MESH:D013667', (273, 276))	('associated', 'Reg', (240, 250))	('TC', 'Phenotype', 'HP:0010788', (273, 275))	('polymorphisms', 'Var', (176, 189))
54302	23230429	Regarding the estrogen receptors, it was demonstrated that polymorphisms in ERalpha are associated with azoospermia and are more likely to be associated with the risk of seminoma and metastasis; whereas polymorphisms in ERbeta are more likely to be link to altered spermatogenesis and with risk of TGCC.	('ERbeta', 'Gene', (220, 226))	('TGCC', 'Disease', (298, 302))	('azoospermia', 'Disease', 'MESH:D053713', (104, 115))	('metastasis', 'Disease', (183, 193))	('polymorphisms', 'Var', (59, 72))	('azoospermia', 'Disease', (104, 115))	('polymorphisms', 'Var', (203, 216))	('seminoma', 'Disease', 'MESH:D018239', (170, 178))	('associated', 'Reg', (142, 152))	('ERalpha', 'Gene', (76, 83))	('TGCC', 'Chemical', '-', (298, 302))	('associated', 'Reg', (88, 98))	('azoospermia', 'Phenotype', 'HP:0000027', (104, 115))	('seminoma', 'Disease', (170, 178))
54303	23230429	New to this, polymorphisms in 17-beta hydroxydehydrogenase-4 which convert androgen and estrogen to weaker hormones were associated with TGCC.	('TGCC', 'Chemical', '-', (137, 141))	('associated', 'Reg', (121, 131))	('TGCC', 'Disease', (137, 141))	('polymorphisms', 'Var', (13, 26))
54304	23230429	In these metabolic pathways, polymorphisms in cytochrome P450 Cyp-1A1 gene, encoding a hormone-metabolizing protein, were identified and inversely correlated with TC.	('cytochrome P450 Cyp-1A1', 'Gene', (46, 69))	('TC', 'Phenotype', 'HP:0010788', (163, 165))	('inversely', 'NegReg', (137, 146))	('cytochrome P450 Cyp-1A1', 'Gene', '1543', (46, 69))	('polymorphisms', 'Var', (29, 42))	('correlated', 'Reg', (147, 157))
54308	23230429	Changes in the length of these polymorphic trinucleotide repeats, (CAG) and/or (GGN), lead to altered transactivation of the AR which has been shown to play a role in several forms of endocrine cancer such as prostate cancer.	('AR', 'Gene', '367', (125, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (209, 224))	('altered', 'Reg', (94, 101))	('play', 'Reg', (152, 156))	('endocrine cancer', 'Disease', (184, 200))	('GGN', 'Gene', (80, 83))	('prostate cancer', 'Disease', (209, 224))	('GGN', 'Gene', '199720', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Changes', 'Var', (0, 7))	('endocrine cancer', 'Disease', 'MESH:D004701', (184, 200))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('transactivation', 'MPA', (102, 117))	('endocrine cancer', 'Phenotype', 'HP:0100568', (184, 200))	('trinucleotide', 'Chemical', '-', (43, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (209, 224))
54347	23230429	Mutations in testosterone pathway genes may alter the level of testosterone in vivo and hypothetically the risk of developing TC.	('testosterone pathway genes', 'Gene', (13, 39))	('testosterone', 'Chemical', 'MESH:D013739', (13, 25))	('alter', 'Reg', (44, 49))	('testosterone', 'Chemical', 'MESH:D013739', (63, 75))	('Mutations', 'Var', (0, 9))	('TC', 'Phenotype', 'HP:0010788', (126, 128))	('level of testosterone', 'MPA', (54, 75))
54375	23230429	Some PCBs (44, 49, and 52) were found to be lower accumulated in patients with seminoma compare to congeners; whereas other PCBs (99, 138, 153, 167, 183, and 195) were significantly higher accumulated in these patients.	('99', 'Var', (130, 132))	('lower', 'NegReg', (44, 49))	('PCBs', 'Chemical', 'MESH:D011078', (124, 128))	('seminoma', 'Disease', 'MESH:D018239', (79, 87))	('PCBs', 'Chemical', 'MESH:D011078', (5, 9))	('higher', 'PosReg', (182, 188))	('patients', 'Species', '9606', (65, 73))	('seminoma', 'Disease', (79, 87))	('patients', 'Species', '9606', (210, 218))
54380	23230429	Consistent with this hypothesis, as polymorphisms in AR and some organochlorine pesticides have been associated to risk of TGCC development, and that some of these organochlorine pesticides present anti-androgenic activities, have studied the potential interaction of AR polymorphisms and exposure to p,p'-DDE and the association with TC risk.	('AR', 'Gene', '367', (268, 270))	('polymorphisms', 'Var', (36, 49))	('TGCC', 'Disease', (123, 127))	('organochlorine', 'Chemical', 'MESH:D006843', (164, 178))	('organochlorine', 'Chemical', 'MESH:D006843', (65, 79))	('AR', 'Gene', '367', (53, 55))	('men', 'Species', '9606', (135, 138))	("p,p'-DDE", 'Chemical', 'MESH:D003633', (301, 309))	('TC', 'Phenotype', 'HP:0010788', (335, 337))	('associated', 'Reg', (101, 111))	('TGCC', 'Chemical', '-', (123, 127))
54396	23230429	TCDD was also observed to reduce the number and size of the Leydig cells.	('reduce', 'NegReg', (26, 32))	('TC', 'Phenotype', 'HP:0010788', (0, 2))	('TCDD', 'Chemical', 'MESH:D000072317', (0, 4))	('TCDD', 'Var', (0, 4))
54397	23230429	Moreover, the use of primary culture of Leydig cells also demonstrate that TCDD represses Cyp11a1 expression, through the alteration of the ability of hCG to increase intracellular cAMP levels.	('Cyp11a1', 'Gene', (90, 97))	('represses', 'NegReg', (80, 89))	('TCDD', 'Var', (75, 79))	('TCDD', 'Chemical', 'MESH:D000072317', (75, 79))	('cAMP', 'Chemical', '-', (181, 185))	('TC', 'Phenotype', 'HP:0010788', (75, 77))	('Cyp11a1', 'Gene', '1583', (90, 97))	('intracellular cAMP levels', 'MPA', (167, 192))	('alteration', 'Reg', (122, 132))	('increase', 'PosReg', (158, 166))	('expression', 'MPA', (98, 108))
54398	23230429	Indeed, experimental models have shown that disruption of the androgen signaling results in feminization of external genitalia.	('external genitalia', 'Disease', (108, 126))	('men', 'Species', '9606', (14, 17))	('disruption', 'Var', (44, 54))	('external genitalia', 'Disease', 'MESH:D012734', (108, 126))	('androgen', 'Protein', (62, 70))	('results in feminization of external genitalia', 'Phenotype', 'HP:0003247', (81, 126))
54406	23230429	Indeed, the SHP KO mice seem to be less sensitive to estrogenic EDs than their wild-type littermates.	('ED', 'Chemical', '-', (64, 66))	('less', 'NegReg', (35, 39))	('sensitive to estrogenic EDs', 'MPA', (40, 67))	('SHP KO', 'Var', (12, 18))	('mice', 'Species', '10090', (19, 23))
54420	23230429	These processes are crucial for reproductive functions, as most of mouse models with specific germline invalidation for gene responsible of DNA or histones modifications led to sterile animals.	('sterile animals', 'CPA', (177, 192))	('modifications', 'Var', (156, 169))	('invalidation', 'NegReg', (103, 115))	('led to', 'Reg', (170, 176))	('histones', 'Protein', (147, 155))	('mouse', 'Species', '10090', (67, 72))
54423	23230429	Such epigenetic modifications have also been demonstrated to be associated with infertility as for example reduced expression of Dnmt3b in patients with spermatogenic arrest.	('associated', 'Reg', (64, 74))	('epigenetic modifications', 'Var', (5, 29))	('Dnmt3b', 'Gene', (129, 135))	('Dnmt3b', 'Gene', '1789', (129, 135))	('patients', 'Species', '9606', (139, 147))	('infertility', 'Disease', 'MESH:D007247', (80, 91))	('infertility', 'Phenotype', 'HP:0000789', (80, 91))	('infertility', 'Disease', (80, 91))	('reduced', 'NegReg', (107, 114))	('spermatogenic arrest', 'Disease', 'MESH:C564030', (153, 173))	('spermatogenic arrest', 'Phenotype', 'HP:0031038', (153, 173))	('expression', 'MPA', (115, 125))	('spermatogenic arrest', 'Disease', (153, 173))
54427	23230429	The epigenetic mechanism involves the alteration of DNA methylation in the germline that appears to transmit transgenerational adult onset disease, including spermatogenic defects and cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('spermatogenic defects', 'Phenotype', 'HP:0008669', (158, 179))	('DNA', 'Gene', (52, 55))	('alteration', 'Var', (38, 48))	('spermatogenic defects', 'Disease', 'OMIM:108420', (158, 179))	('spermatogenic defects', 'Disease', (158, 179))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
54430	23230429	These modifications in epigenetic programing by EDs are of particular interest as they have been suspected to be responsible of the increased rate of pathologies related to the TDS such as TCs.	('modifications', 'Var', (6, 19))	('TC', 'Phenotype', 'HP:0010788', (189, 191))	('epigenetic programing', 'MPA', (23, 44))	('ED', 'Chemical', '-', (48, 50))	('TCs', 'Disease', (189, 192))	('TCs', 'Chemical', 'MESH:D013667', (189, 192))
54444	23230429	The major role of these epigenetic alterations has been demonstrated in carcinogenesis.	('epigenetic alterations', 'Var', (24, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('carcinogenesis', 'Disease', (72, 86))
54448	23230429	Undifferentiated TGCC (seminomas, IGCN unclassified, and gonadoblastomas) are hypomethylated, whereas more differentiated TGCC (teratomas, yolk sac tumors, and choriocarcinomas) show a higher degree of methylation.	('choriocarcinomas', 'Disease', 'MESH:D002822', (160, 176))	('GCN', 'Chemical', '-', (35, 38))	('gonadoblastomas', 'Disease', 'MESH:D018238', (57, 72))	('TGCC', 'Chemical', '-', (17, 21))	('seminomas', 'Disease', 'MESH:D018239', (23, 32))	('teratomas', 'Disease', 'MESH:D013724', (128, 137))	('seminomas', 'Disease', (23, 32))	('TGCC', 'Chemical', '-', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('gonadoblastomas', 'Disease', (57, 72))	('hypomethylated', 'Var', (78, 92))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('teratomas', 'Disease', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('tumors', 'Disease', (148, 154))	('choriocarcinomas', 'Disease', (160, 176))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (160, 175))	('teratoma', 'Phenotype', 'HP:0009792', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('teratomas', 'Phenotype', 'HP:0009792', (128, 137))
54462	23230429	In the same line, the study Oct3/4 showed that seminoma and embryonal carcinoma were hypomethylated.	('Oct3/4', 'Gene', '5460', (28, 34))	('Oct3/4', 'Gene', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('seminoma', 'Disease', (47, 55))	('hypomethylated', 'Var', (85, 99))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (60, 79))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (60, 79))	('embryonal carcinoma', 'Disease', (60, 79))	('seminoma', 'Disease', 'MESH:D018239', (47, 55))
54470	23230429	Another HMT is the enhancer of zeste 2 (EZH2) which trimethylate histone H3 at the lysine 27.	('lysine', 'Chemical', 'MESH:D008239', (83, 89))	('HMT', 'Gene', (8, 11))	('lysine', 'Var', (83, 89))	('HMT', 'Gene', '3176', (8, 11))	('histone H3', 'Protein', (65, 75))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('trimethylate histone H3', 'Chemical', '-', (52, 75))
54472	23230429	DNA methylation, histone methylation are epigenetic modifications functioning in transcriptional control and have been implicated in the deregulation of gene expression in cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('implicated', 'Reg', (119, 129))	('deregulation', 'MPA', (137, 149))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('DNA', 'Var', (0, 3))	('histone', 'MPA', (17, 24))
54479	23230429	This suggested that histone H3-K4 and K9 methylation could be associated with abnormal gene expression in non-seminoma.	('non-seminoma', 'Disease', (106, 118))	('associated', 'Reg', (62, 72))	('histone H3-K4', 'Protein', (20, 33))	('K9 methylation', 'Var', (38, 52))	('non-seminoma', 'Disease', 'MESH:D018239', (106, 118))	('abnormal gene expression', 'MPA', (78, 102))
54480	23230429	Histone modifications determine epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4), and are often associated with active promoters.	('H3K4', 'Gene', (115, 119))	('methylation', 'Var', (76, 87))	('epigenetic patterns', 'MPA', (32, 51))	('lysine', 'Chemical', 'MESH:D008239', (105, 111))
54485	23230429	In spermatogonia, the stainings for H3K9ac, H3K18ac, and H3K23ac were strong.	('H3K18ac', 'Var', (44, 51))	('H3K23ac', 'Chemical', '-', (57, 64))	('H3K23ac', 'Var', (57, 64))	('H3K9ac', 'Var', (36, 42))
54486	23230429	Then spermatocytes, the stainings for H3K9ac, H3K18ac, H3K23ac, and H3K4me3 were reduced in the preleptotene to pachytene stage, but in diplotene stage the stainings for H3K18ac, H3K23ac, and H3K4me3 seemed to become intense in later stages.	('H3K23ac', 'Chemical', '-', (55, 62))	('pachytene', 'Chemical', '-', (112, 121))	('H3K23ac', 'Var', (179, 186))	('H3K4me3', 'Var', (68, 75))	('H3K23ac', 'Var', (55, 62))	('H3K9ac', 'Var', (38, 44))	('preleptotene', 'Chemical', '-', (96, 108))	('reduced', 'NegReg', (81, 88))	('H3K23ac', 'Chemical', '-', (179, 186))	('diplotene', 'Chemical', '-', (136, 145))	('H3K18ac', 'Var', (170, 177))	('H3K18ac', 'Var', (46, 53))
54501	23230429	Among them, miR-449 and miR-34 seems to have common targets on the E2F signaling pathway which is mainly involved in the regulation of male germ cell development.	('miR-449', 'Var', (12, 19))	('targets', 'Reg', (52, 59))	('miR-34', 'Gene', (24, 30))	('men', 'Species', '9606', (157, 160))	('miR-34', 'Gene', '407040', (24, 30))	('E2F signaling pathway', 'Pathway', (67, 88))
54506	23230429	This suggests that PODXL must be a downstream effector mediating the action of miR199a-5p.	('miR199a-5p', 'Var', (79, 89))	('PODXL', 'Gene', (19, 24))	('PODXL', 'Gene', '5420', (19, 24))
54508	23230429	Next to this, miR-371-373 and miR-302 clusters are overexpressed in malignant TGCC.	('overexpressed', 'PosReg', (51, 64))	('miR-371', 'Gene', (14, 21))	('TGCC', 'Chemical', '-', (78, 82))	('miR-302', 'Var', (30, 37))	('miR-371', 'Gene', '442916', (14, 21))
54511	23230429	Thus an abnormal expression of miRNA-383 may potentiate the connections between male infertility and testicular germ cell tumor.	('germ cell tumor', 'Phenotype', 'HP:0100728', (112, 127))	('miRNA-383', 'Gene', (31, 40))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('abnormal', 'Var', (8, 16))	('infertility', 'Disease', 'MESH:D007247', (85, 96))	('potentiate', 'PosReg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('infertility', 'Phenotype', 'HP:0000789', (85, 96))	('tumor', 'Disease', (122, 127))	('infertility', 'Disease', (85, 96))	('connections', 'Interaction', (60, 71))	('male infertility', 'Phenotype', 'HP:0003251', (80, 96))
54515	23230429	Thus, it was suggested that modulation of the Oct4/miR-106b/p21 pathway could open new perspectives in the treatment of chemoresistant TC.	('Oct4', 'Gene', '5460', (46, 50))	('modulation', 'Var', (28, 38))	('TC', 'Phenotype', 'HP:0010788', (135, 137))	('miR-106b', 'Gene', (51, 59))	('Oct4', 'Gene', (46, 50))	('miR-106b', 'Gene', '406900', (51, 59))	('men', 'Species', '9606', (112, 115))	('p21', 'Gene', (60, 63))	('p21', 'Gene', '644914', (60, 63))
54518	23230429	It cannot be exclude that germ cells generated at the beginning of carcinogenesis could transmit altered DNA material, due to genetic, epigenetic perturbation.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('carcinogenesis', 'Disease', (67, 81))	('genetic', 'Var', (126, 133))	('epigenetic perturbation', 'Var', (135, 158))	('DNA material', 'MPA', (105, 117))
54539	32894169	We show that deletion of the Tug1 locus in mice leads to male sterility and also report an underappreciated molecular complexity at the Tug1 locus.	('mice', 'Species', '10090', (43, 47))	('Tug1', 'Gene', (29, 33))	('leads to', 'Reg', (48, 56))	('deletion', 'Var', (13, 21))	('male sterility', 'Disease', (57, 71))
54540	32894169	Using several complementary genetic approaches (gene body deletion with a lacZ reporter knock-in, an inducible Tug1 transgene, and combinations thereof), we provide evidence of a DNA-based repressive element within the Tug1 locus that regulates several genes in cis.	('men', 'Species', '9606', (203, 206))	('genes', 'Gene', (253, 258))	('Tug1', 'Gene', (219, 223))	('deletion', 'Var', (58, 66))	('regulates', 'Reg', (235, 244))	('men', 'Species', '9606', (20, 23))
54543	32894169	The Tug1 locus is enriched with hallmarks of active transcription, such as RNA polymerase II (Pol II) and histone H3 lysine 4-trimethylation (H3K4me3) at its promoter, H3K36me3 across its gene body, and abundant transcription as shown by RNA-seq (Fig.	('active', 'MPA', (45, 51))	('H3K36me3', 'Var', (168, 176))	('Tug1', 'Gene', (4, 8))	('transcription', 'MPA', (212, 225))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
54545	32894169	This atypical combination of H3K9me3 and H3K36me3 histone marks at the Tug1 locus is also conserved in human cells (Additional file 1: Fig.	('human', 'Species', '9606', (103, 108))	('H3K36me3', 'Var', (41, 49))	('H3K9me3', 'Var', (29, 36))
54552	32894169	Notably, this deletion strategy also removed 86 out of 143 amino acids in the predicted ORF (Additional file 3: Fig.	('deletion', 'Var', (14, 22))	('removed', 'NegReg', (37, 44))	('rat', 'Species', '10116', (25, 28))
54554	32894169	Tug1-/- mice are viable and do not display any obvious physiological abnormalities up to 1 year of age, with the exception of a slight reduction in weight in male mice relative to wild-type littermates (Additional file 4: Fig.	('weight', 'MPA', (148, 154))	('reduction', 'NegReg', (135, 144))	('Tug1-/-', 'Var', (0, 7))	('mice', 'Species', '10090', (163, 167))	('mice', 'Species', '10090', (8, 12))
54555	32894169	As previously reported, the progeny of Tug1+/- intercrosses follow normal Mendelian ratios.	('rat', 'Species', '10116', (84, 87))	('Mendelian ratios', 'CPA', (74, 90))	('Tug1+/- intercrosses', 'Var', (39, 59))
54556	32894169	However, we noticed a complete absence of offspring from intercrosses between Tug1-/- mice (n = 4 breeding pairs).	('absence', 'NegReg', (31, 38))	('Tug1-/-', 'Var', (78, 85))	('mice', 'Species', '10090', (86, 90))
54557	32894169	We separately mated Tug1-/-, Tug1+/-, and wild-type males or females to C57BL/6J mice.	('Tug1+/-', 'Var', (29, 36))	('mice', 'Species', '10090', (81, 85))	('Tug1-/-', 'Var', (20, 27))	('rat', 'Species', '10116', (7, 10))
54560	32894169	Next, we quantified sperm production and found a significant reduction in sperm number from Tug1-/- males (mean = 2.35 x 106 +- 0.473 x 106 cells/mL, n = 7), which produced on average only 40% as many sperm as wild-type mice (6.13 x 106 +- 0.636 x 106 cells/mL, n = 9, p = 0.0018) (Fig.	('Tug1-/-', 'Var', (92, 99))	('mice', 'Species', '10090', (220, 224))	('sperm number', 'CPA', (74, 86))	('reduction', 'NegReg', (61, 70))	('sperm', 'CPA', (201, 206))
54561	32894169	Although Tug1-/- males produce fewer sperm, none was found to completely lack sperm (a condition called azoospermia).	('azoospermia', 'Disease', 'MESH:D053713', (104, 115))	('fewer', 'NegReg', (31, 36))	('lack', 'NegReg', (73, 77))	('azoospermia', 'Disease', (104, 115))	('sperm', 'CPA', (37, 42))	('sperm', 'CPA', (78, 83))	('azoospermia', 'Phenotype', 'HP:0000027', (104, 115))	('Tug1-/-', 'Var', (9, 16))
54562	32894169	Overall, the proportion of morphologically normal sperm was significantly lower in Tug1-/- mice (mean = 8.3 +- 3.0%, n = 8, p = 0.0013) compared to wild-type males (mean = 38.9 +- 4.3%, n = 9) (Fig.	('Tug1-/-', 'Var', (83, 90))	('lower', 'NegReg', (74, 79))	('mice', 'Species', '10090', (91, 95))
54563	32894169	Together, these results indicate that the sterility of Tug1-/- males arises from a combination of low sperm count (oligozoospermia) and abnormal sperm morphology (teratozoospermia).	('arises from', 'Reg', (69, 80))	('sperm morphology', 'CPA', (145, 161))	('low', 'NegReg', (98, 101))	('abnormal sperm morphology', 'Phenotype', 'HP:0012864', (136, 161))	('teratozoospermia', 'Phenotype', 'HP:0012864', (163, 179))	('oligozoospermia', 'Disease', (115, 130))	('teratozoospermia', 'Disease', (163, 179))	('low sperm count', 'Phenotype', 'HP:0000798', (98, 113))	('sterility', 'Disease', (42, 51))	('teratozoospermia', 'Disease', 'MESH:D000072660', (163, 179))	('Tug1-/-', 'Var', (55, 62))	('sperm count', 'CPA', (102, 113))	('oligozoospermia', 'Disease', 'MESH:D009845', (115, 130))
54565	32894169	This was even more striking in the epididymis, where multiple sperm aggregates were observed in Tug1-/- mice, while individual sperm appeared to migrate freely throughout the lumen in wild-type mice (Fig.	('rat', 'Species', '10116', (148, 151))	('observed', 'Reg', (84, 92))	('mice', 'Species', '10090', (104, 108))	('Tug1-/-', 'Var', (96, 103))	('men', 'Species', '9606', (177, 180))	('mice', 'Species', '10090', (194, 198))
54570	32894169	Of the 71 genes within this window, we observed that 6 genes (Rnf185, Pla2g3, Selm, Smtn, Gm11946, and 8430429K09Rik) were significantly upregulated in Tug1-/- testes compared to wild type (Fig.	('Smtn', 'Gene', (84, 88))	('Selm', 'Gene', (78, 82))	('Tug1-/- testes', 'Var', (152, 166))	('upregulated', 'PosReg', (137, 148))	('Rnf185', 'Gene', (62, 68))	('Pla2g3', 'Gene', (70, 76))	('8430429K09Rik', 'Gene', (103, 116))	('Pla2g3', 'Gene', '237625', (70, 76))	('Smtn', 'Gene', '29856', (84, 88))	('8430429K09Rik', 'Gene', '71523', (103, 116))	('Rnf185', 'Gene', '193670', (62, 68))	('Selm', 'Gene', '114679', (78, 82))
54571	32894169	To further investigate whether the cis-effect upon deletion of the Tug1 locus is more widespread, we performed RNA-seq on 6 additional tissues (prostate, spleen, eyes, heart, liver, and mouse embryonic fibroblasts (MEFs)) as well as re-analyzed an existing brain dataset from wild-type and Tug1-/- mice (Additional file 7: Table S3).	('MEFs', 'CellLine', 'CVCL:9115', (215, 219))	('mice', 'Species', '10090', (298, 302))	('Tug1', 'Gene', (67, 71))	('mouse', 'Species', '10090', (186, 191))	('deletion', 'Var', (51, 59))
54572	32894169	Of the 7 upregulated genes, the E3 ubiquitin ligase, Rnf185, was consistently upregulated in 8 of 8 Tug1-/- tissues, followed by the selenoprotein M gene, Selm (7 of 8 samples), and 8430429K09Rik (6 of 8 samples) (Fig.	('E3 ubiquitin ligase', 'Enzyme', (32, 51))	('8430429K09Rik', 'Gene', (182, 195))	('upregulated', 'PosReg', (78, 89))	('Rnf185', 'Gene', '193670', (53, 59))	('Selm', 'Gene', '114679', (155, 159))	('8430429K09Rik', 'Gene', '71523', (182, 195))	('Tug1-/-', 'Var', (100, 107))	('Selm', 'Gene', (155, 159))	('selenoprotein M', 'Gene', (133, 148))	('selenoprotein M', 'Gene', '114679', (133, 148))	('Rnf185', 'Gene', (53, 59))
54574	32894169	Since the neighboring genes are upregulated upon deletion of the Tug1 locus, we reasoned that the repressive activity could be mediated either directly by the Tug1 transcript or by regulatory DNA elements within the locus.	('men', 'Species', '9606', (199, 202))	('upregulated', 'PosReg', (32, 43))	('repressive activity', 'MPA', (98, 117))	('deletion', 'Var', (49, 57))	('Tug1', 'Gene', (65, 69))	('Tug1', 'Gene', (159, 163))
54576	32894169	To generate this strain, we crossed Tug1+/- C57BL/6J females with Mus castaneus (Cast/EiJ) males (Fig.	('Cast', 'Gene', (81, 85))	('Cast', 'Gene', '12380', (81, 85))	('rat', 'Species', '10116', (7, 10))	('Tug1+/- C57BL/6J', 'Var', (36, 52))	('Mus castaneus', 'Species', '10091', (66, 79))
54577	32894169	The resulting polymorphisms in the F1 hybrid progeny (~ 1/150 bp between C57BL/6J and Cast/EiJ) allow quantification of gene expression from each strain-specific allele.	('Cast', 'Gene', '12380', (86, 90))	('C57BL/6J', 'Var', (73, 81))	('Cast', 'Gene', (86, 90))
54579	32894169	We then quantified the expression from each allele and found that Rnf185, Selm, and Smtn were significantly upregulated and Morc2a slightly downregulated only on the C57BL/6J allele containing the Tug1 deletion (Fig.	('Selm', 'Gene', (74, 78))	('Morc2a', 'Gene', '74522', (124, 130))	('Smtn', 'Gene', (84, 88))	('downregulated', 'NegReg', (140, 153))	('Tug1', 'Gene', (197, 201))	('Smtn', 'Gene', '29856', (84, 88))	('C57BL/6J', 'Var', (166, 174))	('Rnf185', 'Gene', (66, 72))	('Selm', 'Gene', '114679', (74, 78))	('upregulated', 'PosReg', (108, 119))	('Rnf185', 'Gene', '193670', (66, 72))	('Morc2a', 'Gene', (124, 130))
54581	32894169	From these different mouse models, we conclude that the Tug1 DNA, rather than the lncRNA or the act of transcription, exerts a repressive effect in cis on several genes up to 200 kb downstream of the Tug1 transcription site.	('repressive effect', 'MPA', (127, 144))	('rat', 'Species', '10116', (66, 69))	('Tug1 DNA', 'Var', (56, 64))	('mouse', 'Species', '10090', (21, 26))
54584	32894169	For example, oxidative phosphorylation, Myc targets, and epithelial to mesenchymal transition were found enriched in 7 of the 8 Tug1-/- tissues (Fig.	('Myc', 'Gene', '17869', (40, 43))	('epithelial to mesenchymal transition', 'CPA', (57, 93))	('oxidative', 'CPA', (13, 22))	('Tug1-/-', 'Var', (128, 135))	('Myc', 'Gene', (40, 43))
54588	32894169	To this end, we isolated the testes from wild-type, Tug1-/-, and dox-fed Tug1rescue mice and performed RNA-seq.	('dox', 'Chemical', 'MESH:D004318', (65, 68))	('Tug1rescue', 'Var', (73, 83))	('mice', 'Species', '10090', (84, 88))	('Tug1-/-', 'Var', (52, 59))
54590	32894169	Furthermore, we used fluorescence-activated cell sorting (FACS) and isolated peripheral blood cell types (CD4, CD8, and NK) from wild-type, Tug1+/-, Tug1-/-, and dox-fed Tug1rescue mice.	('CD4', 'Gene', (106, 109))	('mice', 'Species', '10090', (181, 185))	('dox', 'Chemical', 'MESH:D004318', (162, 165))	('CD4', 'Gene', '12504', (106, 109))	('Tug1+/-', 'Var', (140, 147))	('Tug1-/-', 'Var', (149, 156))
54593	32894169	For example, a mitochondrial-related gene, Mrarp, and an aquaporin gene, Aqp2, are significantly upregulated in Tug1-/- testes, but their expression was reduced to wild-type levels in the testes from dox-fed Tug1rescue mice (Fig.	('Aqp2', 'Gene', '11827', (73, 77))	('Tug1-/-', 'Var', (112, 119))	('mice', 'Species', '10090', (219, 223))	('dox', 'Chemical', 'MESH:D004318', (200, 203))	('expression', 'MPA', (138, 148))	('Aqp2', 'Gene', (73, 77))	('Mrarp', 'Gene', (43, 48))	('upregulated', 'PosReg', (97, 108))
54594	32894169	Conversely, the predicted lncRNA gene Gm28181 that is significantly reduced in Tug1-/- testes is significantly upregulated to wild-type levels in the testes from dox-fed Tug1rescue mice (Fig.	('mice', 'Species', '10090', (181, 185))	('dox', 'Chemical', 'MESH:D004318', (162, 165))	('lncRNA gene Gm28181', 'Gene', (26, 45))	('Gm28181', 'Chemical', '-', (38, 45))	('Tug1-/-', 'Var', (79, 86))	('Gm28181', 'Gene', (38, 45))	('reduced', 'NegReg', (68, 75))	('upregulated', 'PosReg', (111, 122))
54596	32894169	Next, we asked if dox-fed Tug1rescue male mice had restored fertility and normal sperm production and morphology.	('dox', 'Chemical', 'MESH:D004318', (18, 21))	('sperm production', 'CPA', (81, 97))	('fertility', 'CPA', (60, 69))	('Tug1rescue', 'Var', (26, 36))	('restored', 'PosReg', (51, 59))	('mice', 'Species', '10090', (42, 46))
54598	32894169	Moreover, we found that dox-fed Tug1rescue males had a low sperm count (mean = 3.20 x 105 +- 8.0 x 103 cells/mL), similar to the levels observed in Tug1-/- males (mean = 4.69 x 105 +- 1.6 x 104 cells/mL) compared to wild type (mean = 9.32 x 105 +- 3.9 x 103 cells/mL) (Additional file 11: Fig.	('Tug1rescue', 'Var', (32, 42))	('sperm count', 'CPA', (59, 70))	('low', 'NegReg', (55, 58))	('low sperm count', 'Phenotype', 'HP:0000798', (55, 70))	('dox', 'Chemical', 'MESH:D004318', (24, 27))
54599	32894169	Further, we observed that dox-fed Tug1rescue mice had a low proportion of normal shaped sperm, which was similar to the sperm observed in Tug1-/- mice (Additional file 11: Fig.	('mice', 'Species', '10090', (45, 49))	('Tug1rescue', 'Var', (34, 44))	('dox', 'Chemical', 'MESH:D004318', (26, 29))	('normal shaped sperm', 'CPA', (74, 93))	('mice', 'Species', '10090', (146, 150))
54612	32894169	Furthermore, the presence of the 5' UTR notably enhances the translation of human and mouse ORF1.	('ORF1', 'Protein', (92, 96))	('mouse', 'Species', '10090', (86, 91))	('translation', 'MPA', (61, 72))	('human', 'Species', '9606', (76, 81))	('presence', 'Var', (17, 25))	('enhances', 'PosReg', (48, 56))
54618	32894169	Notably, cells with either human or mouse TUG1-BOAT showed a reduction in mitochondrial staining by CMXR (22% and 44% CMXR stained cells, respectively), compared to cells in the same culture not expressing TUG1-BOAT (Fig.	('CMXR', 'Var', (100, 104))	('TUG1-BOAT', 'Var', (42, 51))	('mitochondrial staining', 'MPA', (74, 96))	('human', 'Species', '9606', (27, 32))	('reduction', 'NegReg', (61, 70))	('CMXR', 'Chemical', 'MESH:C107472', (100, 104))	('mouse', 'Species', '10090', (36, 41))	('CMXR', 'Chemical', 'MESH:C107472', (118, 122))
54619	32894169	In contrast, cells expressing GFP or Tug1 cDNA  mORF1 were positive for CMXR staining in all cells examined, thus indicating that CMXR staining deficiency is induced by overexpression of the TUG1-BOAT protein alone, rather than the Tug1 RNA (Fig.	('mORF1', 'Gene', '16736', (48, 53))	('CMXR', 'Chemical', 'MESH:C107472', (130, 134))	('mORF1', 'Gene', (48, 53))	('deficiency', 'NegReg', (144, 154))	('Tug1', 'Var', (37, 41))	('rat', 'Species', '10116', (216, 219))	('CMXR', 'Chemical', 'MESH:C107472', (72, 76))	('CMXR', 'Gene', (130, 134))
54631	32894169	A recent study that generated 32 deletion alleles for 25 lncRNA loci in zebrafish reported one mutant with abnormal development.	('deletion', 'Var', (33, 41))	('zebrafish', 'Species', '7955', (72, 81))	('men', 'Species', '9606', (123, 126))	('rat', 'Species', '10116', (24, 27))	('lncRNA loci', 'Gene', (57, 68))
54632	32894169	This dysregulation is consistent with a previous study from our group in which genes located near the Tug1 locus were dysregulated in the brain of Tug1-/- mice.	('Tug1', 'Gene', (102, 106))	('dysregulated', 'Reg', (118, 130))	('mice', 'Species', '10090', (155, 159))	('Tug1-/-', 'Var', (147, 154))
54636	32894169	While the Tug1 transgene was expressed at lower levels than wild-type Tug1 RNA, other lncRNAs such as Hottip and Xist have been shown to exert a biological activity at relatively low copy numbers; thus, Tug1 RNA appears to have functional activity even at low levels.	('biological activity', 'MPA', (145, 164))	('Hottip', 'Gene', (102, 108))	('Hottip', 'Gene', '791364', (102, 108))	('Xist', 'Gene', (113, 117))	('Xist', 'Gene', '213742', (113, 117))	('Tug1 RNA', 'Var', (203, 211))	('functional activity', 'MPA', (228, 247))
54637	32894169	Consistent with our finding of a trans-acting role for Tug1 RNA on gene expression, a previous study found that Tug1 RNA can regulate the levels of Ppargc1a mRNA in cultured podocytes.	('levels', 'MPA', (138, 144))	('Ppargc1a', 'Gene', (148, 156))	('Tug1', 'Var', (112, 116))	('Ppargc1a', 'Gene', '19017', (148, 156))	('regulate', 'Reg', (125, 133))
54650	32894169	Loss-of-function mutations in 2 of the 6 cis genes upregulated in Tug1-/- testes, Smtn and Pla2g3, are characterized to have male fertility and sperm maturation defects.	('Pla2g3', 'Gene', '237625', (91, 97))	('Loss-of-function', 'NegReg', (0, 16))	('Smtn', 'Gene', (82, 86))	('sperm maturation defects', 'Phenotype', 'HP:0031038', (144, 168))	('male fertility', 'CPA', (125, 139))	('rat', 'Species', '10116', (154, 157))	('cis genes', 'Gene', (41, 50))	('Smtn', 'Gene', '29856', (82, 86))	('upregulated', 'PosReg', (51, 62))	('Pla2g3', 'Gene', (91, 97))	('mutations', 'Var', (17, 26))	('sperm maturation defects', 'CPA', (144, 168))
54651	32894169	A role in male fertility for the other four upregulated cis genes upon deletion of Tug1 (Gm11946, Rnf185, Selm, and 8430429K09Rik) have not yet been reported.	('Selm', 'Gene', '114679', (106, 110))	('Selm', 'Gene', (106, 110))	('8430429K09Rik', 'Gene', '71523', (116, 129))	('Rnf185', 'Gene', (98, 104))	('male fertility', 'Disease', (10, 24))	('deletion', 'Var', (71, 79))	('Rnf185', 'Gene', '193670', (98, 104))	('Tug1', 'Gene', (83, 87))	('Gm11946', 'Var', (89, 96))	('8430429K09Rik', 'Gene', (116, 129))
54652	32894169	Mice with a loss-of-function mutation for Selenop, a gene that was found significantly upregulated in Tug1-/- testes and significantly and reciprocally regulated in Tug1rescue testes, are reported to have reduced male fertility.	('male fertility', 'CPA', (213, 227))	('mutation', 'Var', (29, 37))	('Selenop', 'Gene', (42, 49))	('reduced', 'NegReg', (205, 212))	('loss-of-function', 'NegReg', (12, 28))	('Mice', 'Species', '10090', (0, 4))	('upregulated', 'PosReg', (87, 98))	('Selenop', 'Gene', '20363', (42, 49))
54671	32894169	We generated an antisense riboprobe against Tug1 (see the "Sequences and primers" section) from plasmids containing full-length Tug1 cDNA (Ensembl id: ENSMUST00000153313.2) and performed in situ hybridization on a minimum of three C57BL6/J embryos per embryonic stage.	('Tug1', 'Gene', (44, 48))	('rat', 'Species', '10116', (7, 10))	('antisense', 'Var', (16, 25))	('Tug1', 'Gene', (128, 132))
54674	32894169	Embryos were treated with 10 mg/mL proteinase K in PBST for 10 min (E8.0, E9.5) or 30 min (E10.5, E11.5, and E12.5).	('E9.5', 'Var', (74, 78))	('PBST', 'Chemical', '-', (51, 55))	('E12.5', 'Var', (109, 114))	('E11.5', 'Var', (98, 103))
54689	32894169	For the Tug1rescue experiment, sperm counts for control (WT and Tug1+/-) (n = 2), Tug1-/- (n = 2), and Tug1-/-; tg(Tug1); rtTA mice (n = 3) were determined by manual counts using a hemocytometer.	('mice', 'Species', '10090', (127, 131))	('Tug1+/-', 'Var', (64, 71))	('Tug1-/-', 'Var', (82, 89))	('Tug1-/-; tg', 'Var', (103, 114))	('men', 'Species', '9606', (25, 28))
54709	32894169	From this, we then used the UCSC liftOver utility to generate a C57BL/6J, Cast/EiJ diploid transcriptome set.	('Cast', 'Gene', (74, 78))	('rat', 'Species', '10116', (57, 60))	('Cast', 'Gene', '12380', (74, 78))	('C57BL/6J', 'Var', (64, 72))
54731	32894169	We then incubated the membrane with horse radish peroxidase-conjugated secondary antibody (anti-mouse 1:15,000, A9044, Sigma; anti-rabbit 1:10,000, 711035152, Jackson ImmunoResearch), diluted in 5% dried milk/TBST for 1 h at room temperature.	('711035152', 'Var', (148, 157))	('mouse', 'Species', '10090', (96, 101))	('rat', 'Species', '10116', (235, 238))	('TBST', 'Chemical', '-', (209, 213))	('A9044', 'Var', (112, 117))	('horse', 'Species', '9796', (36, 41))	('radish', 'Species', '3726', (42, 48))
54736	32894169	Next, we blocked the coverslips with 5% BSA in PBT for 1 h at room temperature and then incubated the coverslips with properly diluted primary antibody (mouse M2 monoclonal ANTI FLAG, 1:800, F1804, Sigma; rabbit polyclonal Tom20, 1:800, FL-145, Santa Cruz) in 5% BSA in PBT for 3 h at 37  C in a humid chamber.	('rat', 'Species', '10116', (72, 75))	('mouse', 'Species', '10090', (153, 158))	('Tom20', 'Gene', (223, 228))	('Tom20', 'Gene', '67952', (223, 228))	('F1804', 'Var', (191, 196))
54755	32894169	Experimental analyses: M.S., E.J.P., A.F.G., N.D.R., J.L., G.D., A.W., C.G., C.K., K.T., and C.M.	('K.T.', 'Var', (83, 87))	('J.L.', 'Var', (53, 57))	('C.G.', 'Var', (71, 75))	('C.K.', 'Var', (77, 81))	('A.W.', 'Var', (65, 69))	('men', 'Species', '9606', (6, 9))
54774	31901440	The frequency of immediate and late chemotherapy toxicity is closely related to total doses received; if AC BE500Px1 were as effective as BE360Px2, the former would substantially reduce the total chemotherapy burden since approximately half of surveillance cases recur, requiring BE500Px3.	('BE360Px2', 'Var', (138, 146))	('BE500Px3', 'Var', (280, 288))	('toxicity', 'Disease', 'MESH:D064420', (49, 57))	('toxicity', 'Disease', (49, 57))	('reduce', 'NegReg', (179, 185))	('BE500Px1', 'Var', (108, 116))
54779	31901440	Patients had a full clinical assessment including grading of adverse events (AEs) using the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE v3) no later than 4 wk following BE500Px1, then every 2 mo until 6 mo, every 3 mo until 24 mo, every 4 mo during the third year, and every 6 mo during the fourth and fifth years after treatment.	('BE500Px1', 'Var', (204, 212))	('Toxicity', 'Disease', (127, 135))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Toxicity', 'Disease', 'MESH:D064420', (127, 135))
54787	31901440	They also reflect findings in a population-based study by the Swedish and Norwegian Testicular Cancer Project that included patients with low or high risk treated with BE500Px1 or BE500Px2.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BE500Px2', 'Var', (180, 188))	('Norwegian Testicular Cancer', 'Disease', 'MESH:D013736', (74, 101))	('Testicular Cancer', 'Phenotype', 'HP:0010788', (84, 101))	('BE500Px1', 'Var', (168, 176))	('Norwegian Testicular Cancer', 'Disease', (74, 101))
54922	25837470	Changes and mutations in the SRY gene are considered to cause both gonadal dysgenesis as well as tumor development.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('men', 'Species', '9606', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (12, 21))	('gonadal dysgenesis', 'Disease', (67, 85))	('tumor', 'Disease', (97, 102))	('SRY', 'Gene', '6736', (29, 32))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (67, 85))	('Changes', 'Var', (0, 7))	('cause', 'Reg', (56, 61))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (67, 85))	('SRY', 'Gene', (29, 32))
54923	25837470	Cases of both reproductive dysfunction as well as TC occurrence have also been associated with alterations in DNA repair genes and tumor suppressor genes.	('associated', 'Reg', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('reproductive dysfunction', 'Disease', (14, 38))	('tumor', 'Disease', (131, 136))	('TC', 'Phenotype', 'HP:0010788', (50, 52))	('DNA repair genes', 'Gene', (110, 126))	('alterations', 'Var', (95, 106))
54926	25837470	Mutations of p53 may lead to chromosomal and genomic instability, increasing the probability of cancer cell development and additional mutations.	('increasing', 'PosReg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (135, 144))	('lead to', 'Reg', (21, 28))	('men', 'Species', '9606', (115, 118))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('p53', 'Gene', (13, 16))	('cancer', 'Disease', (96, 102))
54928	25837470	Examples for chromosomal alterations include changes to the 12p region, which are usually associated with TC development as well as impaired spermatogenesis.	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (132, 156))	('associated', 'Reg', (90, 100))	('changes', 'Var', (45, 52))	('TC', 'Phenotype', 'HP:0010788', (106, 108))	('men', 'Species', '9606', (116, 119))
54929	25837470	Amplification of the genetic region 12p has been shown to increase the risk for seminoma germ cell cancer (SGCC) development, while additions in the 17q region or deletions in the 10q region are associated with an elevated incidence of non-seminoma germ cell cancers (NSGCC).	('seminoma germ cell cancer', 'Disease', 'MESH:D009373', (80, 105))	('germ cell cancer', 'Phenotype', 'HP:0100728', (89, 105))	('increase', 'PosReg', (58, 66))	('seminoma germ cell cancer', 'Disease', (80, 105))	('Amplification', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('non-seminoma germ cell cancers', 'Disease', 'MESH:D009373', (236, 266))	('non-seminoma germ cell cancers', 'Disease', (236, 266))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('seminoma germ cell cancer', 'Disease', 'MESH:D009373', (240, 265))	('germ cell cancer', 'Phenotype', 'HP:0100728', (249, 265))	('additions', 'Var', (132, 141))	('deletions', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('men', 'Species', '9606', (120, 123))
54930	25837470	Abnormalities of the Y chromosome have been suggested to serve as a link between male infertility and PC.	('PC', 'Phenotype', 'HP:0012125', (102, 104))	('Abnormalities', 'Var', (0, 13))	('infertility', 'Phenotype', 'HP:0000789', (86, 97))	('male infertility', 'Phenotype', 'HP:0003251', (81, 97))	('male infertility', 'Disease', 'MESH:D007248', (81, 97))	('link', 'Reg', (68, 72))	('male infertility', 'Disease', (81, 97))
54931	25837470	While Y microdeletions are believed to be the major genetic cause for oligozoospermia or azoospermia, a study conducted at the University of California showed heterogeneous and differential expression patterns of the Y chromosome genes from prostate tumor samples, suggesting that over- or underexpression of several Y chromosome genes may play a role in an abnormal endocrine stimulation of PC cells.	('oligozoospermia or azoospermia', 'Disease', (70, 100))	('prostate tumor', 'Disease', 'MESH:D011471', (241, 255))	('abnormal endocrine stimulation', 'Phenotype', 'HP:0031072', (358, 388))	('over-', 'PosReg', (281, 286))	('microdeletions', 'Var', (8, 22))	('azoospermia', 'Phenotype', 'HP:0000027', (89, 100))	('oligozoospermia or azoospermia', 'Disease', 'MESH:D009845', (70, 100))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('PC', 'Phenotype', 'HP:0012125', (392, 394))	('prostate tumor', 'Disease', (241, 255))	('prostate tumor', 'Phenotype', 'HP:0100787', (241, 255))	('underexpression', 'NegReg', (290, 305))
54932	25837470	A different genetic abnormality often reported in patients suffering from infertility or PC, are alterations in the CAG repeats in genes encoding the androgen receptor (AR).	('CAG repeats', 'Var', (116, 127))	('genetic abnormality', 'Disease', 'MESH:D030342', (12, 31))	('PC', 'Phenotype', 'HP:0012125', (89, 91))	('alterations', 'Reg', (97, 108))	('androgen receptor', 'Gene', '367', (150, 167))	('patients', 'Species', '9606', (50, 58))	('AR', 'Gene', '367', (169, 171))	('infertility', 'Disease', 'MESH:D007247', (74, 85))	('androgen receptor', 'Gene', (150, 167))	('infertility', 'Phenotype', 'HP:0000789', (74, 85))	('infertility', 'Disease', (74, 85))	('genetic abnormality', 'Disease', (12, 31))
54935	25837470	On the other hand, mutations to the kallikrein-related (KLK) protease gene family may result in abnormal secretion of diverse serine proteases, including the prostate-specific antigen (PSA), a well-known marker for male infertility and PC screening.	('infertility', 'Phenotype', 'HP:0000789', (220, 231))	('result in', 'Reg', (86, 95))	('male infertility', 'Disease', (215, 231))	('KLK', 'Gene', (56, 59))	('male infertility', 'Disease', 'MESH:D007248', (215, 231))	('male infertility', 'Phenotype', 'HP:0003251', (215, 231))	('secretion', 'MPA', (105, 114))	('prostate-specific antigen (PSA', 'Gene', (158, 188))	('mutations', 'Var', (19, 28))	('serine proteases', 'MPA', (126, 142))	('prostate-specific antigen (PSA)', 'Gene', '354', (158, 189))	('PC', 'Phenotype', 'HP:0012125', (236, 238))
54937	25837470	According to Walsh, transcriptional errors in repair genes reported in both germ-line as well as somatic cell DNA, could originate from one source, thus providing a suitable genetic link between PC and male infertility.	('PC', 'Phenotype', 'HP:0012125', (195, 197))	('male infertility', 'Phenotype', 'HP:0003251', (202, 218))	('male infertility', 'Disease', 'MESH:D007248', (202, 218))	('infertility', 'Phenotype', 'HP:0000789', (207, 218))	('transcriptional errors', 'Var', (20, 42))	('male infertility', 'Disease', (202, 218))	('originate', 'Reg', (121, 130))
54939	25837470	Patients diagnosed with Mixed Gonadal Dysgenesis (45X/46XY) are at increased risk for gonadal tumors, impaired fertility, and fibrosis as a result of ongoing structural changes within the reproductive tissue.	('45X/46XY', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Mixed Gonadal Dysgenesis', 'Disease', (24, 48))	('fibrosis', 'Disease', 'MESH:D005355', (126, 134))	('fibrosis', 'Disease', (126, 134))	('gonadal tumors', 'Disease', (86, 100))	('impaired fertility', 'Disease', 'MESH:D009422', (102, 120))	('gonadal tumors', 'Disease', 'MESH:D006058', (86, 100))	('impaired fertility', 'Phenotype', 'HP:0000144', (102, 120))	('gonadal tumors', 'Phenotype', 'HP:0010785', (86, 100))	('Patients', 'Species', '9606', (0, 8))	('increased risk for gonadal tumors', 'Phenotype', 'HP:0008373', (67, 100))	('impaired fertility', 'Disease', (102, 120))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('Mixed Gonadal Dysgenesis', 'Phenotype', 'HP:0000133', (24, 48))
54943	25837470	DNA methylation, which is the most widely studied mechanism of epigenetics, is a collective term that encompasses methylation or demethylation of the methyl group located on the 5' end of cytosine in the DNA sequence.	('DNA', 'Disease', (0, 3))	('demethylation', 'Var', (129, 142))	('cytosine', 'Chemical', 'MESH:D003596', (188, 196))
54944	25837470	Similar epigenetic mechanisms have been proposed to be involved in the development of multiple malignancies, including testicular and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('multiple malignancies', 'Disease', 'MESH:D009369', (86, 107))	('multiple malignancies', 'Disease', (86, 107))	('prostate cancer', 'Disease', (134, 149))	('involved', 'Reg', (55, 63))	('epigenetic mechanisms', 'Var', (8, 29))	('men', 'Species', '9606', (78, 81))	('testicular', 'Disease', (119, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))
54946	25837470	Compared to only a few oncogenes known to be activated by DNA hypomethylation, a large number of tumor suppressor genes are transcriptionally silenced by DNA hypermethylation in cancer cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('silenced', 'NegReg', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('DNA hypermethylation', 'Var', (154, 174))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))
54951	25837470	Recent data indicate a significant epigenetic link between male infertility and PC.	('epigenetic', 'Var', (35, 45))	('male infertility', 'Phenotype', 'HP:0003251', (59, 75))	('male infertility', 'Disease', (59, 75))	('male infertility', 'Disease', 'MESH:D007248', (59, 75))	('PC', 'Phenotype', 'HP:0012125', (80, 82))	('infertility', 'Phenotype', 'HP:0000789', (64, 75))
54952	25837470	An extensive review by Park identifies more than 30 genes undergoing aberrant epigenetic methylation related to prostate cancer development.	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('aberrant epigenetic methylation', 'Var', (69, 100))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancer', 'Disease', (112, 127))	('men', 'Species', '9606', (135, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('related', 'Reg', (101, 108))
54954	25837470	Global and locus-specific changes in chromatin remodeling, altered activity of histone-modifying enzymes as well as microRNA deregulation are additional epigenetic changes proposed to be associated with prostate dysfunction and carcinogenesis, disruption of AR signaling pathways and cell death.	('histone-modifying enzymes', 'Enzyme', (79, 104))	('altered', 'Reg', (59, 66))	('chromatin', 'MPA', (37, 46))	('changes', 'Reg', (26, 33))	('carcinogenesis', 'Disease', (228, 242))	('disruption', 'Reg', (244, 254))	('prostate dysfunction', 'Disease', (203, 223))	('microRNA', 'MPA', (116, 124))	('AR', 'Gene', '367', (258, 260))	('deregulation', 'Var', (125, 137))	('activity', 'MPA', (67, 75))	('death', 'Disease', 'MESH:D003643', (289, 294))	('death', 'Disease', (289, 294))	('prostate dysfunction', 'Disease', 'MESH:D011472', (203, 223))	('carcinogenesis', 'Disease', 'MESH:D063646', (228, 242))
54965	25837470	Disruption of the AhR activity leads to the degradation of sex steroid receptors.	('sex steroid receptors', 'Protein', (59, 80))	('AhR', 'Gene', (18, 21))	('AhR', 'Gene', '196', (18, 21))	('steroid', 'Chemical', 'MESH:D013256', (63, 70))	('degradation', 'MPA', (44, 55))	('Disruption', 'Var', (0, 10))
54995	25837470	At the same time, EDAs have been proven to cause epigenetic mutations that are persistent and transmitted to the offspring.	('EDA', 'Gene', (18, 21))	('epigenetic mutations', 'Var', (49, 69))	('EDA', 'Gene', '1896', (18, 21))
55007	25837470	All the above-indicated pathological changes may individually or collectively lead to decreased semen quality and fertility impairment, being often present at the very time of diagnosis.	('fertility impairment', 'Phenotype', 'HP:0000144', (114, 134))	('fertility impairment', 'Disease', 'MESH:D009422', (114, 134))	('changes', 'Var', (37, 44))	('decreased', 'NegReg', (86, 95))	('semen quality', 'CPA', (96, 109))	('fertility impairment', 'Disease', (114, 134))	('men', 'Species', '9606', (98, 101))	('men', 'Species', '9606', (130, 133))
55022	25837470	At the same time, men with abnormal sperm motility were 2.5 times more susceptible to TC, while men with abnormal morphology had a 3 times higher risk of testicular tumor development.	('abnormal', 'Var', (27, 35))	('susceptible', 'Reg', (71, 82))	('men', 'Species', '9606', (96, 99))	('sperm motility', 'CPA', (36, 50))	('TC', 'Phenotype', 'HP:0010788', (86, 88))	('men', 'Species', '9606', (18, 21))	('abnormal sperm motility', 'Phenotype', 'HP:0012206', (27, 50))	('testicular tumor', 'Disease', 'MESH:D013736', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('testicular tumor', 'Phenotype', 'HP:0010788', (154, 170))	('testicular tumor', 'Disease', (154, 170))	('men', 'Species', '9606', (178, 181))
55061	25837470	showed that patients treated with inhibitors of the testosterone conversion had a 25% lower incidence of a prostate tumor.	('patients', 'Species', '9606', (12, 20))	('lower', 'NegReg', (86, 91))	('inhibitors', 'Var', (34, 44))	('prostate tumor', 'Disease', 'MESH:D011471', (107, 121))	('testosterone', 'Chemical', 'MESH:D013739', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('prostate tumor', 'Phenotype', 'HP:0100787', (107, 121))	('prostate tumor', 'Disease', (107, 121))
55079	25837470	Preliminary studies have reported that miRNAs such as miR-18a, miR-122a and the miR-34 family are emerging as key players in germ cell function and cell fate determination, acting to interpret and transduce cellular signals in order to allow the maintenance of undifferentiated stem cell populations, while on the other hand allowing cell differentiation during spermatogenesis.	('allow', 'Reg', (236, 241))	('miR-122a', 'Gene', (63, 71))	('miR-34', 'Gene', (80, 86))	('undifferentiated stem cell populations', 'CPA', (261, 299))	('miR-18a', 'Var', (54, 61))	('cell differentiation', 'CPA', (334, 354))	('miR-34', 'Gene', '407040', (80, 86))	('allowing', 'Reg', (325, 333))	('miR-122a', 'Gene', '406906', (63, 71))
55089	25837470	Thus, disruptions of the miR-383 expression may lead to spermatogenic failure as well as promotion of testicular carcinoma cell proliferation.	('spermatogenic failure', 'Disease', 'OMIM:108420', (56, 77))	('miR-383', 'Gene', (25, 32))	('testicular carcinoma', 'Disease', 'MESH:D013736', (102, 122))	('testicular carcinoma', 'Disease', (102, 122))	('spermatogenic failure', 'Disease', (56, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('disruptions', 'Var', (6, 17))	('miR-383', 'Gene', '494332', (25, 32))	('lead to', 'Reg', (48, 55))	('promotion', 'PosReg', (89, 98))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (102, 122))
55098	25837470	miR-18a knockdown decreased cell growth in PC cells, and significantly reduced prostate tumorigenesis in in vivo nude mice through apoptotic mechanisms, thus it may represent a therapeutically appealing option for PC treatment.	('cell growth in', 'CPA', (28, 42))	('decreased', 'NegReg', (18, 27))	('knockdown', 'Var', (8, 17))	('prostate tumor', 'Disease', 'MESH:D011471', (79, 93))	('reduced', 'NegReg', (71, 78))	('nude mice', 'Species', '10090', (113, 122))	('prostate tumor', 'Phenotype', 'HP:0100787', (79, 93))	('men', 'Species', '9606', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('prostate tumor', 'Disease', (79, 93))	('PC', 'Phenotype', 'HP:0012125', (214, 216))	('reduced prostate', 'Phenotype', 'HP:0008687', (71, 87))	('PC', 'Phenotype', 'HP:0012125', (43, 45))	('miR-18a', 'Gene', (0, 7))
55278	24198649	Those patients with the highest marker levels at the time of relapse (ie, AFP > 100 kU/l and/or hCG > 100 IU/l) had the poorest outcomes.	('hCG', 'Gene', (96, 99))	('AFP', 'Gene', (74, 77))	('AFP', 'Gene', '174', (74, 77))	('hCG', 'Gene', '93659', (96, 99))	('patients', 'Species', '9606', (6, 14))	('> 100 IU/l', 'Var', (100, 110))
55368	20228134	Candidate gene-association studies have implicated the Y chromosome gr/gr deletion and PDE11A gene mutations as genetic modifiers of FTGCT risk.	('deletion', 'Var', (74, 82))	('FTGCT', 'Disease', (133, 138))	('mutations', 'Var', (99, 108))	('Y chromosome gr/gr', 'Protein', (55, 73))	('PDE11A', 'Gene', '50940', (87, 93))	('PDE11A', 'Gene', (87, 93))
55391	20228134	These disorders are all caused by rare germline mutations in highly penetrant genes, and are associated with dramatically affected pedigrees involving many cases over multiple generations, with earlier-than-usual onset of disease and a tendency to bilateral malignancy when paired organs are at risk.	('tendency to bilateral malignancy', 'Disease', (236, 268))	('germline mutations', 'Var', (39, 57))	('tendency to bilateral malignancy', 'Disease', 'MESH:C536965', (236, 268))	('caused by', 'Reg', (24, 33))	('highly penetrant genes', 'Protein', (61, 83))
55397	20228134	Similar analyses of testicular cancer have shown that sons of men with TGCT have a four- to sixfold increase in TGCT risk, while siblings of men with TGCT have an eight- to tenfold increased risk.	('men', 'Species', '9606', (62, 65))	('men', 'Species', '9606', (141, 144))	('testicular cancer', 'Disease', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TGCT', 'Var', (71, 75))	('testicular cancer', 'Phenotype', 'HP:0010788', (20, 37))	('testicular cancer', 'Disease', 'MESH:D013736', (20, 37))	('increase', 'PosReg', (100, 108))	('TGCT', 'Disease', (112, 116))
55443	20228134	Secondly, based on the frequent detection of somatic mutations in the KIT oncogene in human testicular cancers, the ITCLC screened DNA from 240 multiple-case testicular cancer families, and no germline mutations were detected.	('testicular cancer', 'Disease', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('KIT', 'Gene', (70, 73))	('testicular cancer', 'Phenotype', 'HP:0010788', (92, 109))	('testicular cancer', 'Disease', 'MESH:D013736', (92, 109))	('human', 'Species', '9606', (86, 91))	('mutations', 'Var', (53, 62))	('testicular cancers', 'Phenotype', 'HP:0010788', (92, 110))	('testicular cancer', 'Phenotype', 'HP:0010788', (158, 175))	('testicular cancers', 'Disease', 'MESH:D013736', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('testicular cancer', 'Disease', 'MESH:D013736', (158, 175))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('testicular cancers', 'Disease', (92, 110))
55444	20228134	Thirdly, germline mutations in the mouse Dnd1 gene have been shown to cause testicular tumors in mouse strain 129.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('testicular tumor', 'Phenotype', 'HP:0010788', (76, 92))	('testicular tumors', 'Phenotype', 'HP:0010788', (76, 93))	('mouse', 'Species', '10090', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('testicular tumors', 'Disease', (76, 93))	('mouse', 'Species', '10090', (97, 102))	('Dnd1', 'Gene', (41, 45))	('cause', 'Reg', (70, 75))	('Dnd1', 'Gene', '213236', (41, 45))	('testicular tumors', 'Disease', 'MESH:D013736', (76, 93))	('germline mutations', 'Var', (9, 27))
55446	20228134	ITCLC investigators decided to analyze the potential role of the Y chromosome gr/gr deletion as an FTGCT risk factor, recognizing that male infertility is an established risk factor for sporadic testicular cancer, and that the gr/gr deletion is the most commonly identified genetic cause of male infertility.	('infertility', 'Phenotype', 'HP:0000789', (140, 151))	('infertility', 'Phenotype', 'HP:0000789', (296, 307))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('deletion', 'Var', (84, 92))	('male infertility', 'Phenotype', 'HP:0003251', (291, 307))	('male infertility', 'Disease', (291, 307))	('male infertility', 'Disease', 'MESH:D007248', (291, 307))	('sporadic testicular cancer', 'Disease', 'MESH:D013736', (186, 212))	('testicular cancer', 'Phenotype', 'HP:0010788', (195, 212))	('sporadic testicular cancer', 'Disease', (186, 212))	('deletion', 'Var', (233, 241))	('male infertility', 'Phenotype', 'HP:0003251', (135, 151))	('male infertility', 'Disease', (135, 151))	('male infertility', 'Disease', 'MESH:D007248', (135, 151))
55447	20228134	These findings, which comprise the first documented link between a specific genetic locus and the risk of FTGCT, indicate that the Y chromosome gr/gr microdeletion is a rare, lowpenetrance TGCT susceptibility allele for both the familial and sporadic forms of TGCT.	('microdeletion', 'Var', (150, 163))	('FTGCT', 'Disease', (106, 111))	('men', 'Species', '9606', (45, 48))	('TGCT', 'Disease', (260, 264))
3290	20228134	Pde11a null mice are infertile, and germline variations in this gene have been implicated in adrenal gland neoplasia.	('infertile', 'Disease', 'MESH:D007247', (21, 30))	('Pde11a', 'Gene', '241489', (0, 6))	('adrenal gland neoplasia', 'Phenotype', 'HP:0100631', (93, 116))	('mice', 'Species', '10090', (12, 16))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('adrenal gland neoplasia', 'Disease', 'MESH:D000307', (93, 116))	('infertile', 'Disease', (21, 30))	('Pde11a', 'Gene', (0, 6))	('implicated', 'Reg', (79, 89))	('adrenal gland neoplasia', 'Disease', (93, 116))	('germline variations', 'Var', (36, 55))
55450	20228134	The prevalence of all PDE11A gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002) than among controls; they were detected in 19% of the families studied.	('TGCT', 'Disease', (99, 103))	('PDE11A', 'Gene', (22, 28))	('variants', 'Var', (34, 42))	('patients', 'Species', '9606', (85, 93))	('higher', 'PosReg', (72, 78))	('PDE11A', 'Gene', '50940', (22, 28))
55451	20228134	Functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in testicular tumor samples from mutation carriers.	('mutations', 'Var', (41, 50))	('PDE', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('reduced', 'NegReg', (51, 58))	('PDE11A', 'Gene', (82, 88))	('PDE', 'Gene', '501', (59, 62))	('PDE11A', 'Gene', '50940', (82, 88))	('mutation', 'Var', (167, 175))	('PDE', 'Gene', (59, 62))	('testicular tumor', 'Disease', 'MESH:D013736', (137, 153))	('testicular tumor', 'Phenotype', 'HP:0010788', (137, 153))	('testicular tumor', 'Disease', (137, 153))	('decreased', 'NegReg', (112, 121))	('protein', 'Protein', (89, 96))	('PDE', 'Gene', '501', (82, 85))	('expression', 'MPA', (97, 107))
55452	20228134	We concluded that PDE11A-inactivating sequence variants appear to modify the risk of FTGCT.	('variants', 'Var', (47, 55))	('PDE11A', 'Gene', (18, 24))	('FTGCT', 'Disease', (85, 90))	('PDE11A', 'Gene', '50940', (18, 24))	('modify', 'Reg', (66, 72))
55453	20228134	In contrast to the candidate gene strategy, GWAS is undertaken with no specific genetic target in mind (this approach is often designated 'agnostic'), and it leverages the power of high-throughput genomic technologies to analyze 500 000 to 1 000 000 (or more) genetic variants in the form of single nucleotide polymorphisms (aka 'SNPs') on each of the thousands to tens of thousands of DNA samples.	('single nucleotide polymorphisms', 'Var', (292, 323))	('variants', 'Var', (268, 276))	('000 to 1 000 000', 'Disease', (233, 249))	('000 to 1 000 000', 'Disease', 'MESH:C564120', (233, 249))
55456	20228134	Individuals who were homozygous for chromosome 12 variant alleles had TGCT ORs of 6, currently the strongest association between any GWAS candidate and the risk of any cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('variant', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('TGCT', 'Disease', (70, 74))	('cancer', 'Disease', (168, 174))	('association', 'Interaction', (109, 120))
55466	20228134	Using information from the HapMap3 data set, they illustrated that the prevalence of the KITLG disease-associated variants was significantly higher in normal white versus normal black populations.	('KITLG', 'Gene', (89, 94))	('variants', 'Var', (114, 122))	('higher', 'PosReg', (141, 147))	('KITLG', 'Gene', '4254', (89, 94))
55467	20228134	It is plausible to hypothesize that the racial differences in TGCT incidence may, at least in part, be due to population differences in KITLG variant frequency.	('KITLG', 'Gene', (136, 141))	('variant', 'Var', (142, 149))	('TGCT', 'Disease', (62, 66))	('KITLG', 'Gene', '4254', (136, 141))
55471	20228134	Mutations of KIT and KITLG have other associations with human disease.	('associations', 'Reg', (38, 50))	('human', 'Species', '9606', (56, 61))	('Mutations', 'Var', (0, 9))	('KITLG', 'Gene', '4254', (21, 26))	('human disease', 'Disease', (56, 69))	('KIT', 'Gene', (13, 16))	('KITLG', 'Gene', (21, 26))
55474	20228134	In this regard, it is notable that loss of the transmembrane Kitl isoform increases susceptibility to TGCT in a murine model.	('susceptibility', 'MPA', (84, 98))	('TGCT', 'Disease', (102, 106))	('murine', 'Species', '10090', (112, 118))	('loss', 'Var', (35, 39))
55476	20228134	Elucidating the mechanisms through which the recently identified genetic SNPs affecting the KITLG-KIT pathway contribute to TGCT development has now emerged as a major scientific priority.	('KITLG', 'Gene', '4254', (92, 97))	('KITLG', 'Gene', (92, 97))	('TGCT', 'Disease', (124, 128))	('contribute', 'Reg', (110, 120))	('men', 'Species', '9606', (136, 139))	('genetic SNPs', 'Var', (65, 77))
55478	20228134	Subsequent studies have implicated the Y chromosome gr/gr deletion and germline variants in the PDE11A gene as potential modifiers of FTGCT risk.	('FTGCT', 'Disease', (134, 139))	('PDE11A', 'Gene', (96, 102))	('PDE11A', 'Gene', '50940', (96, 102))	('deletion', 'Var', (58, 66))
55487	20022248	Third, the levels of Traffic Jam, whose 3' UTR generates abundant piRNAs, are increased in piwi mutant follicle clones.	('mutant', 'Var', (96, 102))	('piwi', 'Gene', '34521', (91, 95))	('piwi', 'Gene', (91, 95))	('increased', 'PosReg', (78, 87))	('Traffic Jam', 'Gene', (21, 32))	('Traffic Jam', 'Gene', '35227', (21, 32))	('rat', 'Species', '10116', (51, 54))
55496	20022248	In that study, we demonstrated that OSS cells expresses Piwi but not Aub or AGO3, and consequently express only primary piRNAs.	('AGO3', 'Gene', '3355150', (76, 80))	('AGO3', 'Gene', (76, 80))	('Aub', 'Chemical', '-', (69, 72))	('OSS', 'Chemical', '-', (36, 39))	('Piwi', 'Var', (56, 60))	('rat', 'Species', '10116', (25, 28))
55506	20022248	In fact, 17 of the 40 most highly expressed cis-NAT-siRNA loci were shared by these cell types (Supplementary Table 1B), including CG5148/cher (4th highest-expressed in OSS, #8 in S2), MED21/CG40351 (#5 in OSS, #1 in S2), cenB1A/CG31365 (#6 in OSS, #14 in S2), and CG7739/AGO2 (#7 in OSS, #3 in S2).	('MED21', 'Gene', (185, 190))	('cenB1A', 'Gene', (222, 228))	('OSS', 'Chemical', '-', (244, 247))	('cenB1A', 'Gene', '42735', (222, 228))	('MED21', 'Gene', '3354977', (185, 190))	('OSS', 'Chemical', '-', (169, 172))	('AGO2', 'Gene', '39683', (272, 276))	('AGO2', 'Gene', (272, 276))	('OSS', 'Chemical', '-', (284, 287))	('CG5148/cher', 'Var', (131, 142))	('OSS', 'Chemical', '-', (206, 209))
55528	20022248	Hannon and colleagues observed that all piRNA pathway mutants exhibited decreased levels of TE-piRNAs, but that only piwi, zucchini and flamenco specifically decreased levels of flamenco piRNAs.	('flamenco piRNAs', 'MPA', (178, 193))	('decreased', 'NegReg', (158, 167))	('TE-piRNAs', 'MPA', (92, 101))	('decreased', 'NegReg', (72, 81))	('mutants', 'Var', (54, 61))	('piRNA pathway', 'Gene', (40, 53))	('piwi', 'Gene', '34521', (117, 121))	('levels', 'MPA', (82, 88))	('piwi', 'Gene', (117, 121))
55533	20022248	We also observed that the mutants with the strongest reduction in piRNAs from the ping-pong cluster 42AB--armi, spn-E and krimper --correspondingly exhibited the highest proportions of 3' UTR-piRNAs (Figure 2D).	('spn-E', 'Gene', '41919', (112, 117))	('mutants', 'Var', (26, 33))	('spn-E', 'Gene', (112, 117))	('reduction', 'NegReg', (53, 62))
55535	20022248	While AGO3 mutants had increased proportions of 3' UTR piRNAs, similar to most other ping-pong mutants, aub actually exhibited decreased 3' UTR piRNAs.	('mutants', 'Var', (11, 18))	('decreased', 'NegReg', (127, 136))	("3' UTR piRNAs", 'MPA', (48, 61))	('increased', 'PosReg', (23, 32))	('AGO3', 'Gene', '3355150', (6, 10))	('AGO3', 'Gene', (6, 10))	("3' UTR piRNAs", 'MPA', (137, 150))
55537	20022248	Still, the piwi mutation clearly had greatest effect on 3' UTR piRNA accumulation.	('piwi', 'Gene', '34521', (11, 15))	('mutation', 'Var', (16, 24))	("3' UTR piRNA accumulation", 'MPA', (56, 81))	('piwi', 'Gene', (11, 15))
55559	20022248	Curiously, the peak size of 3' UTR piRNAs in Mili complexes (27-28 nt) was distinctly shorter than those in Miwi complexes (29-30 nt), reminiscent of the observation that different Piwi proteins are associated with characteristic sizes of piRNAs.	('Mili complexes', 'Var', (45, 59))	('shorter', 'NegReg', (86, 93))	('Miwi', 'Gene', (108, 112))	('Miwi', 'Gene', '57749', (108, 112))	('peak size', 'MPA', (15, 24))
55590	20022248	Interestingly, posttranscriptional gene silencing by RNA was a category enriched amongst abundant piRNA-generating mRNAs in both OSS cells and adult murine testes, but not amongst abundant transcripts in either tissue.	('rat', 'Species', '10116', (108, 111))	('RNA', 'Gene', (53, 56))	('posttranscriptional gene', 'Var', (15, 39))	('OSS', 'Chemical', '-', (129, 132))	('murine', 'Species', '10090', (149, 155))
55594	20022248	We examined this in more detail by generating piwi mutant clones in Drosophila ovaries and staining them for TJ, whose mRNA generated the most abundant 3' UTR piRNAs in OSS cells.	('piwi', 'Gene', '34521', (46, 50))	('Drosophila ovaries', 'Disease', 'MESH:D010051', (68, 86))	('piwi', 'Gene', (46, 50))	('OSS', 'Chemical', '-', (169, 172))	('mutant', 'Var', (51, 57))	('rat', 'Species', '10116', (39, 42))	('Drosophila ovaries', 'Disease', (68, 86))	('rat', 'Species', '10116', (128, 131))
55595	20022248	We observed many clones in which TJ protein was upregulated in piwi mutant cells relative to neighboring control cells (Figure 5D).	('upregulated', 'PosReg', (48, 59))	('piwi', 'Gene', '34521', (63, 67))	('TJ protein', 'Protein', (33, 43))	('piwi', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
55611	20022248	We note that TDRD-1 mutants exhibit apoptotic post-pachytene spermatocytes at 15 dpp, and suggest that this reduces the contribution of post-pachytene intergenic piRNAs in total small RNA libraries.	('mutants', 'Var', (20, 27))	('reduces', 'NegReg', (108, 115))	('dpp', 'Chemical', 'MESH:C038694', (81, 84))	('TDRD-1', 'Gene', (13, 19))	('pachytene', 'Chemical', '-', (51, 60))	('pachytene', 'Chemical', '-', (141, 150))
55615	20022248	Since piRNA-generating transcripts were not consistently altered in mili-KO mutants, it is prudent to consider whether these piRNAs might be incidental.	('rat', 'Species', '10116', (16, 19))	('mutants', 'Var', (76, 83))	('mili-KO', 'Gene', (68, 75))
55621	20022248	In support of the former scenario, the tj 3' UTR is one of the most abundant sources of mRNA-derived piRNAs, and we observed increased levels of the transcription factor TJ in piwi mutant clones (Figure 5D).	('mutant', 'Var', (181, 187))	('increased', 'PosReg', (125, 134))	('levels', 'MPA', (135, 141))	('piwi', 'Gene', '34521', (176, 180))	('tj', 'Gene', '35227', (39, 41))	('piwi', 'Gene', (176, 180))
55648	20022248	piwi mutant clones were generated in hs-FLP; piwi[2] FRT40A/ubi-GFP FRT40A animals and stained using rat anti-TJ, rabbit anti-GFP (Molecular Probes) and DAPI, followed by Cy3-conjugated goat anti-rat and Cy2-conjugated goat anti-rabbit (Molecular Probes).	('rat', 'Species', '10116', (101, 104))	('rabbit', 'Species', '9986', (114, 120))	('Cy2', 'Chemical', '-', (204, 207))	('FRT40A', 'Var', (68, 74))	('rabbit', 'Species', '9986', (229, 235))	('goat', 'Species', '9925', (219, 223))	('Cy3', 'Chemical', '-', (171, 174))	('piwi', 'Gene', '34521', (0, 4))	('piwi', 'Gene', '34521', (45, 49))	('DAPI', 'Chemical', 'MESH:C007293', (153, 157))	('piwi', 'Gene', (0, 4))	('piwi', 'Gene', (45, 49))	('rat', 'Species', '10116', (196, 199))	('rat', 'Species', '10116', (28, 31))	('goat', 'Species', '9925', (186, 190))
55649	33986496	Germline risk of clonal haematopoiesis Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality.	('Clonal haematopoiesis', 'Disease', 'MESH:C580365', (39, 60))	('mortality', 'Disease', 'MESH:D003643', (250, 259))	('Clonal haematopoiesis', 'Disease', (39, 60))	('associated with', 'Reg', (147, 162))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (213, 235))	('mutations', 'Var', (129, 138))	('cardiovascular disease', 'Disease', 'MESH:D002318', (213, 235))	('haematological malignancies', 'Disease', (184, 211))	('haematological malignancies', 'Disease', 'MESH:D019337', (184, 211))	('age', 'Gene', (79, 82))	('mortality', 'Disease', (250, 259))	('cardiovascular disease', 'Disease', (213, 235))	('age', 'Gene', '5973', (79, 82))
55650	33986496	CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events.	('chromosomal copy number changes', 'Var', (80, 111))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (61, 78))	('point mutations', 'Var', (20, 35))	('loss of heterozygosity events', 'Var', (116, 145))	('caused by', 'Reg', (10, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('myeloid neoplasms', 'Disease', (61, 78))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (61, 78))
55652	33986496	Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases.	('age', 'Gene', '5973', (128, 131))	('linked', 'Reg', (118, 124))	('variation', 'Var', (65, 74))	('age', 'Gene', (128, 131))	('associated', 'Reg', (75, 85))
55653	33986496	In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.	('age', 'Gene', '5973', (196, 199))	('inherited variation', 'Var', (64, 83))	('age', 'Gene', (196, 199))
55654	33986496	They focus on human germline risk variants and on how these are linked to different forms of CH and their associated disease pathologies.	('human', 'Species', '9606', (14, 19))	('variants', 'Var', (34, 42))	('linked', 'Reg', (64, 70))
55659	33986496	Although the majority of these acquired mutations involves genetic loci that do not lead to phenotypic consequences, mutations can occur in portions of the genome that may confer a relative fitness advantage to affected HSCs.	('fitness advantage', 'Disease', 'MESH:D012640', (190, 207))	('mutations', 'Var', (117, 126))	('mutations', 'Var', (40, 49))	('HSC', 'Gene', (220, 223))	('HSC', 'Gene', '2523', (220, 223))	('fitness advantage', 'Disease', (190, 207))
55661	33986496	Over time, the relative fitness advantage of these mutated HSCs can result in the clonal production of a large number of progeny that all bear the same somatic alterations.	('clonal production', 'CPA', (82, 99))	('fitness advantage', 'Disease', (24, 41))	('result in', 'Reg', (68, 77))	('HSC', 'Gene', (59, 62))	('HSC', 'Gene', '2523', (59, 62))	('fitness advantage', 'Disease', 'MESH:D012640', (24, 41))	('mutated', 'Var', (51, 58))
55666	33986496	Here, we use 'CH' as an umbrella term that refers to the presence of an expanded mutant clone of any sort within the blood, excluding the reactive expansion of immune cells within lymphoid organs and frank malignancy.	('frank malignancy', 'Disease', 'MESH:D009369', (200, 216))	('frank malignancy', 'Disease', (200, 216))	('mutant', 'Var', (81, 87))
55670	33986496	Additionally, mosaic chromosomal alterations (mCAs), single-nucleotide variants (SNVs) and indels in genes associated with myeloid malignancies, and putative incidental mutations/genomic drift (CH with unknown drivers) have all been documented.	('single-nucleotide variants', 'Var', (53, 79))	('mCAs', 'Gene', (46, 50))	('mosaic chromosomal alterations', 'Disease', (14, 44))	('indels', 'Var', (91, 97))	('mCAs', 'Gene', '12927', (46, 50))	('myeloid malignancies', 'Disease', 'MESH:D009369', (123, 143))	('mutations/genomic', 'Var', (169, 186))	('myeloid malignancies', 'Disease', (123, 143))	('men', 'Species', '9606', (237, 240))
55672	33986496	Chromosomal abnormalities, including mLOY and mCAs, can be interrogated using genome-wide genotyping arrays (such as those used for genome-wide association studies (GWAS)), whereas whole-exome or whole-genome sequencing (WGS) data can identify SNVs or indels but is suboptimal for identifying mCA events.	('Chromosomal abnormalities', 'Disease', 'MESH:D002869', (0, 25))	('mCAs', 'Gene', (46, 50))	('mCAs', 'Gene', '12927', (46, 50))	('Chromosomal abnormalities', 'Disease', (0, 25))	('SNVs', 'Var', (244, 248))
55678	33986496	An individual can have both mCAs and CHIP simultaneously, which occurs frequently with point mutations in JAK2 (a tyrosine kinase involved in multiple cytokine signalling pathways) and mCA events at the same locus.	('JAK2', 'Gene', '3717', (106, 110))	('mCAs', 'Gene', '12927', (28, 32))	('JAK2', 'Gene', (106, 110))	('point mutations', 'Var', (87, 102))	('mCAs', 'Gene', (28, 32))
55681	33986496	There are substantial differences across age in the distribution of mutated CHIP genes.	('mutated', 'Var', (68, 75))	('age', 'Gene', '5973', (41, 44))	('age', 'Gene', (41, 44))
55682	33986496	In particular, mutations in the de novo DNA methyltransferase DNMT3A and in JAK2 can be observed with some regularity beginning in the third and fourth decade of life, whereas clones carrying mutations in spliceosome genes are generally detected no earlier than the fifth and sixth decades of life.	('JAK2', 'Gene', (76, 80))	('mutations', 'Var', (15, 24))	('DNMT3A', 'Gene', (62, 68))	('DNMT3A', 'Gene', '1788', (62, 68))	('JAK2', 'Gene', '3717', (76, 80))
55685	33986496	In the case of cytotoxic chemotherapy and radiation therapy, the mutational spectrum exhibits a marked enrichment of mutations in DNA damage response pathway genes.	('men', 'Species', '9606', (109, 112))	('mutations', 'Var', (117, 126))	('age', 'Gene', '5973', (137, 140))	('age', 'Gene', (137, 140))
55686	33986496	The outgrowth of CH clones following anticancer therapy is partly due to the expansion of pre-existing clones with a selective advantage but may also be from the introduction of new mutations by the anticancer agents themselves or due to stochastic effects from a bottleneck event for HSCs.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('age', 'Gene', (133, 136))	('age', 'Gene', (210, 213))	('age', 'Gene', '5973', (133, 136))	('HSC', 'Gene', '2523', (285, 288))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('HSC', 'Gene', (285, 288))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('age', 'Gene', '5973', (210, 213))	('mutations', 'Var', (182, 191))
55693	33986496	All-cause mortality is greater in individuals with CHIP compared to without CHIP; this is partly due to an increased risk of haematological malignancies, which has been observed across many studies.	('haematological malignancies', 'Disease', 'MESH:D019337', (125, 152))	('mortality', 'Disease', 'MESH:D003643', (10, 19))	('haematological malignancies', 'Disease', (125, 152))	('mortality', 'Disease', (10, 19))	('CHIP', 'Var', (51, 55))
55694	33986496	However, individuals with CHIP mutations have excess mortality compared with those who do not harbour such mutations even after controlling for blood cancer deaths.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('blood cancer deaths', 'Disease', (144, 163))	('CHIP mutations', 'Var', (26, 40))	('excess', 'PosReg', (46, 52))	('mortality', 'Disease', (53, 62))	('blood cancer deaths', 'Disease', 'MESH:D007022', (144, 163))	('blood cancer', 'Phenotype', 'HP:0001909', (144, 156))	('mortality', 'Disease', 'MESH:D003643', (53, 62))
55697	33986496	Mouse models of CHIP have demonstrated mechanistic ties between certain common CHIP mutations and accelerated atherosclerosis as well as heart failure.	('atherosclerosis', 'Disease', (110, 125))	('heart failure', 'Disease', (137, 150))	('mutations', 'Var', (84, 93))	('accelerated atherosclerosis', 'Phenotype', 'HP:0004943', (98, 125))	('heart failure', 'Phenotype', 'HP:0001635', (137, 150))	('Mouse', 'Species', '10090', (0, 5))	('heart failure', 'Disease', 'MESH:D006333', (137, 150))	('atherosclerosis', 'Disease', 'MESH:D050197', (110, 125))	('atherosclerosis', 'Phenotype', 'HP:0002621', (110, 125))
55698	33986496	Despite the fact that numerous genes affected by somatic CHIP mutations have been associated with increased cancer and CVD risk, there are early indications of important functional differences in how each mutant gene might contribute to that risk.	('CVD', 'Disease', (119, 122))	('associated', 'Reg', (82, 92))	('CVD', 'Phenotype', 'HP:0001626', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CVD', 'Disease', 'MESH:D002318', (119, 122))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
55699	33986496	For instance, mutations in splicing factor U2AF1 are associated with a higher risk of acute myeloid leukaemia (AML) and with a shorter latency to disease than mutations in DNMT3A.	('AML', 'Disease', 'MESH:D015470', (111, 114))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (86, 109))	('AML', 'Disease', (111, 114))	('AML', 'Phenotype', 'HP:0004808', (111, 114))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (86, 109))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (92, 109))	('DNMT3A', 'Gene', (172, 178))	('acute myeloid leukaemia', 'Disease', (86, 109))	('U2AF1', 'Gene', (43, 48))	('DNMT3A', 'Gene', '1788', (172, 178))	('U2AF1', 'Gene', '7307', (43, 48))	('mutations', 'Var', (14, 23))
55701	33986496	In mouse models, mutations in Tet2, whose gene product recruits HDAC2 for the resolution of IL-6-mediated inflammation, are associated with increased expression of Il1b, Il6, Cxcl1, Cxcl2 and Cxcl3 (refs).	('Il1b', 'Gene', '16176', (164, 168))	('HDAC2', 'Gene', (64, 69))	('Cxcl1', 'Gene', '14825', (175, 180))	('HDAC2', 'Gene', '15182', (64, 69))	('increased', 'PosReg', (140, 149))	('mutations', 'Var', (17, 26))	('Cxcl2', 'Gene', '20310', (182, 187))	('Cxcl2', 'Gene', (182, 187))	('Il6', 'Gene', '16193', (170, 173))	('IL-6', 'Gene', (92, 96))	('Cxcl3', 'Gene', (192, 197))	('inflammation', 'Disease', 'MESH:D007249', (106, 118))	('expression', 'MPA', (150, 160))	('Il6', 'Gene', (170, 173))	('Cxcl1', 'Gene', (175, 180))	('Cxcl3', 'Gene', '330122', (192, 197))	('IL-6', 'Gene', '16193', (92, 96))	('inflammation', 'Disease', (106, 118))	('mouse', 'Species', '10090', (3, 8))	('Il1b', 'Gene', (164, 168))	('Tet2', 'Gene', (30, 34))
55702	33986496	While mutations in Jak2 also lead to higher Il1b expression, they additionally lead to plaque-promoting erythrophagocytosis, secretion of arterial spasm-inducing erythrocyte-derived microvesicles and thrombotic neutrophil extracellular traps.	('Il1b', 'Gene', '16176', (44, 48))	('Jak2', 'Gene', (19, 23))	('arterial spasm', 'Phenotype', 'HP:0025637', (138, 152))	('Il1b', 'Gene', (44, 48))	('spasm', 'Disease', (147, 152))	('higher', 'PosReg', (37, 43))	('lead to', 'Reg', (79, 86))	('Jak2', 'Gene', '3717', (19, 23))	('expression', 'MPA', (49, 59))	('spasm', 'Disease', 'MESH:D013035', (147, 152))	('thrombotic', 'Disease', 'MESH:D013927', (200, 210))	('thrombotic', 'Disease', (200, 210))	('plaque-promoting erythrophagocytosis', 'CPA', (87, 123))	('mutations', 'Var', (6, 15))
55704	33986496	There is accumulating evidence that CHIP mutations may interact with human illnesses beyond cancer and CVD.	('mutations', 'Var', (41, 50))	('CVD', 'Disease', 'MESH:D002318', (103, 106))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('CVD', 'Phenotype', 'HP:0001626', (103, 106))	('human', 'Species', '9606', (69, 74))	('interact', 'Reg', (55, 63))	('CVD', 'Disease', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
55705	33986496	Somatic CHIP mutations have been associated with several diseases in which inflammation features prominently, including chronic obstructive pulmonary disease, adult-onset haemophagocytic lymphohistiocytosis and anti-neutrophil cytoplasmic antibody-associated vasculitis.	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (120, 157))	('haemophagocytic lymphohistiocytosis', 'Disease', 'MESH:D051359', (171, 206))	('chronic obstructive pulmonary disease', 'Disease', (120, 157))	('vasculitis', 'Phenotype', 'HP:0002633', (259, 269))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (128, 157))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (120, 157))	('vasculitis', 'Disease', 'MESH:D014657', (259, 269))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('associated', 'Reg', (33, 43))	('vasculitis', 'Disease', (259, 269))	('haemophagocytic lymphohistiocytosis', 'Disease', (171, 206))	('mutations', 'Var', (13, 22))
55708	33986496	Mutations in CHIP genes involved in the DNA damage response pathway, such as TP53 and PPM1D, are highly enriched following radiation treatment or treatment with a select few cytotoxic chemotherapies.	('men', 'Species', '9606', (151, 154))	('PPM1D', 'Gene', '8493', (86, 91))	('age', 'Gene', (47, 50))	('men', 'Species', '9606', (138, 141))	('Mutations', 'Var', (0, 9))	('age', 'Gene', '5973', (47, 50))	('PPM1D', 'Gene', (86, 91))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
55709	33986496	Additionally, CHIP has been associated with significantly increased mortality following transcatheter aortic valve implantation, which is the first indication that CHIP might have an impact on surgical/procedural outcomes.	('increased', 'PosReg', (58, 67))	('mortality', 'Disease', 'MESH:D003643', (68, 77))	('mortality', 'Disease', (68, 77))	('CHIP', 'Var', (14, 18))	('impact', 'Reg', (183, 189))
55712	33986496	The current evidence (nicely summarized in refs) suggests that donor-derived CHIP is not uncommon in both allogeneic HSCT and autologous HSCT recipients and may increase risks of graft-versus-host disease, donor-derived leukaemia and overall mortality, although the interactions appear to be complex and may depend on both patient characteristics and the CHIP gene in question.	('leukaemia', 'Disease', (220, 229))	('graft-versus-host disease', 'Disease', 'MESH:D006086', (179, 204))	('mortality', 'Disease', (242, 251))	('CHIP', 'Var', (77, 81))	('HSC', 'Gene', (137, 140))	('HSC', 'Gene', '2523', (137, 140))	('leukaemia', 'Disease', 'MESH:D007938', (220, 229))	('increase', 'PosReg', (161, 169))	('patient', 'Species', '9606', (323, 330))	('HSC', 'Gene', (117, 120))	('HSC', 'Gene', '2523', (117, 120))	('mortality', 'Disease', 'MESH:D003643', (242, 251))	('graft-versus-host disease', 'Disease', (179, 204))
55713	33986496	In the next section, we discuss the associations between inherited variants and mLOY, mCAs and CHIP that have been described to date (Fig.	('mCAs', 'Gene', (86, 90))	('mCAs', 'Gene', '12927', (86, 90))	('mLOY', 'Gene', (80, 84))	('associations', 'Interaction', (36, 48))	('variants', 'Var', (67, 75))
55716	33986496	As CHIP mutations are also found in myeloid neoplasia, work on the genetic predispositions to haematological malignancies provided key initial insights linking the germline variation and expansion of somatic haematopoietic mutations.	('haematological malignancies', 'Disease', (94, 121))	('haematological malignancies', 'Disease', 'MESH:D019337', (94, 121))	('mutations', 'Var', (8, 17))	('myeloid neoplasia', 'Phenotype', 'HP:0012324', (36, 53))	('myeloid neoplasia', 'Disease', (36, 53))	('myeloid neoplasia', 'Disease', 'MESH:D009369', (36, 53))	('neoplasia', 'Phenotype', 'HP:0002664', (44, 53))
55718	33986496	Despite the shared origins and patterns of acquired mutations, the vast majority of individuals with CHIP never develop a myeloid malignancy.	('myeloid malignancy', 'Disease', (122, 140))	('myeloid malignancy', 'Disease', 'MESH:D009369', (122, 140))	('mutations', 'Var', (52, 61))
55721	33986496	Future study of the differences between the sets of germline variants predisposing more to CHIP versus the set predisposing more to malignancy may prove informative as to why only a minority of individuals ever progress from one to the other.	('malignancy', 'Disease', (132, 142))	('variants', 'Var', (61, 69))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('CHIP', 'Disease', (91, 95))
55722	33986496	Many of the same germline variants predisposing to JAK2-mutated malignancies have also been associated with JAK2-CH.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('malignancies', 'Disease', (64, 76))	('JAK2', 'Gene', '3717', (51, 55))	('JAK2', 'Gene', '3717', (108, 112))	('variants', 'Var', (26, 34))	('JAK2', 'Gene', (51, 55))	('associated', 'Reg', (92, 102))	('JAK2', 'Gene', (108, 112))
55723	33986496	JAK2 is the most commonly mutated gene in MPNs and the JAK2 p.Val617Phe mutation (JAK2V617F) is a characteristic feature of MPNs incorporated into the World Health Organization diagnostic criteria for over a decade.	('JAK2', 'Gene', '3717', (82, 86))	('JAK2', 'Gene', '3717', (0, 4))	('MPNs', 'Phenotype', 'HP:0005547', (42, 46))	('p.Val617Phe', 'Var', (60, 71))	('MPNs', 'Phenotype', 'HP:0005547', (124, 128))	('JAK2', 'Gene', '3717', (55, 59))	('JAK2', 'Gene', (82, 86))	('JAK2', 'Gene', (0, 4))	('p.Val617Phe', 'Mutation', 'rs77375493', (60, 71))	('JAK2', 'Gene', (55, 59))
55729	33986496	Inherited polymorphisms in the telomerase reverse transcriptase (TERT) locus have also been linked to all varieties of MPNs in several studies and to JAK2V617F-mutated disease in several others.	('MPNs', 'Phenotype', 'HP:0005547', (119, 123))	('JAK2', 'Gene', '3717', (150, 154))	('MPNs', 'Disease', (119, 123))	('polymorphisms', 'Var', (10, 23))	('varieties', 'Disease', (106, 115))	('JAK2', 'Gene', (150, 154))	('linked', 'Reg', (92, 98))	('TERT', 'Gene', (65, 69))	('TERT', 'Gene', '7015', (65, 69))
55736	33986496	While the location of lead SNPs in or near key HSC regulators is strongly suggestive of mechanisms that disrupt normal HSC biology, variant-to-function analyses have provided added evidence in the case of GFI1B and CHEK2.	('HSC', 'Gene', (119, 122))	('HSC', 'Gene', (47, 50))	('HSC', 'Gene', '2523', (119, 122))	('HSC', 'Gene', '2523', (47, 50))	('GFI1B', 'Gene', '8328', (205, 210))	('CHEK2', 'Gene', '11200', (215, 220))	('variant-to-function', 'Var', (132, 151))	('CHEK2', 'Gene', (215, 220))	('GFI1B', 'Gene', (205, 210))
55738	33986496	The second case involves a rare missense variant in CHEK2 and similarly demonstrated increased HSPC self-renewal following the knockdown of gene expression.	('CHEK2', 'Gene', '11200', (52, 57))	('HSPC', 'Gene', '5688', (95, 99))	('CHEK2', 'Gene', (52, 57))	('increased', 'PosReg', (85, 94))	('missense variant', 'Var', (32, 48))	('HSPC', 'Gene', (95, 99))
55741	33986496	Compared to the literature on JAK2, studies of haematological malignancies have been less revealing with respect to what germline factors may increase the risk of somatic mutation in other CHIP genes.	('JAK2', 'Gene', '3717', (30, 34))	('somatic mutation', 'Var', (163, 179))	('haematological malignancies', 'Disease', 'MESH:D019337', (47, 74))	('JAK2', 'Gene', (30, 34))	('haematological malignancies', 'Disease', (47, 74))
55742	33986496	Family-based studies of inherited risk of MDS and AML have noted a high prevalence of non-disease CHIP in carriers of rare inherited variants affecting RUNX1, a member of the core binding factor family of transcription factors and a key regulator of definitive haematopoiesis.	('MDS', 'Disease', (42, 45))	('MDS', 'Disease', 'MESH:D009190', (42, 45))	('MDS', 'Phenotype', 'HP:0002863', (42, 45))	('AML', 'Disease', 'MESH:D015470', (50, 53))	('RUNX1', 'Gene', '861', (152, 157))	('AML', 'Phenotype', 'HP:0004808', (50, 53))	('AML', 'Disease', (50, 53))	('variants', 'Var', (133, 141))	('non-disease CHIP', 'Disease', (86, 102))	('non-disease CHIP', 'Disease', 'MESH:D000073296', (86, 102))	('RUNX1', 'Gene', (152, 157))
55743	33986496	Aside from RUNX1, there are several other germline variants recognized to predispose to myeloid, lymphoid or plasma-cell neoplasms that could presumably also predispose to asymptomatic CHIP.	('RUNX1', 'Gene', '861', (11, 16))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('neoplasms', 'Disease', (121, 130))	('variants', 'Var', (51, 59))	('lymphoid', 'Disease', (97, 105))	('predispose', 'Reg', (74, 84))	('asymptomatic', 'Disease', (172, 184))	('myeloid', 'Disease', (88, 95))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('RUNX1', 'Gene', (11, 16))	('predispose', 'Reg', (158, 168))
55749	33986496	For instance, inherited variants in both intron 2 (SNPs rs2736100, rs2853677 and rs7705526) and intron 3 (SNP rs7726159) of TERT are associated with the risk of developing somatic JAK2V617F clones but only the germline variants in intron 2 have demonstrated a significant association with MPNs.	('MPNs', 'Disease', (289, 293))	('rs2853677', 'Mutation', 'rs2853677', (67, 76))	('JAK2', 'Gene', (180, 184))	('rs2853677', 'Var', (67, 76))	('rs7705526', 'Var', (81, 90))	('MPNs', 'Phenotype', 'HP:0005547', (289, 293))	('TERT', 'Gene', (124, 128))	('rs7705526', 'Mutation', 'rs7705526', (81, 90))	('JAK2', 'Gene', '3717', (180, 184))	('rs2736100', 'Mutation', 'rs2736100', (56, 65))	('SNP rs7726159', 'Var', (106, 119))	('TERT', 'Gene', '7015', (124, 128))	('rs7726159', 'Mutation', 'rs7726159', (110, 119))	('associated', 'Reg', (133, 143))
55750	33986496	Meanwhile, inherited variants affecting MECOM, HBS1L-MYB, RUNX1 (ref.	('variants', 'Var', (21, 29))	('HBS1L', 'Gene', '10767', (47, 52))	('HBS1L', 'Gene', (47, 52))	('RUNX1', 'Gene', '861', (58, 63))	('MECOM', 'Gene', (40, 45))	('MYB', 'Gene', '4602', (53, 56))	('MYB', 'Gene', (53, 56))	('MECOM', 'Gene', '2122', (40, 45))	('RUNX1', 'Gene', (58, 63))
55755	33986496	One possible explanation for this could be that, once individuals with these germline variants develop a JAK2V617F clone, they have a short or non-existent CH phase and progress very quickly to MPNs.	('JAK2', 'Gene', '3717', (105, 109))	('JAK2', 'Gene', (105, 109))	('MPNs', 'Phenotype', 'HP:0005547', (194, 198))	('variants', 'Var', (86, 94))
55758	33986496	The authors looked at the risk-recurrence ratio (lambdas) for mutations within these genes among a set of 391 female sib-ships of French-Canadian ancestry and found no familial risk for DNMT3A mutations but a significantly increased risk for TET2 (lambdas = 2.24 for those >=55 years of age, lambdas = 2.65 for those >=65 years of age).	('DNMT3A', 'Gene', '1788', (186, 192))	('age', 'Gene', (287, 290))	('age', 'Gene', '5973', (331, 334))	('age', 'Gene', '5973', (287, 290))	('mutations', 'Var', (193, 202))	('TET2', 'Gene', (242, 246))	('DNMT3A', 'Gene', (186, 192))	('age', 'Gene', (331, 334))	('mutations', 'Var', (62, 71))
55759	33986496	One sib-ship consisting of seven sisters was notable for having TET2 mutations in 4/7 and a DNMT3A mutation in 1/7 sisters, raising the provocative but unanswered question of whether germline genetics or common environmental exposures did more to shape such a pedigree.	('mutations', 'Var', (69, 78))	('DNMT3A', 'Gene', (92, 98))	('DNMT3A', 'Gene', '1788', (92, 98))	('mutation', 'Var', (99, 107))	('TET2', 'Gene', (64, 68))	('men', 'Species', '9606', (218, 221))
55760	33986496	The larger of the two studies additionally found no increased concordance among MZ pairs for CHIP mutations specifically in DNMT3A or TET2 (ref.).	('mutations', 'Var', (98, 107))	('DNMT3A', 'Gene', '1788', (124, 130))	('TET2', 'Gene', (134, 138))	('DNMT3A', 'Gene', (124, 130))
55761	33986496	Of note, these studies each identified sets of MZ twins that shared identical CH mutations (KDM6A p.Q692X and DNMT3A p.R598X in the UK cohort and SRSF2 p.P95H and c.912_916delCTGGT in DNMT3A in the Denmark cohort), suggesting these mutations occurred in utero; several subsequent studies of patients with MPNs have identified JAK2V617F and DNMT3A mutations that similarly arose during embryogenesis or childhood.	('JAK2', 'Gene', '3717', (326, 330))	('DNMT3A', 'Gene', (340, 346))	('KDM6A', 'Gene', '7403', (92, 97))	('SRSF2', 'Gene', '6427', (146, 151))	('JAK2', 'Gene', (326, 330))	('patients', 'Species', '9606', (291, 299))	('SRSF2', 'Gene', (146, 151))	('DNMT3A', 'Gene', (184, 190))	('DNMT3A', 'Gene', '1788', (110, 116))	('p.Q692X', 'Mutation', 'rs1278018793', (98, 105))	('p.P95H', 'Mutation', 'rs751713049', (152, 158))	('p.R598X', 'Var', (117, 124))	('c.912_916delCTGGT', 'Var', (163, 180))	('DNMT3A', 'Gene', '1788', (340, 346))	('KDM6A', 'Gene', (92, 97))	('MPNs', 'Phenotype', 'HP:0005547', (305, 309))	('p.Q692X', 'Var', (98, 105))	('p.R598X', 'Mutation', 'rs568207978', (117, 124))	('DNMT3A', 'Gene', '1788', (184, 190))	('DNMT3A', 'Gene', (110, 116))	('c.912_916delCTGGT', 'Mutation', 'c.912_916delCTGGT', (163, 180))
55766	33986496	The first germline association with mLOY to be uncovered was with a common SNP (rs2887399) near the 5' end of TCL1A, which encodes the protein T cell leukaemia/lymphoma 1A (TCL1A).	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('T cell leukaemia/lymphoma 1A', 'Gene', '8115', (143, 171))	('rs2887399', 'Mutation', 'rs2887399', (80, 89))	('TCL1A', 'Gene', (110, 115))	('rs2887399', 'Var', (80, 89))	('TCL1A', 'Gene', (173, 178))	('TCL1A', 'Gene', '8115', (110, 115))	('TCL1A', 'Gene', '8115', (173, 178))	('T cell leukaemia/lymphoma 1A', 'Gene', (143, 171))
55772	33986496	Unlike mLOY, which only involves the unpaired Y chromosome, these mCAs may also be associated with variants that provide a strong selection pressure towards CN-LOH events.	('mCAs', 'Gene', '12927', (66, 70))	('mCAs', 'Gene', (66, 70))	('variants', 'Var', (99, 107))
55774	33986496	Variants in TERT and the related TERC (encoding telomerase RNA component) as well as variants in SP140 (encoding a lymphoid-restricted nuclear body protein involved in B cell antigen response) are associated with mCAs occurring anywhere in the genome, whereas the remaining inherited variants have only been associated with trans mCAs on a particular chromosome (Table 1).	('SP140', 'Gene', '11262', (97, 102))	('Variants', 'Var', (0, 8))	('mCAs', 'Gene', '12927', (213, 217))	('mCAs', 'Gene', '12927', (330, 334))	('TERT', 'Gene', '7015', (12, 16))	('variants', 'Var', (85, 93))	('TERC', 'Gene', '7012', (33, 37))	('mCAs', 'Gene', (213, 217))	('associated', 'Reg', (197, 207))	('mCAs', 'Gene', (330, 334))	('TERT', 'Gene', (12, 16))	('TERC', 'Gene', (33, 37))	('SP140', 'Gene', (97, 102))
55776	33986496	Many of these rare germline variants are missense or nonsense mutations predicted to damage protein function.	('missense', 'Var', (41, 49))	('nonsense', 'Var', (53, 61))	('age', 'Gene', '5973', (88, 91))	('protein', 'Protein', (92, 99))	('age', 'Gene', (88, 91))
55778	33986496	Conversely, the presence of damaging germline variants in the MPL gene, which encodes the thrombopoietin receptor important for HSC self-renewal, are associated with the duplication of the non-damaged allele.	('duplication', 'MPA', (170, 181))	('thrombopoietin receptor', 'Gene', '4352', (90, 113))	('age', 'Gene', (196, 199))	('MPL', 'Gene', (62, 65))	('thrombopoietin receptor', 'Gene', (90, 113))	('germline variants', 'Var', (37, 54))	('age', 'Gene', '5973', (196, 199))	('HSC', 'Gene', (128, 131))	('HSC', 'Gene', '2523', (128, 131))	('MPL', 'Gene', '4352', (62, 65))
55779	33986496	Preferential CN-LOH duplication arising from germline alleles that confer a relative fitness advantage may also extend to polygenic risk.	('fitness advantage', 'Disease', 'MESH:D012640', (85, 102))	('CN-LOH', 'Gene', (13, 19))	('duplication', 'Var', (20, 31))	('fitness advantage', 'Disease', (85, 102))
55781	33986496	The specific inherited variants associated with mCAs and the spectrum of mCAs themselves may differ significantly across populations.	('mCAs', 'Gene', (48, 52))	('mCAs', 'Gene', (73, 77))	('mCAs', 'Gene', '12927', (48, 52))	('mCAs', 'Gene', '12927', (73, 77))	('associated', 'Reg', (32, 42))	('variants', 'Var', (23, 31))
55784	33986496	For example, the incidences of chromosome 12 gain, 13q loss and 13q CN-LOH are between twofold to sixfold less in the BBJ cohort; these mCAs are often seen in chronic lymphocytic leukaemia, a malignancy that is four to five times more common among Europeans than among Japanese individuals.	('chromosome', 'Var', (31, 41))	('loss', 'NegReg', (55, 59))	('13q', 'Gene', (51, 54))	('lymphocytic leukaemia', 'Disease', (167, 188))	('gain', 'PosReg', (45, 49))	('malignancy', 'Disease', (192, 202))	('lymphocytic leukaemia', 'Disease', 'MESH:D007945', (167, 188))	('less', 'NegReg', (106, 110))	('13q', 'Gene', (64, 67))	('mCAs', 'Gene', (136, 140))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (159, 188))	('malignancy', 'Disease', 'MESH:D009369', (192, 202))	('mCAs', 'Gene', '12927', (136, 140))
55785	33986496	Mirroring one of the main signals found with JAK2, one study using the deCODE cohort from Iceland found that variation in the TERT locus (lead SNP rs34002450) was associated with CH (OR = 1.37, minor allele frequency (MAF) = 0.41) as defined by an outlier status on WGS.	('variation', 'Var', (109, 118))	('TERT', 'Gene', (126, 130))	('JAK2', 'Gene', '3717', (45, 49))	('TERT', 'Gene', '7015', (126, 130))	('JAK2', 'Gene', (45, 49))	('rs34002450', 'Mutation', 'rs34002450', (147, 157))	('rs34002450', 'Var', (147, 157))
55787	33986496	An analysis of the NHLBI Trans-Omics for Precision Medicine (TOPMed) cohort in the USA recapitulated the association between rs34002450 and CHIP (OR = 1.3), although this study identified a different lead SNP (rs7705526; MAF = 0.29; r2 = 0.55 with rs34002450) as well as a second SNP in TERT that was independently associated with CHIP (rs13167280; OR = 1.3; MAF = 0.11; r2 = 0.2 with rs7705526).	('rs7705526', 'Mutation', 'rs7705526', (210, 219))	('TERT', 'Gene', (287, 291))	('rs34002450', 'Var', (125, 135))	('rs34002450', 'Var', (248, 258))	('rs7705526;', 'Var', (210, 220))	('TERT', 'Gene', '7015', (287, 291))	('rs7705526', 'Var', (385, 394))	('rs13167280;', 'Var', (337, 348))	('rs13167280', 'Mutation', 'rs13167280', (337, 347))	('rs7705526', 'Mutation', 'rs7705526', (385, 394))	('rs34002450', 'Mutation', 'rs34002450', (125, 135))	('rs34002450', 'Mutation', 'rs34002450', (248, 258))
55788	33986496	Additionally, an analysis of the UKB similarly identified associations with CHIP for an SNP in linkage disequilibrium with rs34002450 (rs7726159; OR = 1.33; MAF = 0.33; r2 = 0.70 with rs34002450) and for a second independent SNP in TERT (rs2853677; OR = 1.32; MAF = 0.42).	('rs2853677;', 'Var', (238, 248))	('TERT', 'Gene', (232, 236))	('rs34002450', 'Var', (184, 194))	('age', 'Gene', (99, 102))	('associations', 'Interaction', (58, 70))	('rs34002450', 'Mutation', 'rs34002450', (184, 194))	('TERT', 'Gene', '7015', (232, 236))	('age', 'Gene', '5973', (99, 102))	('rs34002450', 'Mutation', 'rs34002450', (123, 133))	('rs34002450 (rs7726159', 'Var', (123, 144))	('rs7726159', 'Mutation', 'rs7726159', (135, 144))	('rs2853677', 'Mutation', 'rs2853677', (238, 247))	('rs7726159;', 'Var', (135, 145))
55789	33986496	One variant (rs1210060191) is quite common (risk allele frequency = 0.54) and lies in the intronic region of TRIM59 but has a relatively weaker association with CHIP (OR = 1.16) than the TERT SNPs.	('TRIM59', 'Gene', '286827', (109, 115))	('rs1210060191', 'Mutation', 'rs1210060191', (13, 25))	('TERT', 'Gene', (187, 191))	('TRIM59', 'Gene', (109, 115))	('rs1210060191', 'Var', (13, 25))	('TERT', 'Gene', '7015', (187, 191))
55790	33986496	The second is a variant in an intergenic region near TET2 (rs144418061), which is specific to individuals with African ancestry (MAF = 0.035 in African ancestry, not present in samples without African ancestry), that is strongly associated with CHIP (OR = 2.4).	('CHIP', 'Disease', (245, 249))	('rs144418061', 'Var', (59, 70))	('rs144418061', 'Mutation', 'rs144418061', (59, 70))	('TET2', 'Gene', (53, 57))	('associated', 'Reg', (229, 239))
55791	33986496	A subsequent variant-to-function analysis of this second locus revealed a variant (rs79901204) that is predicted to disrupt a GATA/E-box in an enhancer element.	('men', 'Species', '9606', (155, 158))	('rs79901204', 'Mutation', 'rs79901204', (83, 93))	('GATA/E-box', 'Gene', (126, 136))	('rs79901204', 'Var', (83, 93))	('disrupt', 'NegReg', (116, 123))
55792	33986496	The risk allele for this variant indeed reduced luciferase activation fourfold in an in vitro experiment and had a dose-dependent association with decreased TET2 gene expression in whole-blood samples from patients.	('men', 'Species', '9606', (100, 103))	('TET2 gene', 'Gene', (157, 166))	('decreased', 'NegReg', (147, 156))	('activation', 'MPA', (59, 69))	('reduced', 'NegReg', (40, 47))	('luciferase', 'Enzyme', (48, 58))	('patients', 'Species', '9606', (206, 214))	('variant', 'Var', (25, 32))	('expression', 'MPA', (167, 177))
55793	33986496	Increased rates of cell division may increase DNA replication strain and increase the likelihood of acquiring a lesion in a CHIP gene in the first place and/or the germline TET2 SNP might have a synergistic cooperativity with any subsequent incidental CHIP mutations to increase the relative fitness of the HSC.	('mutations', 'Var', (257, 266))	('increase', 'PosReg', (73, 81))	('cell division', 'CPA', (19, 32))	('fitness', 'Disease', 'MESH:D012640', (292, 299))	('increase', 'PosReg', (270, 278))	('increase', 'PosReg', (37, 45))	('fitness', 'Disease', (292, 299))	('lesion', 'Var', (112, 118))	('DNA replication strain', 'MPA', (46, 68))	('HSC', 'Gene', (307, 310))	('HSC', 'Gene', '2523', (307, 310))
55795	33986496	Although there were no significant associations with TET2, there was a significant association for DNMT3A with variant rs2887399 (OR = 1.23; MAF = 0.23).	('rs2887399', 'Mutation', 'rs2887399', (119, 128))	('DNMT3A', 'Gene', (99, 105))	('variant rs2887399', 'Var', (111, 128))	('DNMT3A', 'Gene', '1788', (99, 105))
55799	33986496	In addition to the associations with MPNs described above, many of the inherited risk variants for CH also predispose to haematological and non-haematological cancers.	('predispose', 'Reg', (107, 117))	('haematological cancer', 'Phenotype', 'HP:0004377', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('haematological cancers', 'Disease', 'MESH:D009369', (144, 166))	('variants', 'Var', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('haematological cancers', 'Disease', (144, 166))	('MPNs', 'Phenotype', 'HP:0005547', (37, 41))
55801	33986496	Inherited putative loss-of-function variants in CHEK2 (refs) and TP53 (refs) have long been known to be a cause of autosomal dominant familial cancer syndromes, while mutations in NBN (causing the autosomal recessive Nijmegen Breakage Syndrome) and MRE11 (refs) confer an increased susceptibility to the development of a malignancy.	('TP53', 'Gene', '7157', (65, 69))	('mutations', 'Var', (167, 176))	('autosomal recessive Nijmegen Breakage Syndrome', 'Disease', (197, 243))	('men', 'Species', '9606', (311, 314))	('loss-of-function', 'NegReg', (19, 35))	('NBN', 'Gene', '4683', (180, 183))	('MRE11', 'Gene', (249, 254))	('malignancy', 'Disease', 'MESH:D009369', (321, 331))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('autosomal dominant familial cancer syndromes', 'Disease', (115, 159))	('TP53', 'Gene', (65, 69))	('CHEK2', 'Gene', (48, 53))	('MRE11', 'Gene', '4361', (249, 254))	('NBN', 'Gene', (180, 183))	('malignancy', 'Disease', (321, 331))	('CHEK2', 'Gene', '11200', (48, 53))	('autosomal recessive Nijmegen Breakage Syndrome', 'Disease', 'MESH:D049932', (197, 243))	('variants', 'Var', (36, 44))	('autosomal dominant familial cancer syndromes', 'Disease', 'MESH:D009369', (115, 159))
55802	33986496	Similarly, mutations in ATM, the aetiological agent of the autosomal recessive ataxia telangiectasia syndrome, are associated with an increased risk of numerous types of cancer, including leukaemia and lymphoma, breast cancer, and prostate cancer, among many others.	('mutations', 'Var', (11, 20))	('ATM', 'Gene', '472', (24, 27))	('cancer', 'Disease', (170, 176))	('autosomal recessive ataxia telangiectasia syndrome', 'Disease', 'MESH:D001260', (59, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (240, 246))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('breast cancer', 'Disease', (212, 225))	('age', 'Gene', '5973', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('prostate cancer', 'Disease', 'MESH:D011471', (231, 246))	('ATM', 'Gene', (24, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (231, 246))	('telangiectasia', 'Phenotype', 'HP:0001009', (86, 100))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('prostate cancer', 'Disease', (231, 246))	('leukaemia and lymphoma', 'Disease', 'MESH:D008223', (188, 210))	('associated', 'Reg', (115, 125))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('ataxia', 'Phenotype', 'HP:0001251', (79, 85))	('autosomal recessive ataxia telangiectasia syndrome', 'Disease', (59, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('age', 'Gene', (46, 49))
55803	33986496	Germline mutations in NPAT (nuclear protein, ataxia telangiectasia locus), whose gene product has been implicated in the transcriptional regulation of histone genes as well as ATM, has been reported as a risk factor for Hodgkin lymphoma.	('Germline mutations', 'Var', (0, 18))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (45, 66))	('NPAT', 'Gene', (22, 26))	('Hodgkin lymphoma', 'Disease', (220, 236))	('ataxia', 'Phenotype', 'HP:0001251', (45, 51))	('risk factor', 'Reg', (204, 215))	('ataxia telangiectasia', 'Disease', (45, 66))	('ATM', 'Gene', '472', (176, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (228, 236))	('reported', 'Reg', (190, 198))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (220, 236))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (220, 236))	('NPAT', 'Gene', '4863', (22, 26))	('telangiectasia', 'Phenotype', 'HP:0001009', (52, 66))	('ATM', 'Gene', (176, 179))
55804	33986496	The most plausible mechanism of action for the contribution of these inherited variants is similar to their role in cancer : establishing a cellular context that is permissive of DNA mutation : rather than the direct effects on clonal proliferation.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('variants', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
55805	33986496	By contrast, other inherited variants may directly influence proliferation or augment the rapidity of proliferation by later CH mutations.	('augment', 'NegReg', (78, 85))	('mutations', 'Var', (128, 137))	('rapidity', 'MPA', (90, 98))	('variants', 'Var', (29, 37))	('men', 'Species', '9606', (81, 84))	('influence', 'Reg', (51, 60))	('proliferation', 'CPA', (61, 74))
55806	33986496	Mutation or experimental deletion of TET2, which is often mutated in familial myeloid and lymphoid malignancies, leads to increased HSC proliferation and secretion of pro-inflammatory cytokines.	('men', 'Species', '9606', (18, 21))	('secretion of pro-inflammatory cytokines', 'MPA', (154, 193))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (90, 111))	('Mutation', 'Var', (0, 8))	('increased HSC', 'Phenotype', 'HP:0001899', (122, 135))	('deletion', 'Var', (25, 33))	('familial myeloid and lymphoid malignancies', 'Disease', 'MESH:D008223', (69, 111))	('TET2', 'Gene', (37, 41))	('increased', 'PosReg', (122, 131))	('HSC', 'Gene', (132, 135))	('HSC', 'Gene', '2523', (132, 135))
55807	33986496	Lastly, variants in SH2B3, a negative regulator of the pro-proliferative JAK-STAT signalling pathway in haematopoietic cells, are associated with malignancies, including in the blood, breast, lung and colon.	('JAK', 'Gene', (73, 76))	('breast', 'Disease', (184, 190))	('variants', 'Var', (8, 16))	('malignancies', 'Disease', 'MESH:D009369', (146, 158))	('SH2B3', 'Gene', '10019', (20, 25))	('lung', 'Disease', (192, 196))	('SH2B3', 'Gene', (20, 25))	('malignancies', 'Disease', (146, 158))	('colon', 'Disease', (201, 206))	('associated with', 'Reg', (130, 145))	('JAK', 'Gene', '3717;16452', (73, 76))
55809	33986496	Early epidemiological and functional studies of CHIP identified strong links between CHIP mutations and CVD, raising the question of whether these entities exhibit shared germline predispositions.	('CHIP', 'Gene', (85, 89))	('CVD', 'Phenotype', 'HP:0001626', (104, 107))	('mutations', 'Var', (90, 99))	('CVD', 'Disease', 'MESH:D002318', (104, 107))	('links', 'Interaction', (71, 76))	('CVD', 'Disease', (104, 107))
55810	33986496	In addition to the risk of a haematological malignancy, germline TET2 mutations have also been associated with pulmonary arterial hypertension, which is a lethal vasculopathy.	('TET2', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (111, 142))	('haematological malignancy', 'Disease', 'MESH:D019337', (29, 54))	('hypertension', 'Phenotype', 'HP:0000822', (130, 142))	('vasculopathy', 'Disease', 'MESH:D020144', (162, 174))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (111, 142))	('pulmonary arterial hypertension', 'Disease', (111, 142))	('vasculopathy', 'Disease', (162, 174))	('associated with', 'Reg', (95, 110))	('haematological malignancy', 'Disease', (29, 54))
55811	33986496	In contrast to the role of this epigenetic regulator in tumorigenesis, which is thought to rest on increased HSPC self-renewal, lineage skewing and an increased tendency towards mutation, the contribution of mutant TET2 to pulmonary arterial hypertension may stem from overproduction of inflammatory cytokines (for example, IL-1beta) in differentiated immune cells.	('IL-1beta', 'Gene', (324, 332))	('hypertension', 'Phenotype', 'HP:0000822', (242, 254))	('age', 'Gene', '5973', (132, 135))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (223, 254))	('mutant', 'Var', (208, 214))	('overproduction', 'PosReg', (269, 283))	('TET2', 'Gene', (215, 219))	('pulmonary arterial hypertension', 'Disease', (223, 254))	('HSPC', 'Gene', '5688', (109, 113))	('age', 'Gene', (132, 135))	('HSPC', 'Gene', (109, 113))	('IL-1beta', 'Gene', '3552', (324, 332))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (223, 254))
55812	33986496	Meanwhile, genetic variation in the gene SH2B3 has been linked to numerous aspects of cardiovascular dysfunction, including hypertension, aortic dissection, atherosclerosis and stroke.	('genetic variation', 'Var', (11, 28))	('SH2B3', 'Gene', (41, 46))	('linked', 'Reg', (56, 62))	('stroke', 'Disease', 'MESH:D020521', (177, 183))	('aortic dissection', 'Phenotype', 'HP:0002647', (138, 155))	('atherosclerosis', 'Phenotype', 'HP:0002621', (157, 172))	('hypertension', 'Disease', 'MESH:D006973', (124, 136))	('cardiovascular dysfunction', 'Disease', (86, 112))	('atherosclerosis', 'Disease', 'MESH:D050197', (157, 172))	('cardiovascular dysfunction', 'Disease', 'MESH:D002318', (86, 112))	('aortic dissection', 'Disease', (138, 155))	('hypertension', 'Disease', (124, 136))	('stroke', 'Phenotype', 'HP:0001297', (177, 183))	('hypertension', 'Phenotype', 'HP:0000822', (124, 136))	('atherosclerosis', 'Disease', (157, 172))	('cardiovascular dysfunction', 'Phenotype', 'HP:0001626', (86, 112))	('SH2B3', 'Gene', '10019', (41, 46))	('stroke', 'Disease', (177, 183))
55813	33986496	However, for at least one well-studied variant, there appears to be a trade-off between CVD risk and cancer risk: the C allele of rs3184504, which encodes SH2B3 p.R262W, is associated with a reduced risk of CVD (OR = 0.95) but a heightened risk of cancer (OR = 1.03).	('cancer', 'Disease', (248, 254))	('CVD', 'Disease', (207, 210))	('CVD', 'Disease', (88, 91))	('SH2B3', 'Gene', '10019', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('p.R262W', 'Mutation', 'rs3184504', (161, 168))	('CVD', 'Phenotype', 'HP:0001626', (207, 210))	('SH2B3', 'Gene', (155, 160))	('rs3184504', 'Var', (130, 139))	('CVD', 'Disease', 'MESH:D002318', (88, 91))	('CVD', 'Disease', 'MESH:D002318', (207, 210))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('CVD', 'Phenotype', 'HP:0001626', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs3184504', 'Mutation', 'rs3184504', (130, 139))	('p.R262W', 'Var', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (248, 254))
55817	33986496	However, even though CH is strongly associated with ageing, the germline variation in telomere genes that predisposes to CH tends to associate with longer telomeres not shorter.	('age', 'Gene', '5973', (52, 55))	('germline variation', 'Var', (64, 82))	('telomere genes', 'Gene', (86, 100))	('associate', 'Reg', (133, 142))	('longer', 'PosReg', (148, 154))	('age', 'Gene', (52, 55))
55818	33986496	The TERT intron 2 SNPs rs7705526 (ref.)	('rs7705526', 'Var', (23, 32))	('TERT', 'Gene', (4, 8))	('TERT', 'Gene', '7015', (4, 8))	('rs7705526', 'Mutation', 'rs7705526', (23, 32))
55824	33986496	The rate of epigenetic ageing has a heritable component, including variation at loci associated with CH risk: TERT, TET2, TRIM59 and KPNA4 (ref.).	('age', 'Gene', (23, 26))	('KPNA4', 'Gene', (133, 138))	('age', 'Gene', '5973', (23, 26))	('KPNA4', 'Gene', '3840', (133, 138))	('TERT', 'Gene', (110, 114))	('TRIM59', 'Gene', '286827', (122, 128))	('TERT', 'Gene', '7015', (110, 114))	('TRIM59', 'Gene', (122, 128))	('variation', 'Var', (67, 76))
55825	33986496	Paradoxically, faster epigenetic ageing is linked to TERT variants associated with longer telomeres, matching the directionality of the CH risk variants at this locus.	('age', 'Gene', (33, 36))	('TERT', 'Gene', (53, 57))	('epigenetic', 'MPA', (22, 32))	('TERT', 'Gene', '7015', (53, 57))	('variants', 'Var', (58, 66))	('age', 'Gene', '5973', (33, 36))	('faster', 'PosReg', (15, 21))
55826	33986496	It is also worth noting that several of the genes that are most often affected by somatic CHIP mutations are epigenetic regulators whose (impaired) performance could plausibly shape an individual's rate of epigenetic ageing.	('age', 'Gene', '5973', (217, 220))	('shape', 'Reg', (176, 181))	('age', 'Gene', (217, 220))	('mutations', 'Var', (95, 104))
55828	33986496	Less common CHIP mutations in IDH1 and IDH2 lead to the production of the metabolite 2-hydroxyglutarate, which interferes with the function of TET2 (ref.).	('lead to', 'Reg', (44, 51))	('IDH2', 'Gene', (39, 43))	('interferes', 'NegReg', (111, 121))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', '3418', (39, 43))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (85, 103))	('function', 'MPA', (131, 139))	('mutations', 'Var', (17, 26))	('IDH1', 'Gene', '3417', (30, 34))	('production of the metabolite 2-hydroxyglutarate', 'MPA', (56, 103))
55829	33986496	Additionally, interestingly, many of the CpG sites used in the Horvath epigenetic clock are near target genes of Polycomb repressive complex 2 (PRC2), a protein complex whose function is impaired by CHIP mutations in ASXL1 (ref.).	('PRC2', 'Gene', (144, 148))	('function', 'MPA', (175, 183))	('mutations', 'Var', (204, 213))	('ASXL1', 'Gene', '171023', (217, 222))	('ASXL1', 'Gene', (217, 222))	('impaired', 'NegReg', (187, 195))
55830	33986496	Yet, the extent to which CHIP, or CH more broadly, might cause alterations in epigenetic ageing remains to be determined.	('age', 'Gene', '5973', (89, 92))	('age', 'Gene', (89, 92))	('cause alterations', 'Reg', (57, 74))	('CHIP', 'Var', (25, 29))
55846	33986496	Moving forward, we expect studies in this field to focus not just on how inherited variation influences the risk of somatic mutations but also on how inherited variation interacts with these acquired mutations to influence disease phenotypes and biological ageing.	('age', 'Gene', (257, 260))	('variation', 'Var', (83, 92))	('somatic mutations', 'Disease', (116, 133))	('influence', 'Reg', (213, 222))	('influences', 'Reg', (93, 103))	('age', 'Gene', '5973', (257, 260))	('interacts', 'Interaction', (170, 179))
55848	33986496	Recent work has identified an inherited polymorphism in the IL-6 receptor that reduces the likelihood of heart disease in individuals with CHIP; however, the full extent to which germline factors mitigate or contribute to disease manifestations in individuals with CHIP is still to be explored.	('heart disease', 'Disease', 'MESH:D006331', (105, 118))	('IL-6', 'Gene', (60, 64))	('IL-6', 'Gene', '16193', (60, 64))	('reduces', 'NegReg', (79, 86))	('polymorphism', 'Var', (40, 52))	('heart disease', 'Disease', (105, 118))
55859	33986496	A clinical term for a type of clonal haematopoiesis defined by single-nucleotide variants or small insertions/deletions (indels) in genes associated with myeloid malignancies in the presence of normal blood counts and at >=2% variant allele fraction.	('single-nucleotide variants', 'Var', (63, 89))	('myeloid malignancies', 'Disease', (154, 174))	('myeloid malignancies', 'Disease', 'MESH:D009369', (154, 174))
55860	33986496	The percentage of measured DNA alleles that contain a specified variant.	('age', 'Gene', (11, 14))	('age', 'Gene', '5973', (11, 14))	('variant', 'Var', (64, 71))
55893	31572301	Further investigation is needed to elucidate if a functional abrogation of PTTG1 might be used in order to offer new therapeutic approaches in the clinical workout of seminoma.	('PTTG1', 'Gene', (75, 80))	('PTTG1', 'Gene', '9232', (75, 80))	('abrogation', 'Var', (61, 71))	('seminoma', 'Disease', (167, 175))	('seminoma', 'Disease', 'MESH:D018239', (167, 175))
55942	31572301	Moreover, high expression of PTTG1 is associated with greatly aggressive tumor and with the onset of metastasis.	('PTTG1', 'Gene', (29, 34))	('PTTG1', 'Gene', '9232', (29, 34))	('associated', 'Reg', (38, 48))	('aggressive tumor', 'Disease', 'MESH:D001523', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('high', 'Var', (10, 14))	('aggressive tumor', 'Disease', (62, 78))
55945	31572301	demonstrated that the co-expression of PTTG1 and MMP9 is associated with tumor cell migration and proliferation.	('PTTG1', 'Gene', '9232', (39, 44))	('co-expression', 'Var', (22, 35))	('PTTG1', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MMP9', 'Gene', (49, 53))	('MMP9', 'Gene', '4318', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('proliferation', 'CPA', (98, 111))	('associated', 'Reg', (57, 67))
55965	31572301	Further investigation are needed to extend the number of clinical cases investigated, to analyze the co-localization of PTTG1 with MMP2, MMP9, VEGF and to clarify if a functional abrogation of PTTG1 might represent a novel therapeutic approaches in the clinical management of seminoma.	('MMP2', 'Gene', '4313', (131, 135))	('seminoma', 'Disease', (276, 284))	('PTTG1', 'Gene', '9232', (193, 198))	('VEGF', 'Gene', '7422', (143, 147))	('PTTG1', 'Gene', (193, 198))	('PTTG1', 'Gene', (120, 125))	('men', 'Species', '9606', (268, 271))	('PTTG1', 'Gene', '9232', (120, 125))	('VEGF', 'Gene', (143, 147))	('seminoma', 'Disease', 'MESH:D018239', (276, 284))	('abrogation', 'Var', (179, 189))	('MMP9', 'Gene', (137, 141))	('MMP2', 'Gene', (131, 135))	('MMP9', 'Gene', '4318', (137, 141))
55980	24586194	Hybrids with some alleles of Prdm9 from domesticus show pachytene arrest of meiosis.	('arrest of meiosis', 'Disease', (66, 83))	('arrest of meiosis', 'Disease', 'MESH:D006323', (66, 83))	('alleles', 'Var', (18, 25))	('Prdm9', 'Gene', (29, 34))
55982	24586194	We measured levels of misexpression in F1 and F2 hybrids to identify major alterations in gene expression pattern associated with sterility in M. m. domesticus (WSB/EiJ; hereafter domesticus WSB) - M. m. musculus (PWD/PhJ; hereafter musculus PWD) hybrids.	('m. musculus', 'Species', '10090', (201, 212))	('sterility', 'Disease', (130, 139))	('gene expression pattern', 'MPA', (90, 113))	('alterations', 'Reg', (75, 86))	('hybrids', 'Var', (247, 254))	('m. domesticus', 'Species', '10092', (146, 159))
55984	24586194	By contrast, all traits in DxM F1s (except seminiferous tubule area) were within the range observed in the parental lines.	('DxM', 'Var', (27, 30))	('seminiferous tubule area', 'CPA', (43, 67))	('DxM', 'Chemical', '-', (27, 30))
56003	24586194	Mouse models with mutations in MSCI genes show meiotic arrest during the pachytene stage.	('meiotic arrest', 'Disease', (47, 61))	('meiotic arrest', 'Disease', 'MESH:D006323', (47, 61))	('Mouse', 'Species', '10090', (0, 5))	('MSCI genes', 'Gene', (31, 41))	('mutations', 'Var', (18, 27))
56005	24586194	Prdm9 heterozygosity and a musculus X were necessary but not sufficient for the full meiotic arrest phenotype.	('meiotic arrest', 'Disease', 'MESH:D006323', (85, 99))	('heterozygosity', 'Var', (6, 20))	('meiotic arrest', 'Disease', (85, 99))	('Prdm9', 'Gene', (0, 5))
56008	24586194	Disruptions in postmeiotic sex chromosome repression (PSCR) have also been associated with male sterility in mice.	('associated', 'Reg', (75, 85))	('Disruptions', 'Var', (0, 11))	('male sterility', 'Disease', (91, 105))	('mice', 'Species', '10090', (109, 113))
56009	24586194	Expansion and increased copy number variation of some of these genes was observed in mice from a natural hybrid zone, suggesting unequal recombination in hybrids might exacerbate effects of copy-number imbalance on PSCR.	('mice', 'Species', '10090', (85, 89))	('exacerbate', 'PosReg', (168, 178))	('effects', 'MPA', (179, 186))	('unequal', 'Var', (129, 136))	('PSCR', 'Disease', (215, 219))	('hybrids', 'Var', (154, 161))	('copy-number imbalance', 'MPA', (190, 211))	('copy number variation', 'MPA', (24, 45))	('imbalance', 'Phenotype', 'HP:0002172', (202, 211))
56014	24586194	Lmna (lamin A) knockouts have severely impaired spermatogenesis associated with failed chromosomal synapsis.	('knockouts', 'Var', (15, 24))	('impaired', 'NegReg', (39, 47))	('lamin A', 'Gene', (6, 13))	('spermatogenesis', 'CPA', (48, 63))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (39, 63))	('Lmna', 'Gene', (0, 4))	('lamin A', 'Gene', '16905', (6, 13))	('Lmna', 'Gene', '16905', (0, 4))
56016	24586194	Males with hypomorphic Rad51c alleles are infertile due to arrest of spermatogenesis in early meiotic prophase I related to failed double-strand break repair by recombination.	('failed', 'NegReg', (124, 130))	('infertile', 'Disease', 'MESH:D007247', (42, 51))	('Rad51c', 'Gene', (23, 29))	('double-strand break repair', 'MPA', (131, 157))	('infertile', 'Disease', (42, 51))	('spermatogenesis', 'CPA', (69, 84))	('arrest', 'Disease', (59, 65))	('Rad51c', 'Gene', '114714', (23, 29))	('arrest of spermatogenesis', 'Phenotype', 'HP:0031038', (59, 84))	('hypomorphic', 'Var', (11, 22))	('alleles', 'Var', (30, 37))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
56018	24586194	Males carrying null alleles at Dnmt3l show phenotypes similar to those documented in F1s associated with the X-17 interaction, including hypogonadism, asynapsis during meiosis, abnormal formation of the sex body, and deregulation of X-linked and autosomal genes.	('deregulation', 'Var', (217, 229))	('autosomal genes', 'Gene', (246, 261))	('Dnmt3l', 'Gene', '54427', (31, 37))	('asynapsis', 'Disease', (151, 160))	('X-linked', 'Gene', (233, 241))	('hypogonadism', 'Disease', 'MESH:D007006', (137, 149))	('hypogonadism', 'Phenotype', 'HP:0000135', (137, 149))	('hypogonadism', 'Disease', (137, 149))	('sex body', 'Phenotype', 'HP:0030214', (203, 211))	('Dnmt3l', 'Gene', (31, 37))
56020	24586194	Misexpression of Dnmt3a was reported previously in sterile F1 hybrids.	('Dnmt3a', 'Gene', '13435', (17, 23))	('Dnmt3a', 'Gene', (17, 23))	('Misexpression', 'Var', (0, 13))
56093	22211005	By the actuarial assumption, the adjusted number of person-years at risk is   and the number of cancer deaths in Ij follows a binomial distribution, i.e., dxj ~ Bin(rxj, lambdaj(x)).	('dxj', 'Var', (155, 158))	('cancer deaths', 'Disease', 'MESH:D003643', (96, 109))	('dxj', 'Chemical', '-', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer deaths', 'Disease', (96, 109))	('person', 'Species', '9606', (52, 58))
56111	22211005	Since the fit of the JPSM's are nested within the permutations, the computing time for fitting a PTB survival model is therefore from (1000x75)=75,000 to (5000x75)=375,000 times longer than for an analogous incidence or mortality model.	('PTB', 'Chemical', '-', (97, 100))	('5000x75)=375,000', 'Var', (155, 171))	('1000x75)=75,000', 'Var', (135, 150))
56129	22211005	Notice that the population of patients with (c = 0, mu = 60) or (c = 0.7, mu = 10) have the best chance of survival and can live for a longer time, thus leaving not much room for the improvement in survival.	('c = 0', 'Var', (45, 50))	('patients', 'Species', '9606', (30, 38))	('c = 0.7', 'Var', (65, 72))	('men', 'Species', '9606', (190, 193))
56137	22211005	For example, if APC=-20%, then the referent death rate lambdaj(x) = 50% induces an absolute reduction of 10% in death rates, while the lambdaj(x) = 10% only leads to a 2% decrease in death rates.	('APC=', 'Gene', (16, 20))	('death rates', 'MPA', (112, 123))	('reduction', 'NegReg', (92, 101))	('lambdaj', 'Var', (55, 62))	('APC=', 'Gene', '324', (16, 20))
56147	22211005	Because the results for n = 1000 or 5000 for Case 2 are similar, so is that for n = 1000 or 500 for Case 8, we conducted new simulations using the PTB procedure for n = 1000, 500 for Case 2 and for n = 5000, 1000 for Case 8.	('n = 5000', 'Var', (198, 206))	('n = 1000', 'Var', (165, 173))	('PTB', 'Chemical', '-', (147, 150))
56221	21170301	Histone Deacetylases Suppress CGG Repeat-Induced Neurodegeneration Via Transcriptional Silencing in Models of Fragile X Tremor Ataxia Syndrome Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS) gene, FMR1.	('Tremor', 'Phenotype', 'HP:0001337', (120, 126))	('Neurodegeneration Via Transcriptional Silencing', 'Disease', 'MESH:D019636', (49, 96))	('caused by', 'Reg', (233, 242))	('Fragile X Tremor Ataxia Syndrome', 'Disease', 'MESH:C564105', (143, 175))	('Ataxia', 'Phenotype', 'HP:0001251', (160, 166))	('Fragile X Tremor Ataxia Syndrome', 'Disease', 'MESH:C564105', (110, 142))	('inherited neurodegenerative disorder', 'Disease', (196, 232))	('FMR1', 'Gene', (334, 338))	('Ataxia', 'Phenotype', 'HP:0001251', (127, 133))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (206, 232))	('fragile X syndrome', 'Disease', 'MESH:D005600', (303, 321))	('Neurodegeneration Via Transcriptional Silencing', 'Disease', (49, 96))	('Suppress', 'NegReg', (21, 29))	('expansion', 'Var', (243, 252))	('FXS', 'Disease', (323, 326))	('Fragile X Tremor Ataxia Syndrome', 'Disease', (143, 175))	('FXS', 'Disease', 'MESH:D005600', (323, 326))	('Tremor', 'Phenotype', 'HP:0001337', (153, 159))	('Fragile X Tremor Ataxia Syndrome', 'Disease', (110, 142))	('inherited neurodegenerative disorder', 'Disease', 'MESH:D019636', (196, 232))	('fragile X syndrome', 'Disease', (303, 321))	('Neurodegeneration', 'Phenotype', 'HP:0002180', (49, 66))
56222	21170301	The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased.	('mRNA levels for', 'MPA', (84, 99))	('toxicity', 'Disease', 'MESH:D064420', (45, 53))	('toxicity', 'Disease', (45, 53))	('patients', 'Species', '9606', (75, 83))	('CGG', 'Gene', (13, 16))	('increased', 'PosReg', (118, 127))	('expanded', 'Var', (4, 12))
56225	21170301	In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines.	('FXS', 'Disease', (210, 213))	('histones', 'Protein', (135, 143))	('FXS', 'Disease', 'MESH:D005600', (210, 213))	('increased', 'PosReg', (110, 119))	('patient', 'Species', '9606', (3, 10))	('FMR1', 'Gene', (151, 155))	('acetylation', 'MPA', (120, 131))	('pre-mutation', 'Var', (165, 177))
56234	21170301	Expansion to greater than 200 CGGs leads to transcriptional silencing of FMR1, causing Fragile X Syndrome, a common inherited cause of mental retardation.	('mental retardation', 'Disease', (135, 153))	('mental retardation', 'Phenotype', 'HP:0001249', (135, 153))	('Fragile X Syndrome', 'Disease', (87, 105))	('mental retardation', 'Disease', 'MESH:D008607', (135, 153))	('causing', 'Reg', (79, 86))	('transcriptional', 'MPA', (44, 59))	('Fragile X Syndrome', 'Disease', 'MESH:D005600', (87, 105))	('FMR1', 'Gene', (73, 77))	('Expansion', 'Var', (0, 9))
56240	21170301	Evidence against this mechanism includes normal FMR1 mRNA levels in a patient with a deleterious point mutation in FMRP and in patients with very large unmethylated CGG repeats who translate little or no protein.	('FMRP', 'Gene', (115, 119))	('FMR1 mRNA levels', 'MPA', (48, 64))	('patient', 'Species', '9606', (127, 134))	('patient', 'Species', '9606', (70, 77))	('patients', 'Species', '9606', (127, 135))	('point mutation', 'Var', (97, 111))	('FMRP', 'Gene', '2332', (115, 119))
56242	21170301	Our results provide evidence both that the expanded CGG repeat enhances its own transcription in cis via alterations in local chromatin structure and that this transcriptional augmentation may be pharmacologically modifiable.	('men', 'Species', '9606', (179, 182))	('CGG', 'Protein', (52, 55))	('transcription', 'MPA', (80, 93))	('alterations', 'Reg', (105, 116))	('enhances', 'PosReg', (63, 71))	('expanded', 'Var', (43, 51))	('local chromatin structure', 'MPA', (120, 145))
56245	21170301	In lines expressing the transgene at higher levels, the rough eye is more severe, with loss of normal oomatidia formation and frank necrosis, especially when flies are reared at higher temperatures (Figure 1B versus Figure 1A, 1E).	('rough eye', 'Disease', (56, 65))	('loss of normal oomatidia', 'Disease', 'MESH:C537354', (87, 111))	('necrosis', 'Disease', (132, 140))	('transgene', 'Var', (24, 33))	('loss of normal oomatidia', 'Disease', (87, 111))	('necrosis', 'Disease', 'MESH:D009336', (132, 140))
56251	21170301	Most relevant to the current study, overexpression of dHDAC6 can rescue polyglutamine induced neurodegeneration in an autophagy-dependent manner in a Drosophila model.	('neurodegeneration', 'Phenotype', 'HP:0002180', (94, 111))	('overexpression', 'PosReg', (36, 50))	('polyglutamine', 'Chemical', 'MESH:C097188', (72, 85))	('Drosophila', 'Species', '7227', (150, 160))	('dHDAC6', 'Gene', (54, 60))	('neurodegeneration', 'Disease', (94, 111))	('neurodegeneration', 'Disease', 'MESH:D019636', (94, 111))	('dHDAC6', 'Gene', '32461', (54, 60))	('man', 'Species', '9606', (138, 141))	('polyglutamine', 'Var', (72, 85))
56254	21170301	Conversely, siRNA knockdown of dHDAC6 enhanced the CGG repeat induced phenotype (Figure 1F compared to Figure 1E and 1G, note that the black material on the eye in Figure 1F is eschar from necrosis).	('knockdown', 'Var', (18, 27))	('dHDAC6', 'Gene', '32461', (31, 37))	('necrosis', 'Disease', (189, 197))	('enhanced', 'PosReg', (38, 46))	('necrosis', 'Disease', 'MESH:D009336', (189, 197))	('CGG repeat induced phenotype', 'CPA', (51, 79))	('dHDAC6', 'Gene', (31, 37))
56269	21170301	Moreover, global HDAC inhibition or selective siRNA knockdown of HDAC3 or 6 does not alter expression of uas-HTT transgenes in a separate Drosophila model of polyglutamine disease.	('HDAC3', 'Gene', (65, 70))	('polyglutamine disease', 'Disease', (158, 179))	('polyglutamine disease', 'Disease', 'MESH:D030342', (158, 179))	('Drosophila', 'Species', '7227', (138, 148))	('knockdown', 'Var', (52, 61))
56273	21170301	Two of the pre-mutation lymphoblast cell lines (#C0051.004, (CGG)90, and #C014.004, (CGG)91, a kind gift from Stephanie Sherman) were derived from patients with clinically probable FXTAS.	('#C014.004', 'Var', (73, 82))	('FXTAS', 'Disease', (181, 186))	('patients', 'Species', '9606', (147, 155))	('man', 'Species', '9606', (124, 127))	('#C0051.004', 'Var', (48, 58))
56276	21170301	The increased association of acetylated histones at both histone H3K9 and histone H4 with the FMR1 locus correlated with CGG repeat length (Figure 4F and Figure S5A, S5B, S5C, S5D).	('S5D', 'Mutation', 'p.S5D', (176, 179))	('histone', 'Protein', (74, 81))	('association', 'Interaction', (14, 25))	('CGG repeat length', 'Var', (121, 138))	('FMR1', 'Gene', (94, 98))	('increased', 'PosReg', (4, 13))
56278	21170301	Although analysis of EBV-transformed lymphoblast cell lines has been a mainstay of research related to chromatin changes associated with Fragile X spectrum disorders, evidence suggests that epigenetic changes in these cell lines do not always reflect the chromatin state in the starting tissues.	('Fragile X spectrum disorders', 'Phenotype', 'HP:0000729', (137, 165))	('Fragile X spectrum disorders', 'Disease', (137, 165))	('epigenetic', 'Var', (190, 200))	('Fragile X spectrum disorders', 'Disease', 'MESH:D005600', (137, 165))
56309	21170301	In Drosophila transgenic for the CGG expansion and co-expressed a ubiquitous GeneSwitch driver (under the Tubulin promoter), there was very few fly deaths over 2 weeks in the absence of RU-486 (Figure 7A, no drug).	('transgenic', 'Var', (14, 24))	('Tubulin', 'Gene', '39130', (106, 113))	('Tubulin', 'Gene', (106, 113))	('Drosophila', 'Species', '7227', (3, 13))	('RU-486', 'Chemical', 'MESH:D015735', (186, 192))	('CGG expansion', 'Var', (33, 46))
56313	21170301	To test whether HAT inhibitors could extend the lifespan of adult uas-(CGG)90 eGFP flies triggered to express the transgene ubiquitously, 1-3 day-old adult animals were placed on food that contained either RU-486 +DMSO or RU-486+ increasing doses of Garcinol.	('DMSO', 'Chemical', 'MESH:D004121', (214, 218))	('Garcinol', 'Chemical', 'MESH:C054597', (250, 258))	('RU-486', 'Chemical', 'MESH:D015735', (206, 212))	('extend', 'PosReg', (37, 43))	('RU-486+', 'Var', (222, 229))	('lifespan', 'CPA', (48, 56))	('RU-486', 'Chemical', 'MESH:D015735', (222, 228))
56314	21170301	As shown in Figure 7B, for (CGG)90eGFP line 1, Garcinol led to a dose-dependent increase in survival that was statistically significant at the highest two doses (Garcinol 100 microM versus DMSO, Log Rank test, chi2 = 2.92, p = 0.08; Garcinol 200 microM versus DMSO, Log Rank test, chi2 = 16.89, p<0.0001; Garcinol 400 microM versus DMSO, chi2 = 10.98, p = 0.0003), with a 42% mean increase in lifespan on Garcinol 200 microM.	('Garcinol', 'Chemical', 'MESH:C054597', (162, 170))	('survival', 'CPA', (92, 100))	('lifespan', 'CPA', (393, 401))	('increase', 'PosReg', (80, 88))	('DMSO', 'Chemical', 'MESH:D004121', (332, 336))	('DMSO', 'Chemical', 'MESH:D004121', (260, 264))	('Garcinol', 'Var', (47, 55))	('Garcinol', 'Chemical', 'MESH:C054597', (305, 313))	('Garcinol', 'Chemical', 'MESH:C054597', (47, 55))	('Garcinol', 'Chemical', 'MESH:C054597', (405, 413))	('increase', 'PosReg', (381, 389))	('DMSO', 'Chemical', 'MESH:D004121', (189, 193))	('Garcinol', 'Chemical', 'MESH:C054597', (233, 241))
56323	21170301	First, because the CGG repeat expansion impairs translation of FMR1 mRNA into protein, the increase could result from a feedback loop driven by lower levels of the Fragile X Mental Retardation Protein, FMRP.	('CGG repeat expansion', 'Var', (19, 39))	('impairs', 'NegReg', (40, 47))	('Fragile X Mental Retardation Protein', 'Gene', (164, 200))	('lower', 'NegReg', (144, 149))	('Fragile X Mental Retardation Protein', 'Gene', '2332', (164, 200))	('FMR1', 'Gene', (63, 67))	('FMRP', 'Gene', '2332', (202, 206))	('Mental Retardation', 'Phenotype', 'HP:0001249', (174, 192))	('FMRP', 'Gene', (202, 206))	('translation', 'MPA', (48, 59))
56324	21170301	Consistent with a primary effect of the CGG expansion in cis on transcription, we observed increased (CGG)90-eGFP mRNA expression in two Drosophila lines compared to control eGFP mRNA expression with the same promoter and driver (Figure 3A).	('Drosophila', 'Species', '7227', (137, 147))	('expansion', 'Var', (44, 53))	('mRNA expression', 'MPA', (114, 129))	('increased', 'PosReg', (91, 100))
56325	21170301	Extensive work has characterized the regulation of basal and activity-dependent transcription of the FMR1 gene with a normal sized CGG repeat versus the fully expanded repeat of Fragile X Mental Retardation (FXS).	('Fragile X Mental Retardation', 'Disease', 'MESH:D005600', (178, 206))	('Fragile X Mental Retardation', 'Disease', (178, 206))	('FXS', 'Disease', (208, 211))	('Mental Retardation', 'Phenotype', 'HP:0001249', (188, 206))	('FMR1', 'Gene', (101, 105))	('FXS', 'Disease', 'MESH:D005600', (208, 211))	('CGG repeat', 'Var', (131, 141))
56327	21170301	This combination of hypermethylation and heterochromatin results in transcriptional silencing of the FMR1 gene and the symptoms of FXS.	('hypermethylation', 'Var', (20, 36))	('FMR1 gene', 'Gene', (101, 110))	('heterochromatin', 'Var', (41, 56))	('silencing', 'NegReg', (84, 93))	('FXS', 'Disease', (131, 134))	('FXS', 'Disease', 'MESH:D005600', (131, 134))	('transcriptional', 'MPA', (68, 83))
56329	21170301	Previous work has also characterized chromatin changes in fibroblasts and lymphoblasts derived from unmethylated full mutation(>200 CGG repeats) patients.	('patients', 'Species', '9606', (145, 153))	('chromatin', 'MPA', (37, 46))	('>200 CGG repeats', 'Var', (127, 143))
56334	21170301	Perhaps most convincing are data from a fragile X syndrome patient with a point mutation that encodes a nonfunctioning but stable FMRP.	('point mutation', 'Var', (74, 88))	('fragile X syndrome', 'Disease', (40, 58))	('fragile X syndrome', 'Disease', 'MESH:D005600', (40, 58))	('FMRP', 'Gene', '2332', (130, 134))	('patient', 'Species', '9606', (59, 66))	('FMRP', 'Gene', (130, 134))
56336	21170301	Similarly, a knock-in model of this same mutation into the FMR1 locus in mice recapitulates many features of the Fragile X phenotype but FMR1 mRNA levels were not altered.	('mutation', 'Var', (41, 49))	('mice', 'Species', '10090', (73, 77))	('FMR1', 'Gene', (59, 63))	('man', 'Species', '9606', (92, 95))
56343	21170301	HDAC inhibition has emerged as a potential therapeutic strategy in numerous neurodegenerative diseases, including polyglutamine disorders.	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (76, 101))	('numerous neurodegenerative diseases', 'Disease', 'MESH:D019636', (67, 102))	('polyglutamine disorders', 'Disease', 'MESH:D030342', (114, 137))	('inhibition', 'Var', (5, 15))	('polyglutamine disorders', 'Disease', (114, 137))	('numerous neurodegenerative diseases', 'Disease', (67, 102))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (76, 102))	('HDAC', 'Protein', (0, 4))
56364	21170301	In summary, we provide evidence that HDAC expression in vivo or pharmacologic treatment with HAT inhibitors in patient cells can correct the transcriptional upregulation associated with pre-mutation length expanded CGG repeat sequences.	('transcriptional', 'MPA', (141, 156))	('expanded CGG repeat sequences', 'Var', (206, 235))	('men', 'Species', '9606', (83, 86))	('upregulation', 'PosReg', (157, 169))	('patient', 'Species', '9606', (111, 118))
56365	21170301	Our data support a model whereby the expanded CGG repeat sequence in the FMR1 gene in FXTAS patients alters local chromatin structure in cis to favor increased FMR1 transcription.	('alters', 'Reg', (101, 107))	('favor increased', 'PosReg', (144, 159))	('transcription', 'MPA', (165, 178))	('FXTAS', 'Disease', (86, 91))	('patients', 'Species', '9606', (92, 100))	('expanded CGG repeat sequence', 'Var', (37, 65))	('local chromatin structure', 'MPA', (108, 133))	('FMR1', 'Gene', (73, 77))	('FMR1', 'Gene', (160, 164))
56367	21170301	Importantly, our results suggest that these alterations in chromatin structure at the FMR1 locus are dynamic and modifiable, such that various genetic and pharmacologic manipulations of the state of histone acetylation at and near the CGG repeat can change the level of transcription in human cells and in animal models.	('change', 'Reg', (250, 256))	('manipulations', 'Var', (169, 182))	('man', 'Species', '9606', (169, 172))	('FMR1', 'Gene', (86, 90))	('man', 'Species', '9606', (289, 292))	('human', 'Species', '9606', (287, 292))	('level of transcription', 'MPA', (261, 283))
56373	21170301	The cDNA for Drosophila HDAC3 and HDAC6 were amplified from the expressed sequence tag (EST) clones LD23745 and LD43531, respectively.	('LD43531', 'Var', (112, 119))	('LD23745', 'Var', (100, 107))	('HDAC6', 'Gene', (34, 39))	('Drosophila', 'Species', '7227', (13, 23))
56377	21170301	The dHDAC expression was activated in genetic crosses trans to the yeast GAL4 transcription factor, which was in turn regulated by the eye-specific promoter GMR upstream of the yeast GAL4 cDNA.	('GMR', 'Gene', (157, 160))	('yeast', 'Species', '4932', (177, 182))	('yeast', 'Species', '4932', (67, 72))	('dHDAC', 'Chemical', '-', (4, 9))	('dHDAC', 'Gene', (4, 9))	('GMR', 'Gene', '1438', (157, 160))	('activated', 'PosReg', (25, 34))	('crosses', 'Var', (46, 53))
56390	21170301	C0051.004, (CGG 90) Definite FXTAS; Onset at 59, postural tremor with mild gait imbalance.	('tremor', 'Phenotype', 'HP:0001337', (58, 64))	('imbalance', 'Phenotype', 'HP:0002172', (80, 89))	('tremor', 'Disease', 'MESH:D014202', (58, 64))	('tremor', 'Disease', (58, 64))	('C0051.004', 'Var', (0, 9))	('postural tremor', 'Phenotype', 'HP:0002174', (49, 64))	('gait imbalance', 'Phenotype', 'HP:0002141', (75, 89))
56448	20551952	Inhibition of the VEGF/VEGFR system has already become a clinically relevant strategy for innovative treatment of several urological tumours.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('VEGFR', 'Gene', (23, 28))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('tumours', 'Disease', (133, 140))	('Inhibition', 'Var', (0, 10))	('VEGFR', 'Gene', '3791', (23, 28))	('men', 'Species', '9606', (106, 109))
56469	20551952	Proteins were transferred to PVDF membranes by electroblotting for 1.5 h. Blots were blocked in 5% skim milk powder solution (Merck, Darmstadt, Germany) for 1 h, and then incubated at 4  C overnight with antibodies directed against ERK1/2 and pERK1/2 (1 : 500 or 1 : 1000, Santa Cruz Biotechnology, Santa Cruz, CA, USA) as well as with p21waf1/cip1 (1 : 200 Cell Signaling, Danvers, MA, USA) and p27Kip1 (1 : 2000 Cell Signaling).	('p27Kip1', 'Gene', (396, 403))	('ERK1/2', 'Gene', (244, 250))	('ERK1/2', 'Gene', '5595;5594', (244, 250))	('p21waf1/cip1', 'Gene', '1026', (336, 348))	('p21waf1/cip1', 'Gene', (336, 348))	('1 : 500', 'Var', (252, 259))	('ERK1/2', 'Gene', (232, 238))	('ERK1/2', 'Gene', '5595;5594', (232, 238))	('p27Kip1', 'Gene', '1027', (396, 403))
56490	20551952	Both, HP-2 as well as HP-14 led to time- and dose-dependent growth inhibition of HUVEC, EA.hy926 and TGCT cells (Tera-1, Tera-2 and 2102EP) of up to >80%.	('HP-14', 'Chemical', '-', (22, 27))	('HP-', 'Chemical', 'MESH:C035699', (22, 25))	('HP-14', 'Var', (22, 27))	('Tera-2', 'CellLine', 'CVCL:2777', (121, 127))	('HP-2', 'Gene', (6, 10))	('Tera-1', 'CellLine', 'CVCL:2776', (113, 119))	('growth', 'CPA', (60, 66))	('HUVEC', 'CellLine', 'CVCL:2959', (81, 86))	('HP-', 'Chemical', 'MESH:C035699', (6, 9))	('EA.hy926', 'CellLine', 'CVCL:3901', (88, 96))	('TGCT', 'Phenotype', 'HP:0010788', (101, 105))
56522	20551952	Especially the smaller supplying vessels were influenced by HP-2 treatment (Figure 6E), whereas no obvious influence was observed on the capillary plexus (star).	('influenced', 'Reg', (46, 56))	('HP-2', 'Gene', (60, 64))	('HP-', 'Chemical', 'MESH:C035699', (60, 63))	('men', 'Species', '9606', (70, 73))	('treatment', 'Var', (65, 74))	('smaller', 'NegReg', (15, 22))
56524	20551952	HP-14 (10 mu, 48 h) led to an increase in non-perfused areas and to an obvious degeneration of the vasculature and the capillary plexus (Figures 6F and I).	('HP-14', 'Chemical', '-', (0, 5))	('non-perfused areas', 'CPA', (42, 60))	('HP-14', 'Var', (0, 5))	('increase', 'PosReg', (30, 38))	('degeneration', 'NegReg', (79, 91))
56533	20551952	Inhibition of the VEGF/VEGFR system has already become a clinically relevant strategy for treatment of some urological cancers, especially those refractory to the standard chemotherapy, whereas TGCTs are not systematically analysed in this respect.	('urological cancers', 'Disease', (108, 126))	('VEGFR', 'Gene', (23, 28))	('TGCT', 'Phenotype', 'HP:0010788', (194, 198))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('men', 'Species', '9606', (95, 98))	('Inhibition', 'Var', (0, 10))	('VEGFR', 'Gene', '3791', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('urological cancers', 'Disease', 'MESH:D014571', (108, 126))
56548	20551952	HP-14 also increased the expression of antiangiogenic genes such as the angiogenesis inhibitor endostatin (COL18A1).	('HP-14', 'Chemical', '-', (0, 5))	('endostatin', 'Gene', '80781', (95, 105))	('increased', 'PosReg', (11, 20))	('endostatin', 'Gene', (95, 105))	('expression', 'MPA', (25, 35))	('antiangiogenic genes', 'Gene', (39, 59))	('HP-14', 'Var', (0, 5))	('COL18A1', 'Gene', (107, 114))	('COL18A1', 'Gene', '80781', (107, 114))
56554	20551952	Our observation that HP-treatment-induced S-phase arrest and p21 overexpression is in agreement with a previous report that transduction of the p21 gene resulted in an S-phase arrest.	('S-phase', 'MPA', (168, 175))	('p21', 'Gene', (144, 147))	('transduction', 'Var', (124, 136))	('men', 'Species', '9606', (91, 94))	('p21', 'Gene', '1026', (61, 64))	('men', 'Species', '9606', (29, 32))	('overexpression', 'PosReg', (65, 79))	('HP-', 'Chemical', 'MESH:C035699', (21, 24))	('p21', 'Gene', (61, 64))	('S-phase arrest', 'CPA', (42, 56))	('p21', 'Gene', '1026', (144, 147))
56561	20551952	In our gene array experiments, we also observed an inhibition of the AKT because of HP-14 treatment.	('inhibition', 'NegReg', (51, 61))	('men', 'Species', '9606', (24, 27))	('AKT', 'Gene', (69, 72))	('HP-14', 'Gene', (84, 89))	('men', 'Species', '9606', (95, 98))	('HP-14', 'Chemical', '-', (84, 89))	('treatment', 'Var', (90, 99))	('AKT', 'Gene', '207', (69, 72))
56598	31480363	Other risk factors are white ethnicity, small birth weight, preterm birth, small gestational age, inguinal hernia, twinning, subfertility, testicular dysgenesis syndrome, adult height, and low BMI (Body mass index) :possibly as proxies of the birth-cohort effect.	('inguinal hernia', 'Disease', 'MESH:D006552', (98, 113))	('inguinal hernia', 'Phenotype', 'HP:0000023', (98, 113))	('twinning', 'Disease', (115, 123))	('low BMI', 'Phenotype', 'HP:0045082', (189, 196))	('subfertility', 'Disease', (125, 137))	('low BMI', 'Var', (189, 196))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (139, 160))	('hernia', 'Phenotype', 'HP:0100790', (107, 113))	('small gestational age', 'Phenotype', 'HP:0001518', (75, 96))	('testicular dysgenesis syndrome', 'Disease', (139, 169))	('preterm birth', 'Phenotype', 'HP:0001622', (60, 73))	('testicular dysgenesis syndrome', 'Disease', 'MESH:D013733', (139, 169))	('inguinal hernia', 'Disease', (98, 113))	('small birth weight', 'Phenotype', 'HP:0001518', (40, 58))
56609	31480363	The histology codes were grouped into the following four categories: seminoma (ICDO-3 codes: 9060-9064), non-seminoma (ICDO-3 codes: 9065, 9070-9072, 9080-9085, 9100-9102), other, and unspecified.	('seminoma', 'Disease', (109, 117))	('non-seminoma', 'Disease', 'MESH:D018239', (105, 117))	('9070-9072', 'Var', (139, 148))	('seminoma', 'Disease', 'MESH:D018239', (69, 77))	('seminoma', 'Disease', 'MESH:D018239', (109, 117))	('seminoma', 'Disease', (69, 77))	('9100-9102', 'Var', (161, 170))	('unspecified', 'Species', '32644', (184, 195))	('9080-9085', 'Var', (150, 159))	('non-seminoma', 'Disease', (105, 117))
56754	30858829	Chemotherapy, especially platinum-based treatment, is associated with paraesthesia, hypogonadism, hypercholesterolemia, and hypertension, and also with memory problems and lower cognitive performance in TCSs.	('man', 'Species', '9606', (194, 197))	('hypogonadism', 'Disease', 'MESH:D007006', (84, 96))	('lower', 'NegReg', (172, 177))	('platinum-based treatment', 'Var', (25, 49))	('memory problems', 'Phenotype', 'HP:0002354', (152, 167))	('platinum', 'Chemical', 'MESH:D010984', (25, 33))	('hypertension', 'Phenotype', 'HP:0000822', (124, 136))	('paraesthesia', 'Disease', (70, 82))	('hypercholesterolemia', 'Phenotype', 'HP:0003124', (98, 118))	('hypercholesterolemia', 'Disease', 'MESH:D006937', (98, 118))	('TC', 'Phenotype', 'HP:0010788', (203, 205))	('hypogonadism', 'Disease', (84, 96))	('lower cognitive performance', 'Phenotype', 'HP:0001249', (172, 199))	('hypercholesterolemia', 'Disease', (98, 118))	('memory problems', 'CPA', (152, 167))	('men', 'Species', '9606', (45, 48))	('hypogonadism', 'Phenotype', 'HP:0000135', (84, 96))	('TCSs', 'Chemical', '-', (203, 207))	('hypertension', 'Disease', 'MESH:D006973', (124, 136))	('Chemotherapy', 'Var', (0, 12))	('hypertension', 'Disease', (124, 136))
56828	30858829	This discrepancy may be correlated with the fact that people with a higher level of education have a greater chance of being employed after their cancer diagnosis than less educated patients job type is also a factor, e.g., manual labor is negatively associated with a return to work due to its physically strenuous nature.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('negatively', 'NegReg', (240, 250))	('patients', 'Species', '9606', (182, 190))	('people', 'Species', '9606', (54, 60))	('man', 'Species', '9606', (224, 227))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('manual labor', 'Var', (224, 236))
56830	30858829	reported that TCSs with poorer avoidance coping skills fared worse in terms of paired relationships and paid work than TCSs with a better approach to coping.	('TC', 'Phenotype', 'HP:0010788', (14, 16))	('TCSs', 'Chemical', '-', (119, 123))	('paid work', 'CPA', (104, 113))	('TCSs', 'Chemical', '-', (14, 18))	('avoidance coping skills', 'CPA', (31, 54))	('paired relationships', 'CPA', (79, 99))	('TC', 'Phenotype', 'HP:0010788', (119, 121))	('poorer', 'Var', (24, 30))
56897	28900475	They have stressed on the associations between chronic inflammation, persistent infection, and cancer, where autocrine and paracrine signals mediate oncogenic action, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('epigenetic factors', 'Var', (250, 268))	('cancer', 'Disease', (95, 101))	('chronic inflammation', 'Disease', 'MESH:D007249', (47, 67))	('changes', 'Reg', (175, 182))	('chronic inflammation', 'Disease', (47, 67))	('infection', 'Disease', (80, 89))	('persistent infection', 'Phenotype', 'HP:0031035', (69, 89))	('infection', 'Disease', 'MESH:D007239', (80, 89))
56993	27195317	Although mean age of patients was lower in ITGCN group (32.6 years old), it was not significantly different from the overall group.	('patients', 'Species', '9606', (21, 29))	('lower', 'NegReg', (34, 39))	('ITGCN', 'Chemical', '-', (43, 48))	('ITGCN', 'Var', (43, 48))
57021	26265322	Overall, the small RNA deregulation in TGCT provides new insight into the small RNA interplay.	('TGCT', 'Gene', (39, 43))	('deregulation', 'Var', (23, 35))	('nt', 'Chemical', 'MESH:D009711', (66, 68))	('nt', 'Chemical', 'MESH:D009711', (85, 87))
57026	26265322	Precise control of miRNA expression is crucial for keeping cells in normal physiological states, and dysregulation of miRNAs may lead to oncogenesis.	('lead to', 'Reg', (129, 136))	('oncogenesis', 'CPA', (137, 148))	('nt', 'Chemical', 'MESH:D009711', (10, 12))	('miRNAs', 'Protein', (118, 124))	('dysregulation', 'Var', (101, 114))
57028	26265322	Moreover, the miRNAs miR-371-373, miR-302 and miR-146 have previously been shown to display a TGCT-specific expression pattern, indicating a potential role for miRNAs in TGCT pathogenesis.	('miR-371', 'Gene', (21, 28))	('miR-302', 'Var', (34, 41))	('miR-146', 'Var', (46, 53))	('miR-371', 'Gene', '442916', (21, 28))	('TGCT-specific', 'Disease', (94, 107))	('nt', 'Chemical', 'MESH:D009711', (145, 147))	('expression', 'MPA', (108, 118))
57044	26265322	Combined, these findings indicate that epigenetic disruption is a hallmark for the development of testicular tumors, and that it is affected by the sncRNA expression.	('nt', 'Chemical', 'MESH:D009711', (92, 94))	('men', 'Species', '9606', (90, 93))	('testicular tumors', 'Phenotype', 'HP:0010788', (98, 115))	('testicular tumors', 'Disease', 'MESH:D013736', (98, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('epigenetic disruption', 'Var', (39, 60))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('testicular tumors', 'Disease', (98, 115))
57056	26265322	Additionally, sequences 32-34 nt in length in all sample groups show a significant enrichment for 5'G, corresponding to the decrease in sequences containing 5'U (Fig.	('nt', 'Chemical', 'MESH:D009711', (30, 32))	('sequences', 'MPA', (136, 145))	('nt', 'Chemical', 'MESH:D009711', (80, 82))	("5'U", 'Var', (157, 160))	('decrease', 'NegReg', (124, 132))	('nt', 'Chemical', 'MESH:D009711', (148, 150))	('men', 'Species', '9606', (89, 92))	('nt', 'Chemical', 'MESH:D009711', (91, 93))
57083	26265322	The expression of corresponding tRNA halves and tRFs correlate (log scale), however, a few tRNAs (tRNA-Val-GTG/GTY, tRNA-Gly-GGY/GGG) have a higher abundance in tRFs compared to tRNA halves (Additional file 3A-B).	('tRNA-Gly-GGY/GGG', 'Var', (116, 132))	('tRF', 'Gene', '7013', (48, 51))	('Val', 'Chemical', 'MESH:D014633', (103, 106))	('tRNA-Val-GTG/GTY', 'Var', (98, 114))	('tRF', 'Gene', (161, 164))	('Gly', 'Chemical', 'MESH:D005998', (121, 124))	('tRF', 'Gene', (48, 51))	('tRF', 'Gene', '7013', (161, 164))
57091	26265322	The most significantly differentially expressed miRNAs were from the miRNA clusters miR-302/367 and miR-371-373, seen in the upper right corner of the plot.	('nt', 'Chemical', 'MESH:D009711', (30, 32))	('differentially', 'Reg', (23, 37))	('miR-371', 'Gene', (100, 107))	('nt', 'Chemical', 'MESH:D009711', (18, 20))	('miR-302/367', 'Var', (84, 95))	('miR-371', 'Gene', '442916', (100, 107))
57121	26265322	and Ushida et al.. Our results confirm previous findings indicating that miRNAs have a relevant role during testicular carcinogenesis, since overexpression of the miR-371-373, miR-302 and miR-367-3p clusters was noted in malignant TGCT tissue.	('miR-367', 'Gene', (188, 195))	('testicular carcinogenesis', 'Disease', 'MESH:D063646', (108, 133))	('miR-302', 'Var', (176, 183))	('testicular carcinogenesis', 'Disease', (108, 133))	('miR-371', 'Gene', (163, 170))	('miR-367', 'Gene', '442912', (188, 195))	('nt', 'Chemical', 'MESH:D009711', (93, 95))	('overexpression', 'PosReg', (141, 155))	('nt', 'Chemical', 'MESH:D009711', (228, 230))	('miR-371', 'Gene', '442916', (163, 170))
57123	26265322	A study using a genetic screen of primary human cells supported this observation and found that both miR-372-373 and miR-302 may act as TGCT oncogenes through inhibition of target genes such as Large Tumor Suppressor homolog 2 (LATS2).	('LATS2', 'Gene', (228, 233))	('LATS2', 'Gene', '26524', (228, 233))	('miR-302', 'Var', (117, 124))	('miR-372', 'Gene', '442917', (101, 108))	('Large Tumor Suppressor homolog 2', 'Gene', (194, 226))	('human', 'Species', '9606', (42, 47))	('Large Tumor Suppressor homolog 2', 'Gene', '26524', (194, 226))	('Tumor', 'Phenotype', 'HP:0002664', (200, 205))	('miR-372', 'Gene', (101, 108))	('inhibition', 'NegReg', (159, 169))
57137	26265322	Several of the miR-371-373 and miR-302/367 cluster members have shown a sufficiently strong association with TGCT  to serve as biomarkers of TGCT.	('miR-302/367', 'Var', (31, 42))	('miR-371', 'Gene', '442916', (15, 22))	('nt', 'Chemical', 'MESH:D009711', (80, 82))	('TGCT', 'Disease', (109, 113))	('miR-371', 'Gene', (15, 22))	('association', 'Interaction', (92, 103))
57140	26265322	We have confirmed the association between TGCT and high expression of the miR-371-373 and miR-302/367 clusters.	('high expression', 'MPA', (51, 66))	('miR-302/367', 'Var', (90, 101))	('miR-371', 'Gene', '442916', (74, 81))	('TGCT', 'Disease', (42, 46))	('association', 'Interaction', (22, 33))	('miR-371', 'Gene', (74, 81))
57254	23226724	Male athymic mice (n=12), 10-12 weeks of age, were inoculated with 5x105 B16FO melanoma cells in 100 mul of PBS into the right testis, while the left testis was left untreated.	('mice', 'Species', '10090', (13, 17))	('5x105 B16FO', 'Var', (67, 78))	('PBS', 'Chemical', 'MESH:D007854', (108, 111))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
57275	23226724	A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has demonstrated anticancer activity in a number of human cancer cell lines, inhibiting cancer cell growth, MMP secretion, invasion, metastasis and angiogenesis.	('invasion', 'CPA', (211, 219))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tea', 'Gene', '11988', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inhibiting', 'NegReg', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('metastasis', 'CPA', (221, 231))	('ascorbic acid', 'Chemical', 'MESH:D001205', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tea', 'Gene', (76, 79))	('lysine', 'Chemical', 'MESH:D008239', (35, 41))	('proline', 'Chemical', 'MESH:D011392', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('lysine', 'Var', (35, 41))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NM', 'Chemical', '-', (20, 22))	('human', 'Species', '9606', (140, 145))	('MMP secretion', 'CPA', (196, 209))	('angiogenesis', 'CPA', (236, 248))	('cancer', 'Disease', (176, 182))
57286	23226724	The NM 1% diet comprised the following in the ratio indicated: vitamin C (as ascorbic acid and as Mg, Ca, and palmitate ascorbate) 700 mg; L-lysine 1000 mg; L-proline 750 mg; L-arginine 500 mg; N-acetyl cysteine 200 mg; standardized green tea extract (80% polyphenol) 1000 mg; selenium 30 mug; copper 2 mg; manganese 1 mg.	('L-proline', 'Var', (157, 166))	('ascorbic acid', 'Chemical', 'MESH:D001205', (77, 90))	('vitamin C', 'Chemical', 'MESH:D001205', (63, 72))	('NM', 'Chemical', '-', (4, 6))	('L-arginine', 'Chemical', 'MESH:D001120', (175, 185))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (194, 211))	('selenium', 'MPA', (277, 285))	('L-lysine', 'Chemical', 'MESH:D008239', (139, 147))	('tea', 'Gene', (239, 242))	('palmitate', 'Chemical', 'MESH:D010168', (110, 119))	('tea', 'Gene', '11988', (239, 242))	('copper', 'Chemical', 'MESH:D003300', (294, 300))	('selenium', 'Chemical', 'MESH:D012643', (277, 285))	('manganese', 'Chemical', 'MESH:D008345', (307, 316))	('ascorbate', 'Chemical', 'MESH:D001205', (120, 129))	('polyphenol', 'Chemical', 'MESH:D059808', (256, 266))	('L-proline', 'Chemical', 'MESH:D011392', (157, 166))
57307	23226724	By contrast, some enlargement of the right testis was evident in the NM 1% group, although it was much smaller than that observed in the control group.	('NM', 'Chemical', '-', (69, 71))	('enlargement', 'PosReg', (18, 29))	('men', 'Species', '9606', (25, 28))	('NM 1%', 'Var', (69, 74))
57331	23226724	Lysine interferes with the activation of plasminogen into plasmin by tissue plasminogen activator (tPA) by binding to plasminogen active sites, thereby affecting the plasmin-induced MMP activation cascade.	('interferes', 'NegReg', (7, 17))	('plasmin-induced', 'MPA', (166, 181))	('activation', 'MPA', (27, 37))	('Lysine', 'Var', (0, 6))	('affecting', 'Reg', (152, 161))	('binding', 'Interaction', (107, 114))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
57338	23226724	N-acetyl cysteine has been observed to inhibit MMP-9 activity and invasive activities of tumor cells.	('inhibit', 'NegReg', (39, 46))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MMP-9', 'Gene', '17395', (47, 52))	('MMP-9', 'Gene', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('N-acetyl', 'Var', (0, 8))
57346	18162130	Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs).	('TCSs', 'Chemical', '-', (357, 361))	('testicular cancer', 'Phenotype', 'HP:0010788', (50, 67))	('polymorphisms', 'Var', (82, 95))	('neuro-toxicities in testicular cancer', 'Disease', (30, 67))	('neuro-toxicities in testicular cancer', 'Disease', 'MESH:D013736', (30, 67))	('testicular cancer', 'Phenotype', 'HP:0010788', (328, 345))	('TC', 'Phenotype', 'HP:0010788', (357, 359))	('Glutathione S-transferase (GST) -P1, -M1, and -T1', 'Gene', '2950;2944;2952', (216, 265))	('toxicities in testicular cancer', 'Disease', 'MESH:D013736', (314, 345))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Association', 'Interaction', (0, 11))	('toxicities in testicular cancer', 'Disease', (314, 345))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('toxicities in testicular cancer', 'Disease', 'MESH:D013736', (36, 67))
57348	18162130	From all TCSs lymphocyte-derived DNA was analyzed for the functional A G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1.	('GST-M1', 'Gene', '2944', (123, 129))	('GSTP1', 'Gene', (99, 104))	('GST-T1', 'Gene', (134, 140))	('GST-M1', 'Gene', (123, 129))	('GSTP1', 'Gene', '2950', (99, 104))	('TC', 'Phenotype', 'HP:0010788', (9, 11))	('deletions', 'Var', (110, 119))	('TCSs', 'Chemical', '-', (9, 13))	('GST-T1', 'Gene', '2952', (134, 140))
57349	18162130	Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.	('associations', 'Interaction', (14, 26))	('toxicities', 'Disease', 'MESH:D064420', (71, 81))	('polymorphisms', 'Var', (39, 52))	('GST', 'Gene', (35, 38))	('GST', 'Gene', '373156', (35, 38))	('toxicities', 'Disease', (71, 81))
57352	18162130	Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08-3.03]).	('GSTM1', 'Gene', (35, 40))	('hearing impairment', 'Disease', 'MESH:D034381', (59, 77))	('hearing impairment', 'Phenotype', 'HP:0000365', (59, 77))	('absence', 'Var', (13, 20))	('hearing impairment', 'Disease', (59, 77))	('GSTM1', 'Gene', '2944', (35, 40))
57353	18162130	In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1.	('GSTP1', 'Gene', (112, 117))	('toxicities', 'Disease', 'MESH:D064420', (53, 63))	('associated', 'Reg', (68, 78))	('polymorphisms', 'Var', (95, 108))	('GSTM1', 'Gene', '2944', (122, 127))	('GSTP1', 'Gene', '2950', (112, 117))	('toxicities', 'Disease', (53, 63))	('GSTM1', 'Gene', (122, 127))	('TCSs', 'Chemical', '-', (3, 7))	('TC', 'Phenotype', 'HP:0010788', (3, 5))
57354	18162130	Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1.	('absence', 'Var', (16, 23))	('GST-P1', 'Gene', '2950', (92, 98))	('GST-M1', 'Gene', '2944', (27, 33))	('glutathione', 'MPA', (46, 57))	('more', 'PosReg', (41, 45))	('GST-P1', 'Gene', (92, 98))	('glutathione', 'Chemical', 'MESH:D005978', (46, 57))	('GST-M1', 'Gene', (27, 33))
57355	18162130	Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('testicular cancer', 'Phenotype', 'HP:0010788', (118, 135))	('testicular cancer', 'Disease', 'MESH:D013736', (118, 135))	('GSTs', 'Gene', '373156', (20, 24))	('testicular cancer', 'Disease', (118, 135))	('GSTs', 'Gene', (20, 24))	('Genotyping', 'Var', (0, 10))	('patients', 'Species', '9606', (93, 101))
57370	18162130	We considered germ-line polymorphisms within GST genes as promising candidates for the exploration of the large inter-individual variability of long-term treatment toxicities.	('GST', 'Gene', (45, 48))	('GST', 'Gene', '373156', (45, 48))	('toxicities', 'Disease', 'MESH:D064420', (164, 174))	('polymorphisms', 'Var', (24, 37))	('toxicities', 'Disease', (164, 174))
57378	18162130	Whole blood EDTA samples were collected from the TCSs, lymphocyte-DNA extracted, and submitted to genetic analyses of functional polymorphisms in the genes coding for GSTT1, -M1, and -P1.	('polymorphisms', 'Var', (129, 142))	('TC', 'Phenotype', 'HP:0010788', (49, 51))	('GSTT1', 'Gene', (167, 172))	('GSTT1', 'Gene', '2952', (167, 172))	('TCSs', 'Chemical', '-', (49, 53))	('EDTA', 'Chemical', 'MESH:D004492', (12, 16))
57380	18162130	The known inherited homozygous deletions in GSTT1 and GSTM1 are equivalent to non-functional enzymes.	('GSTT1', 'Gene', '2952', (44, 49))	('GSTM1', 'Gene', '2944', (54, 59))	('GSTT1', 'Gene', (44, 49))	('GSTM1', 'Gene', (54, 59))	('deletions', 'Var', (31, 40))
57381	18162130	A functional single nucleotide polymorphism (SNP) in the GSTP1 gene at base pair 315 between Adenosine (A) and Guanine (G) leads to the expression of either isoleucine (Ile) or valine (Val) at codon 105 (Ile105, Val105).	('Val', 'Chemical', 'MESH:D014633', (212, 215))	('GSTP1', 'Gene', (57, 62))	('expression', 'MPA', (136, 146))	('valine', 'MPA', (177, 183))	('Val', 'Chemical', 'MESH:D014633', (185, 188))	('valine', 'Chemical', 'MESH:D014633', (177, 183))	('single nucleotide polymorphism', 'Var', (13, 43))	('Ile105', 'Chemical', '-', (204, 210))	('Val105', 'Chemical', '-', (212, 218))	('GSTP1', 'Gene', '2950', (57, 62))	('Adenosine', 'Chemical', 'MESH:D000241', (93, 102))	('Ile', 'Chemical', 'MESH:D007532', (169, 172))	('Ile', 'Chemical', 'MESH:D007532', (204, 207))	('Guanine', 'Chemical', 'MESH:D006147', (111, 118))	('isoleucine', 'Chemical', 'MESH:D007532', (157, 167))	('leads to', 'Reg', (123, 131))	('isoleucine', 'MPA', (157, 167))
57403	18162130	Paresthesias in fingers/toes as well as tinnitus and hearing impairment were significantly associated with polymorphic alleles of GSTP1 and/or GSTM1.	('GSTP1', 'Gene', (130, 135))	('Paresthesias', 'Phenotype', 'HP:0003401', (0, 12))	('tinnitus and hearing impairment', 'Disease', 'MESH:D034381', (40, 71))	('hearing impairment', 'Phenotype', 'HP:0000365', (53, 71))	('GSTM1', 'Gene', '2944', (143, 148))	('GSTP1', 'Gene', '2950', (130, 135))	('Paresthesias', 'Disease', (0, 12))	('polymorphic alleles', 'Var', (107, 126))	('GSTM1', 'Gene', (143, 148))	('tinnitus', 'Phenotype', 'HP:0000360', (40, 48))	('associated', 'Reg', (91, 101))
57405	18162130	Functional GSTM1 increased the risk of hearing impairment by 1.8 (table 3).	('GSTM1', 'Gene', (11, 16))	('hearing impairment', 'Disease', (39, 57))	('Functional', 'Var', (0, 10))	('hearing impairment', 'Phenotype', 'HP:0000365', (39, 57))	('GSTM1', 'Gene', '2944', (11, 16))	('hearing impairment', 'Disease', 'MESH:D034381', (39, 57))
57406	18162130	Presence of both GSTP1-G alleles reduced the risk of peripheral paresthesias in the fingers and in the toes, and of tinnitus by at least the factor two.	('tinnitus', 'Disease', 'MESH:D014012', (116, 124))	('GSTP1', 'Gene', (17, 22))	('peripheral paresthesias in the fingers', 'Disease', (53, 91))	('paresthesias', 'Phenotype', 'HP:0003401', (64, 76))	('tinnitus', 'Disease', (116, 124))	('reduced', 'NegReg', (33, 40))	('GSTP1', 'Gene', '2950', (17, 22))	('Presence', 'Var', (0, 8))	('tinnitus', 'Phenotype', 'HP:0000360', (116, 124))
57408	18162130	In order to illustrate these relations we depicted the scorings of TCSs with either one or none GSTP1-G alleles (n = 201) opposed to those with both alleles (n = 37), figure 2.	('TCSs', 'Chemical', '-', (67, 71))	('TC', 'Phenotype', 'HP:0010788', (67, 69))	('alleles', 'Var', (104, 111))	('GSTP1', 'Gene', (96, 101))	('GSTP1', 'Gene', '2950', (96, 101))
57409	18162130	Statistical analysis by chi2 tests for trends revealed significantly protective effect of GSTP1-G homozygosity against paresthesias in the fingers and toes (p = 0.040 and p = 0.025, respectively), Raynaud-like phenomena in the toes (p = 0.032), and tinnitus (p = 0.003).	('homozygosity', 'Var', (98, 110))	('GSTP1', 'Gene', '2950', (90, 95))	('Raynaud-like phenomena', 'Phenotype', 'HP:0030880', (197, 219))	('tinnitus', 'Disease', (249, 257))	('paresthesias', 'Phenotype', 'HP:0003401', (119, 131))	('paresthesias', 'Disease', (119, 131))	('GSTP1', 'Gene', (90, 95))	('Raynaud-like phenomena', 'Disease', (197, 219))	('tinnitus', 'Disease', 'MESH:D014012', (249, 257))	('tinnitus', 'Phenotype', 'HP:0000360', (249, 257))
57411	18162130	Furthermore, presence of functional GSTM1 nearly doubled the risk of hearing impairment.	('GSTM1', 'Gene', '2944', (36, 41))	('hearing impairment', 'Disease', 'MESH:D034381', (69, 87))	('GSTM1', 'Gene', (36, 41))	('presence', 'Var', (13, 21))	('hearing impairment', 'Phenotype', 'HP:0000365', (69, 87))	('hearing impairment', 'Disease', (69, 87))
57413	18162130	Cisplatin leads to loss of outer hair cells in the cochlea, and thereby also to hearing impairment, which was limited by absence of GSTM1.	('GSTM1', 'Gene', '2944', (132, 137))	('outer', 'Protein', (27, 32))	('GSTM1', 'Gene', (132, 137))	('loss', 'NegReg', (19, 23))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('hearing impairment', 'Disease', 'MESH:D034381', (80, 98))	('Cisplatin', 'Var', (0, 9))	('hearing impairment', 'Phenotype', 'HP:0000365', (80, 98))	('hearing impairment', 'Disease', (80, 98))
57414	18162130	In the subgroup of 173 TCSs in whom audiometry was performed such a beneficial effect of non-functional GSTM1 was found for objectively measured cisplatin-induced hearing impairment, which in addition was strongly associated with the genotype GSTP1-GG .	('GSTM1', 'Gene', (104, 109))	('non-functional', 'Var', (89, 103))	('TCSs', 'Chemical', '-', (23, 27))	('GSTP1', 'Gene', (243, 248))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('hearing impairment', 'Disease', 'MESH:D034381', (163, 181))	('TC', 'Phenotype', 'HP:0010788', (23, 25))	('genotype', 'Var', (234, 242))	('hearing impairment', 'Disease', (163, 181))	('GSTP1', 'Gene', '2950', (243, 248))	('beneficial', 'PosReg', (68, 78))	('associated', 'Reg', (214, 224))	('hearing impairment', 'Phenotype', 'HP:0000365', (163, 181))	('GSTM1', 'Gene', '2944', (104, 109))
57422	18162130	The protective effect of GSTP1-GG presence most likely mirrors an increased tolerance to this drug.	('GSTP1', 'Gene', '2950', (25, 30))	('tolerance', 'MPA', (76, 85))	('increased', 'PosReg', (66, 75))	('GSTP1', 'Gene', (25, 30))	('presence', 'Var', (34, 42))
57428	18162130	Induction of leukemia and neurotoxicity by chemotherapy is apparently curbed by strictly opposite GSTP1 polymorphisms.	('GSTP1', 'Gene', (98, 103))	('GSTP1', 'Gene', '2950', (98, 103))	('leukemia and neurotoxicity', 'Disease', 'MESH:D020258', (13, 39))	('polymorphisms', 'Var', (104, 117))	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))
57430	18162130	The examined SNP A G causes substitution of isoleucine by valine in GSTP1 at codon 105, a residue regulating the affinity and detoxification efficacy for electrophilic substrates.	('GSTP1', 'Gene', '2950', (68, 73))	('GSTP1', 'Gene', (68, 73))	('isoleucine', 'MPA', (44, 54))	('substitution', 'Var', (28, 40))	('isoleucine', 'Chemical', 'MESH:D007532', (44, 54))	('valine', 'Chemical', 'MESH:D014633', (58, 64))
57440	18162130	Inhibition of JNK in cisplatin-treated guinea pigs increased ototoxicity.	('JNK', 'Gene', (14, 17))	('guinea pigs', 'Species', '10141', (39, 50))	('ototoxicity', 'Disease', (61, 72))	('ototoxicity', 'Disease', 'MESH:D006311', (61, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('JNK', 'Gene', '5599', (14, 17))	('Inhibition', 'Var', (0, 10))
57444	18162130	Deletion of GST-M1, resulting in absence of this functional enzyme might thereby increase the risk of cisplatin-induced apoptosis.	('absence', 'NegReg', (33, 40))	('cisplatin-induced apoptosis', 'MPA', (102, 129))	('GST-M1', 'Gene', (12, 18))	('functional', 'MPA', (49, 59))	('GST-M1', 'Gene', '2944', (12, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('increase', 'PosReg', (81, 89))	('Deletion', 'Var', (0, 8))
57448	18162130	Glutathione's protective potential might correlate with GST polymorphisms.	('polymorphisms', 'Var', (60, 73))	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('GST', 'Gene', (56, 59))	('GST', 'Gene', '373156', (56, 59))	('protective potential', 'CPA', (14, 34))	('Glutathione', 'Protein', (0, 11))
57453	18162130	In conclusion, presence of both GSTP1-G alleles and/or absence of functional GSTM1 protect its carriers against several chemotherapy-induced long-term toxicities.	('GSTM1', 'Gene', '2944', (77, 82))	('GSTP1', 'Gene', '2950', (32, 37))	('presence', 'Var', (15, 23))	('toxicities', 'Disease', 'MESH:D064420', (151, 161))	('GSTM1', 'Gene', (77, 82))	('absence', 'NegReg', (55, 62))	('GSTP1', 'Gene', (32, 37))	('toxicities', 'Disease', (151, 161))
57455	18162130	However, the concordance between audiometrically evaluated cisplatin-induced hearing impairment and the observations presented here builds a strong case for the presence of relevant associations between GST polymorphisms and long-term chemotherapy-induced toxicities.	('GST', 'Gene', (203, 206))	('hearing impairment', 'Disease', (77, 95))	('toxicities', 'Disease', 'MESH:D064420', (256, 266))	('GST', 'Gene', '373156', (203, 206))	('hearing impairment', 'Phenotype', 'HP:0000365', (77, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('toxicities', 'Disease', (256, 266))	('polymorphisms', 'Var', (207, 220))	('hearing impairment', 'Disease', 'MESH:D034381', (77, 95))
57457	26716509	We performed a genome-wide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs).	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('correlation', 'Interaction', (157, 168))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('endometrial cancer', 'Disease', (91, 109))	('mutations', 'Var', (192, 201))	('patients', 'Species', '9606', (110, 118))
57458	26716509	A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('endometrial cancer', 'Disease', (131, 149))	('endometrial cancer', 'Phenotype', 'HP:0012114', (131, 149))	('single nucleotide variations', 'Var', (72, 100))	('endometrial cancer', 'Disease', 'MESH:D016889', (131, 149))	('patient', 'Species', '9606', (166, 173))
57459	26716509	We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing.	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('solid tumors', 'Disease', 'MESH:D009369', (231, 243))	('mutational', 'Var', (46, 56))	('solid tumors', 'Disease', (231, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
57473	26716509	We distinguished driver mutations from functionally neutral passenger mutations with the DawnRank algorithm, and included prior-identified genes from TCGA in the prioritization step.	('mutations', 'Var', (24, 33))	('Ran', 'Gene', '5901', (93, 96))	('Ran', 'Gene', (93, 96))
57475	26716509	The number of driver mutations showed a significant association with the tumor histology (Kruskal-Wallis rank sum p = 0.0011, Supplementary Figure 2B), but not disease stage (Kruskal-Wallis rank sum p = 0.7212) or tumor grade (Kruskal-Wallis rank sum p = 0.1017).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (214, 219))	('mutations', 'Var', (21, 30))
57476	26716509	Pairwise comparisons revealed significant difference between borne driver mutations of the endometrioid subtype compared to serous-like endometrial cancer (Bonferroni-adjusted Wilcoxon p = 0.0026, Figure 2B).	('endometrial cancer', 'Disease', 'MESH:D016889', (136, 154))	('serous', 'Chemical', '-', (124, 130))	('endometrioid', 'Disease', (91, 103))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('endometrial cancer', 'Disease', (136, 154))	('endometrial cancer', 'Phenotype', 'HP:0012114', (136, 154))
57478	26716509	Among all prioritized driver eSNVs, 3 were cis-acting mutational loci (Table 1), which were separately located on ATF7IP (chr12:14576892 T > C), TP53 (chr17:7578271 C > T), and XPO7 (chr8:21827087 C > T).	('XPO7', 'Gene', (177, 181))	('ATF7IP', 'Gene', (114, 120))	('chr12:14576892', 'Var', (122, 136))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('21827087 C > T', 'Mutation', 'g.21827087C>T', (188, 202))	('chr17:7578271', 'Var', (151, 164))	('chr8:21827087', 'Var', (183, 196))	('14576892 T > C', 'Mutation', 'g.14576892T>C', (128, 142))	('ATF7IP', 'Gene', '55729', (114, 120))	('7578271 C > T', 'Mutation', 'rs786201838', (157, 170))	('XPO7', 'Gene', '23039', (177, 181))
57481	26716509	The identified mutational clusters showed significant correlations with endometrial cancer patients' clinical profiles, including disease stage (Fisher's exact p = 0.0207) and tumor histology (Fisher's exact p = 0.0065), but not tumor grade (Fisher's exact p = 0.3861).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('patients', 'Species', '9606', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('endometrial cancer', 'Disease', (72, 90))	('mutational', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (176, 181))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('correlations', 'Reg', (54, 66))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
57485	26716509	As mutational clusters were also associated with disease aggressiveness, these factors were further adjusted for to avoid biased estimations of the effects of the identified clusters on the prognostic potential.	('aggressiveness', 'Disease', (57, 71))	('aggressiveness', 'Phenotype', 'HP:0000718', (57, 71))	('associated', 'Reg', (33, 43))	('aggressiveness', 'Disease', 'MESH:D001523', (57, 71))	('mutational', 'Var', (3, 13))
57487	26716509	Therefore, a series of analyses suggested that a prominent role of patients' mutation profiles contributed to disease biology discovery in endometrial cancer.	('patients', 'Species', '9606', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutation', 'Var', (77, 85))	('endometrial cancer', 'Disease', (139, 157))	('endometrial cancer', 'Phenotype', 'HP:0012114', (139, 157))	('contributed', 'Reg', (95, 106))	('endometrial cancer', 'Disease', 'MESH:D016889', (139, 157))
57488	26716509	To identify biological candidate risk mutational variations in endometrial cancer patients, we conducted integrative analyses based on 542 candidate driver eSNVs and 1,894 genes the transcript levels of which were correlated with the mutational statuses of eSNVs.	('endometrial cancer', 'Disease', (63, 81))	('patients', 'Species', '9606', (82, 90))	('variations', 'Var', (49, 59))	('endometrial cancer', 'Phenotype', 'HP:0012114', (63, 81))	('endometrial cancer', 'Disease', 'MESH:D016889', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
57494	26716509	As shown, the mutation profiles of 13 eSNVs were significantly associated with progression-free survival of endometrial cancer patients (HR = 9.3927, 95% CI = 4.82~18.31, p = 4.86x10-11, Figure 4A).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('eSNVs', 'Gene', (38, 43))	('progression-free survival', 'CPA', (79, 104))	('endometrial cancer', 'Disease', (108, 126))	('associated with', 'Reg', (63, 78))	('mutation', 'Var', (14, 22))	('patients', 'Species', '9606', (127, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (108, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (108, 126))
57495	26716509	This result indicated a significant correlation between mutations and UCEC patient survival outcomes, and further confirmed the potential clinical utility of the 10 identified genes in an eSNV-based manner.	('mutations', 'Var', (56, 65))	('patient', 'Species', '9606', (75, 82))	('correlation', 'Reg', (36, 47))
57497	26716509	Surprisingly, patients who bore the CTNNB1 mutation were significantly enriched in cluster 1 compared to clusters 2 and 3 (Chi-square p = 2.75 x 10-5).	('mutation', 'Var', (43, 51))	('CTNNB1', 'Gene', (36, 42))	('patients', 'Species', '9606', (14, 22))	('CTNNB1', 'Gene', '1499', (36, 42))
57498	26716509	Similarly, the PIK3CA mutation was significantly enriched in patients in cluster 3 (Chi-square p = 3.62 x 10-4).	('patients', 'Species', '9606', (61, 69))	('PIK3CA', 'Gene', '5290', (15, 21))	('mutation', 'Var', (22, 30))	('PIK3CA', 'Gene', (15, 21))
57499	26716509	In contrast, the number of patients with the TP53 mutation was higher in cluster 2 compared to clusters 1 and 3 (not significant, Chi-square p = 0.1926).	('patients', 'Species', '9606', (27, 35))	('TP53', 'Gene', '7157', (45, 49))	('TP53', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))
57500	26716509	Notably, our results matched previous observations that mutations of TP53 and PPP2R1A were more common in the serous-like, which was enriched in cluster 2.	('PPP2R1A', 'Gene', '5518', (78, 85))	('mutations', 'Var', (56, 65))	('common', 'Reg', (96, 102))	('TP53', 'Gene', '7157', (69, 73))	('serous', 'Chemical', '-', (110, 116))	('TP53', 'Gene', (69, 73))	('serous-like', 'Disease', (110, 121))	('PPP2R1A', 'Gene', (78, 85))
57501	26716509	Comparatively, mutations of PTEN and ARID1A were more common in endometrioid endometrial cancer, which was enriched in clusters 1 and 3.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('ARID1A', 'Gene', '8289', (37, 43))	('mutations', 'Var', (15, 24))	('endometrioid endometrial cancer', 'Disease', 'MESH:D016889', (64, 95))	('endometrioid endometrial cancer', 'Disease', (64, 95))	('common', 'Reg', (54, 60))	('ARID1A', 'Gene', (37, 43))	('endometrial cancer', 'Phenotype', 'HP:0012114', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
57502	26716509	For instance, 4 of 6 eSNVs in CTNNB1 were enriched in cluster 1 patients and showed mutually exclusive patterns.	('eSNVs', 'Var', (21, 26))	('CTNNB1', 'Gene', '1499', (30, 36))	('patients', 'Species', '9606', (64, 72))	('CTNNB1', 'Gene', (30, 36))
57505	26716509	In addition, although most patients possessing TP53 mutations were enriched in cluster 2, this confirms previous results that the TP53 mutation is linked to poorer outcomes; however, the TP53 rs121913343 variation was only observed in cluster 1 patients.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (245, 253))	('rs121913343', 'Mutation', 'rs121913343', (192, 203))	('TP53', 'Gene', '7157', (187, 191))	('patients', 'Species', '9606', (27, 35))	('TP53', 'Gene', (187, 191))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', '7157', (130, 134))	('mutation', 'Var', (135, 143))	('TP53', 'Gene', (130, 134))	('TP53', 'Gene', (47, 51))	('rs121913343', 'Var', (192, 203))
57506	26716509	To identify cooperative dysregulation of eSNVs and gene transcription which may contribute to tumorigenesis and cancer progression, we derived a cluster-centric pairwise mutation-mutation correlation analysis based on beta-coefficients of transcript levels of associated genes (Supplementary Figure 3C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('dysregulation', 'Var', (24, 37))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('contribute', 'Reg', (80, 90))
57515	26716509	Second, we showed that patients' mutation profiles can be used to stratify UCECs, further linking disease aggressiveness and patient prognoses, thus providing a rationale to facilitate the fast-tracking of potential therapeutic targets in endometrial cancer.	('mutation', 'Var', (33, 41))	('endometrial cancer', 'Disease', 'MESH:D016889', (239, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('patients', 'Species', '9606', (23, 31))	('linking disease aggressiveness', 'Disease', 'MESH:D038901', (90, 120))	('aggressiveness', 'Phenotype', 'HP:0000718', (106, 120))	('linking disease aggressiveness', 'Disease', (90, 120))	('patient', 'Species', '9606', (125, 132))	('endometrial cancer', 'Disease', (239, 257))	('endometrial cancer', 'Phenotype', 'HP:0012114', (239, 257))	('patient', 'Species', '9606', (23, 30))
57516	26716509	Third, we emphasized the importance of depicting somatic mutation profiles in an SNV-based manner, as different mutations in the same genes may link to distinct aggressiveness and prognostic outcomes in cancer patients.	('link to', 'Reg', (144, 151))	('aggressiveness', 'Disease', 'MESH:D001523', (161, 175))	('mutations', 'Var', (112, 121))	('aggressiveness', 'Disease', (161, 175))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Disease', (203, 209))	('patients', 'Species', '9606', (210, 218))	('aggressiveness', 'Phenotype', 'HP:0000718', (161, 175))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
57517	26716509	In 3 identified endometrial cancer-related cis-eSNVs, we mentioned that alterations in TP53 (tumor protein p53) are well-studied in endometrial cancer, and our results revealed that 14 eSNVs were significantly correlated with transcript levels of 267 genes, demonstrating a wide regulatory role of TP53 somatic alterations in endometrial cancer.	('p53', 'Gene', (107, 110))	('endometrial cancer', 'Disease', (16, 34))	('transcript levels', 'MPA', (226, 243))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('endometrial cancer', 'Disease', 'MESH:D016889', (16, 34))	('TP53', 'Gene', (298, 302))	('correlated', 'Reg', (210, 220))	('TP53', 'Gene', '7157', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alterations', 'Var', (311, 322))	('endometrial cancer', 'Phenotype', 'HP:0012114', (132, 150))	('endometrial cancer', 'Disease', 'MESH:D016889', (326, 344))	('endometrial cancer', 'Disease', (132, 150))	('TP53', 'Gene', '7157', (298, 302))	('endometrial cancer', 'Phenotype', 'HP:0012114', (326, 344))	('endometrial cancer', 'Disease', 'MESH:D016889', (132, 150))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('p53', 'Gene', '7157', (107, 110))	('TP53', 'Gene', (87, 91))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('endometrial cancer', 'Disease', (326, 344))	('endometrial cancer', 'Phenotype', 'HP:0012114', (16, 34))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
57519	26716509	Two eSNVs (chr12:14576892 and chr12:14649176) on ATF7IP were identified to cause dysregulation of 100 genes.	('cause', 'Reg', (75, 80))	('ATF7IP', 'Gene', (49, 55))	('dysregulation', 'MPA', (81, 94))	('ATF7IP', 'Gene', '55729', (49, 55))	('chr12:14649176', 'Var', (30, 44))
57522	26716509	In addition, 1 somatic alteration (chr8:21827087) on XPO7 (Ran GTPase binding protein) was identified to be expression-associated in endometrial cancer, which was correlated with expression levels of 32 genes.	('Ran', 'Gene', '5901', (59, 62))	('XPO7', 'Gene', '23039', (53, 57))	('XPO7', 'Gene', (53, 57))	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('alteration', 'Var', (23, 33))	('endometrial cancer', 'Disease', 'MESH:D016889', (133, 151))	('Ran', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('endometrial cancer', 'Disease', (133, 151))
57527	26716509	Since late-stage (stages III + IV) and serous-like endometrial cancer patients were enriched in cluster 2 compared to clusters 1 and 3, the recurrent gain of these mutations may therefore be reflected by the disease progression, and further linked to disease aggressiveness in patients.	('aggressiveness', 'Phenotype', 'HP:0000718', (259, 273))	('patients', 'Species', '9606', (70, 78))	('linked to disease aggressiveness', 'Disease', (241, 273))	('endometrial cancer', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('patients', 'Species', '9606', (277, 285))	('serous', 'Chemical', '-', (39, 45))	('endometrial cancer', 'Disease', 'MESH:D016889', (51, 69))	('linked to disease aggressiveness', 'Disease', 'MESH:D038901', (241, 273))	('mutations', 'Var', (164, 173))	('gain', 'PosReg', (150, 154))
57529	26716509	Taken together, we have enumerated 31 cluster-related and/or prognostic-related eSNV-based mutational signatures, and linking their mutational changes to various genes transcription level changes can highlight the underlying mechanism of how these somatic alterations incarnate disease aggressiveness and prognostic potential in endometrial cancer patients.	('patients', 'Species', '9606', (348, 356))	('endometrial cancer', 'Phenotype', 'HP:0012114', (329, 347))	('aggressiveness', 'Disease', 'MESH:D001523', (286, 300))	('endometrial cancer', 'Disease', 'MESH:D016889', (329, 347))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('eSNV-based', 'Gene', (80, 90))	('mutational', 'Var', (91, 101))	('aggressiveness', 'Disease', (286, 300))	('alterations', 'Var', (256, 267))	('aggressiveness', 'Phenotype', 'HP:0000718', (286, 300))	('incarnate', 'Reg', (268, 277))	('endometrial cancer', 'Disease', (329, 347))
57532	26716509	As an illustration, somatic alterations, including chr4:153249510 (FBXW7), chr5:67591246 (PIK3R1), rs28934576 and rs11540652 (TP53), rs121913399 (CTNNB1), and chr19:52716323 (PPP2R1A), were specifically enriched in cluster 2, which was linked to higher tumor aggression and poor prognoses.	('chr5:67591246', 'Var', (75, 88))	('TP53', 'Gene', (126, 130))	('higher', 'PosReg', (246, 252))	('CTNNB1', 'Gene', '1499', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('FBXW7', 'Gene', '55294', (67, 72))	('rs11540652', 'Mutation', 'rs11540652', (114, 124))	('PPP2R1A', 'Gene', '5518', (175, 182))	('chr4:153249510', 'Var', (51, 65))	('tumor aggression', 'Disease', (253, 269))	('PIK3R1', 'Gene', (90, 96))	('TP53', 'Gene', '7157', (126, 130))	('CTNNB1', 'Gene', (146, 152))	('PPP2R1A', 'Gene', (175, 182))	('tumor aggression', 'Disease', 'MESH:D001523', (253, 269))	('chr19:52716323', 'Var', (159, 173))	('aggression', 'Phenotype', 'HP:0000718', (259, 269))	('FBXW7', 'Gene', (67, 72))	('PIK3R1', 'Gene', '5295', (90, 96))	('rs28934576', 'Var', (99, 109))	('rs11540652', 'Var', (114, 124))	('rs121913399', 'Var', (133, 144))	('rs121913399', 'Mutation', 'rs121913399', (133, 144))	('rs28934576', 'Mutation', 'rs28934576', (99, 109))
57533	26716509	However, rs121913343 in TP53 and rs121913403, rs28931588, and 121913413 in CTNNB1 were specifically enriched in cluster 1, which was identified to be less aggressive (see Supplementary note: SNV-based somatic mutation profiles).	('CTNNB1', 'Gene', (75, 81))	('121913413', 'Var', (62, 71))	('rs121913403', 'Var', (33, 44))	('rs28931588', 'Var', (46, 56))	('TP53', 'Gene', (24, 28))	('rs121913343', 'Var', (9, 20))	('CTNNB1', 'Gene', '1499', (75, 81))	('rs28931588', 'Mutation', 'rs28931588', (46, 56))	('rs121913403', 'Mutation', 'rs121913403', (33, 44))	('rs121913343', 'Mutation', 'rs121913343', (9, 20))	('TP53', 'Gene', '7157', (24, 28))
57571	26716509	In short, the DawnRank algorithm evaluated the connectivity and number of differentially expressed genes to measure the impact of a mutation, utilized a dynamic damping factor to rank mutated genes based on their ability to perturb downstream genes, and returned personalized ranked mutated gene lists of every single UCEC sample.	('mutation', 'Var', (132, 140))	('Ran', 'Gene', (18, 21))	('Ran', 'Gene', '5901', (18, 21))	('perturb', 'Reg', (224, 231))
57631	19959033	Further analysis of the same St. Jude cohort showed that the 20-year cumulative incidence of CNS tumors increased in conjunction with radiation dose: 1% at 10-21Gy; 1.7% at >21-30 Gy; and 3.2% at >30Gy.	('CNS tumors', 'Disease', (93, 103))	('10-21Gy', 'Var', (156, 163))	('CNS tumors', 'Disease', 'MESH:D009369', (93, 103))	('increased', 'PosReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
57636	19959033	Secondary leukemias associated with high dose alkylating agent exposure usually occur in older children, have a latency of 4-10 years, and are associated with myelodysplasia and deletions in chromosomes 5 and 7.	('myelodysplasia', 'Disease', 'MESH:D009190', (159, 173))	('myelodysplasia', 'Disease', (159, 173))	('associated', 'Reg', (143, 153))	('leukemias', 'Disease', 'MESH:D007938', (10, 19))	('deletions', 'Var', (178, 187))	('leukemia', 'Phenotype', 'HP:0001909', (10, 18))	('children', 'Species', '9606', (95, 103))	('myelodysplasia', 'Phenotype', 'HP:0002863', (159, 173))	('leukemias', 'Phenotype', 'HP:0001909', (10, 19))	('leukemias', 'Disease', (10, 19))
57637	19959033	In contrast, topoisomerase II-induced secondary leukemias are typically diagnosed in younger children, have a short latency period (median 1-3 years), and are associated with balanced chromosomal translocation 11q23, or less frequently 21q22.	('children', 'Species', '9606', (93, 101))	('leukemias', 'Disease', 'MESH:D007938', (48, 57))	('secondary leukemia', 'Disease', 'MESH:D060085', (38, 56))	('leukemia', 'Phenotype', 'HP:0001909', (48, 56))	('secondary leukemia', 'Disease', (38, 56))	('leukemias', 'Phenotype', 'HP:0001909', (48, 57))	('topoisomerase II-induced', 'Enzyme', (13, 37))	('21q22', 'Var', (236, 241))	('leukemias', 'Disease', (48, 57))
57640	19959033	In addition, the administration schedule of epipdophyllotoxins appears to contribute to the risk of secondary leukemias, as prolonged infusions were found to be an independent risk factor.	('epipdophyllotoxins', 'Var', (44, 62))	('leukemias', 'Phenotype', 'HP:0001909', (110, 119))	('leukemias', 'Disease', (110, 119))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('leukemias', 'Disease', 'MESH:D007938', (110, 119))	('epipdophyllotoxins', 'Chemical', '-', (44, 62))	('secondary leukemia', 'Disease', 'MESH:D060085', (100, 118))	('secondary leukemia', 'Disease', (100, 118))
57645	19959033	Approximately 40% of cases of RB are hereditary, with an identifiable germline deletion in the Rb-1 tumor suppressor gene which confers a genetic predisposition to subsequent neoplasms.	('neoplasms', 'Disease', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('RB', 'Phenotype', 'HP:0009919', (30, 32))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('Rb-1', 'Gene', (95, 99))	('deletion', 'Var', (79, 87))	('RB', 'Gene', '5925', (30, 32))	('neoplasms', 'Disease', 'MESH:D009369', (175, 184))
57646	19959033	The specific secondary malignancies for which survivors with hereditary RB are at the highest risk include soft tissue sarcomas, bone sarcomas, and malignant melanoma.	('bone sarcomas', 'Disease', 'MESH:D001847', (129, 142))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (107, 127))	('bone sarcomas', 'Disease', (129, 142))	('bone sarcomas', 'Phenotype', 'HP:0002669', (129, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('bone sarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('RB', 'Phenotype', 'HP:0009919', (72, 74))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('malignant melanoma', 'Disease', (148, 166))	('hereditary', 'Var', (61, 71))	('malignancies', 'Disease', (23, 35))	('RB', 'Gene', '5925', (72, 74))	('soft tissue sarcomas', 'Disease', (107, 127))	('malignant melanoma', 'Phenotype', 'HP:0002861', (148, 166))	('sarcomas', 'Phenotype', 'HP:0100242', (119, 127))	('malignant melanoma', 'Disease', 'MESH:D008545', (148, 166))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (107, 127))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (107, 126))
57653	19959033	In general, survivors of nonhereditary RB are not considered to be at increased risk of secondary malignancies except for soft tissue sarcomas (SIR 21.9, 95% CI 4.5-63.7), and female breast cancer (SIR 2.8, 95% CI 1.1-5.9).	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (122, 142))	('soft tissue sarcomas', 'Disease', (122, 142))	('malignancies', 'Disease', (98, 110))	('RB', 'Phenotype', 'HP:0009919', (39, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('RB', 'Gene', '5925', (39, 41))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (122, 142))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (122, 141))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('breast cancer', 'Disease', (183, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('nonhereditary', 'Var', (25, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
57705	19959033	While alkylating agent chemotherapy for HL is associated with a subsequently reduced risk of breast cancer through a deleterious effect on ovarian function, increased risks of lung cancer risk ensue.	('HL', 'Phenotype', 'HP:0012189', (40, 42))	('alkylating agent', 'Var', (6, 22))	('ovarian', 'MPA', (139, 146))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('HL', 'CellLine', 'CVCL:2492', (40, 42))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('reduced', 'NegReg', (77, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
57739	19959033	When the dose-response analyses were focused on patients <45 years of age when irradiated, women treated with postlumpectomy radiation (which was associated with higher doses to the contralateral breast) had a significantly 1.5-fold increased risk of contralateral breast cancer compared with patients treated with postmastectomy radiation therapy.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('contralateral breast cancer', 'Disease', (251, 278))	('women', 'Species', '9606', (91, 96))	('postlumpectomy radiation', 'Var', (110, 134))	('patients', 'Species', '9606', (48, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (265, 278))	('contralateral breast cancer', 'Disease', 'MESH:D001943', (251, 278))	('patients', 'Species', '9606', (293, 301))
57869	28239427	Tissue distribution of 5alpha-reductase varies during the life span and the enzyme expression is hormonally regulated; for example, 5alpha-reductase mRNA expression in rat prostate is upregulated by DHT.	('5alpha-reductase', 'Enzyme', (132, 148))	('DHT', 'Var', (199, 202))	('rat', 'Species', '10116', (168, 171))	('DHT', 'Chemical', 'MESH:D013196', (199, 202))	('mRNA expression', 'MPA', (149, 164))	('upregulated', 'PosReg', (184, 195))
57912	28239427	Androgen ablation generally leads to a decrease of PCa in a significant number of patients; however, eventually, many patients relapse with a more aggressive and metastatic stage of PCa which is androgen-insensitive, thus known as castration-resistant prostate cancer (CRPC).	('man', 'Species', '9606', (113, 116))	('ablation', 'Var', (9, 17))	('PCa', 'Disease', (182, 185))	('prostate cancer', 'Disease', (252, 267))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('rat', 'Species', '10116', (235, 238))	('PCa', 'Disease', (51, 54))	('PCa', 'Phenotype', 'HP:0012125', (182, 185))	('prostate cancer', 'Disease', 'MESH:D011471', (252, 267))	('prostate cancer', 'Phenotype', 'HP:0012125', (252, 267))	('PCa', 'Phenotype', 'HP:0012125', (51, 54))	('patients', 'Species', '9606', (118, 126))
57922	28239427	More convincingly, exposures to several antiandrogenic pesticides and/or plasticizers have been shown to induce cryptorchidism, hypospadias, and reduced semen quality in humans and rodents and are often linked to shortened ano-genital distance (typical of females).	('induce', 'PosReg', (105, 111))	('men', 'Species', '9606', (155, 158))	('reduced', 'NegReg', (145, 152))	('humans', 'Species', '9606', (170, 176))	('hypospadias', 'Disease', 'MESH:D007021', (128, 139))	('shortened', 'NegReg', (213, 222))	('exposures', 'Var', (19, 28))	('cryptorchidism', 'Disease', (112, 126))	('hypospadias', 'Disease', (128, 139))	('hypospadias', 'Phenotype', 'HP:0000047', (128, 139))	('semen quality', 'CPA', (153, 166))	('cryptorchidism', 'Phenotype', 'HP:0000028', (112, 126))
57941	28239427	This environmentally induced epigenetic transgenerational inheritance of disease is considered a component of the etiology of male infertility.	('men', 'Species', '9606', (12, 15))	('male infertility', 'Phenotype', 'HP:0003251', (126, 142))	('male infertility', 'Disease', (126, 142))	('male infertility', 'Disease', 'MESH:D007248', (126, 142))	('infertility', 'Phenotype', 'HP:0000789', (131, 142))	('epigenetic transgenerational', 'Var', (29, 57))	('rat', 'Species', '10116', (49, 52))
57946	28239427	Furthermore, VIN decreased both AR nuclear accumulation and its phosphorylation in vitro, thus impairing the conformational changes necessary to induce the AR-mediated transcriptional activation modulated by the AF-1 region.	('AR nuclear accumulation', 'MPA', (32, 55))	('phosphorylation', 'MPA', (64, 79))	('conformational changes', 'MPA', (109, 131))	('decreased', 'NegReg', (17, 26))	('AF-1', 'Gene', (212, 216))	('AF-1', 'Gene', '1946', (212, 216))	('impairing', 'NegReg', (95, 104))	('VIN', 'Var', (13, 16))
57955	28239427	In particular, the reproductive hormone profile showed significantly reduced levels of serum DHT in male rats at ETU 0.3 mg/kg body weight/day, which corresponded to the dose at which the hypothyroid status was more evident.	('hypothyroid status', 'Phenotype', 'HP:0000821', (188, 206))	('hypothyroid', 'Disease', 'MESH:D007037', (188, 199))	('reduced', 'NegReg', (69, 76))	('DHT', 'Chemical', 'MESH:D013196', (93, 96))	('ETU', 'Chemical', 'MESH:D005031', (113, 116))	('serum DHT', 'MPA', (87, 96))	('hypothyroid', 'Disease', (188, 199))	('ETU 0.3 mg/kg', 'Var', (113, 126))	('rats', 'Species', '10116', (105, 109))
57968	28239427	Therefore, it has been suggested that GA could act through a mutated AR bearing the point mutation T877A expressed in LNCaP cells.	('T877A', 'Mutation', 'c.877T>A', (99, 104))	('LNCaP', 'CellLine', 'CVCL:0395', (118, 123))	('GA', 'Chemical', 'MESH:C003121', (38, 40))	('T877A', 'Var', (99, 104))	('mutated', 'Var', (61, 68))
57995	28239427	Phthalates have been shown to reduce testicular T levels in fetal and neonatal male rats.	('testicular T levels', 'MPA', (37, 56))	('Phthalates', 'Var', (0, 10))	('Phthalates', 'Chemical', 'MESH:C032279', (0, 10))	('reduce testicular', 'Phenotype', 'HP:0008734', (30, 47))	('reduce', 'NegReg', (30, 36))	('rats', 'Species', '10116', (84, 88))
58006	28239427	All cell models used expressed the AR full length (i.e., 110 kDa), while prostate cancer cells were positive for several AR splicing forms (e.g., ARDeltaLBD or AR 75-80 kDa).	('prostate cancer', 'Disease', (73, 88))	('AR 75-80 kDa', 'Var', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))
58008	28239427	These data have recently been confirmed in HeLa cells transiently transfected with AR full length (110 kDa) or AR mutants (i.e., AR ~80 kDa and AR ~28 kDa) (Marino and Pellegrini, personnel communication) and have been established by other authors with different AR mutants.	('AR ~80 kDa', 'Var', (129, 139))	('AR ~28 kDa', 'Var', (144, 154))	('110 kDa', 'Var', (99, 106))	('HeLa', 'CellLine', 'CVCL:0030', (43, 47))
58009	28239427	Thus, androgen signaling seems to be less prone to BPA interference when wild-type AR is expressed, but BPA could interfere with the therapy in patients with advanced PCa via mutant ARs.	('interfere', 'NegReg', (114, 123))	('PCa', 'Disease', (167, 170))	('PCa', 'Phenotype', 'HP:0012125', (167, 170))	('therapy', 'MPA', (133, 140))	('BPA', 'Chemical', 'MESH:C006780', (51, 54))	('BPA', 'Chemical', 'MESH:C006780', (104, 107))	('patients', 'Species', '9606', (144, 152))	('ARs', 'Protein', (182, 185))	('mutant', 'Var', (175, 181))
58010	28239427	Experiments performed in rodent models and human prostate cell lines showed that BPA can influence carcinogenesis, modulate PCa cell proliferation, and for some tumors, stimulate progression.	('BPA', 'Chemical', 'MESH:C006780', (81, 84))	('modulate', 'Reg', (115, 123))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('influence', 'Reg', (89, 98))	('human', 'Species', '9606', (43, 48))	('PCa', 'Disease', (124, 127))	('progression', 'CPA', (179, 190))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('carcinogenesis', 'Disease', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('rat', 'Species', '10116', (140, 143))	('PCa', 'Phenotype', 'HP:0012125', (124, 127))	('BPA', 'Var', (81, 84))	('stimulate', 'PosReg', (169, 178))	('men', 'Species', '9606', (6, 9))
58032	28239427	Moreover, QRC caused downregulation of AR expression and activity in PCa cells in which mutant ARs were expressed.	('QRC', 'Var', (10, 13))	('QRC', 'Chemical', 'MESH:D011794', (10, 13))	('expression', 'MPA', (42, 52))	('downregulation', 'NegReg', (21, 35))	('mutant', 'Var', (88, 94))	('activity', 'MPA', (57, 65))	('PCa', 'Phenotype', 'HP:0012125', (69, 72))
58034	28239427	The repression effects on AR expression can actually reduce its function; moreover, QRC inhibited PSA and KLK2 secretion, two proteins known as androgen-regulated tumor markers.	('reduce', 'NegReg', (53, 59))	('inhibited', 'NegReg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('QRC', 'Var', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('KLK2', 'Gene', (106, 110))	('tumor', 'Disease', (163, 168))	('QRC', 'Chemical', 'MESH:D011794', (84, 87))	('KLK2', 'Gene', '3817', (106, 110))	('PSA', 'Gene', '354', (98, 101))	('PSA', 'Gene', (98, 101))	('function', 'MPA', (64, 72))
58036	28239427	QRC can also downregulate the expression of other prostate-specific genes, such as NKX3.1 whose expression is associated with a more aggressive phenotype of PCa.	('QRC', 'Chemical', 'MESH:D011794', (0, 3))	('expression', 'MPA', (30, 40))	('QRC', 'Var', (0, 3))	('NKX3.1', 'Gene', (83, 89))	('PCa', 'Disease', (157, 160))	('PCa', 'Phenotype', 'HP:0012125', (157, 160))	('expression', 'MPA', (96, 106))	('downregulate', 'NegReg', (13, 25))	('associated with', 'Reg', (110, 125))	('NKX3.1', 'Gene', '4824', (83, 89))
58042	28239427	Finally, QRC can inhibit the AR expression at the transcriptional level, and thereby downregulate the androgen-inducible genes including PSA, KLK2, NKX3.1, and ODC, which play roles in development and progression of PCa.	('NKX3.1', 'Gene', (148, 154))	('ODC', 'Gene', (160, 163))	('PCa', 'Disease', (216, 219))	('KLK2', 'Gene', '3817', (142, 146))	('downregulate', 'NegReg', (85, 97))	('QRC', 'Chemical', 'MESH:D011794', (9, 12))	('androgen-inducible genes', 'Gene', (102, 126))	('inhibit', 'NegReg', (17, 24))	('QRC', 'Var', (9, 12))	('PCa', 'Phenotype', 'HP:0012125', (216, 219))	('ODC', 'Gene', '4953', (160, 163))	('men', 'Species', '9606', (192, 195))	('NKX3.1', 'Gene', '4824', (148, 154))	('PSA', 'Gene', (137, 140))	('KLK2', 'Gene', (142, 146))	('PSA', 'Gene', '354', (137, 140))	('AR expression', 'MPA', (29, 42))
58102	28239427	As a whole, the combined effect of EDCs on androgen-dependent gene expression and, more general, on animal physiology is very complex because many EDCs can act as modulator of AR or estrogen receptors leading to the activation and the interaction of multiple signaling pathways, and in turn, EDCs can affect reproduction and development by more than one mechanism.	('development', 'CPA', (325, 336))	('activation', 'PosReg', (216, 226))	('estrogen receptor', 'Gene', (182, 199))	('estrogen receptor', 'Gene', '2099', (182, 199))	('EDCs', 'Gene', (147, 151))	('reproduction', 'CPA', (308, 320))	('affect', 'Reg', (301, 307))	('EDCs', 'Var', (292, 296))	('interaction', 'Interaction', (235, 246))	('man', 'Species', '9606', (142, 145))	('men', 'Species', '9606', (332, 335))
58103	28239427	Moreover, the evidence that AR mutant gain the ability to utilize some EDCs (e.g., BPA) as an agonist enlarge the effect of these substances.	('gain', 'PosReg', (38, 42))	('effect', 'MPA', (114, 120))	('mutant', 'Var', (31, 37))	('ability', 'MPA', (47, 54))	('enlarge', 'PosReg', (102, 109))	('BPA', 'Chemical', 'MESH:C006780', (83, 86))
58105	28239427	Since the alteration of androgen signaling can induce a variety of endocrine disruptive responses, further studies are required to identify the downstream targets of EDC-modulated AR signaling, in order to elucidate their specific impact on male health.	('alteration', 'Var', (10, 20))	('induce', 'Reg', (47, 53))	('rat', 'Species', '10116', (14, 17))	('endocrine disruptive responses', 'MPA', (67, 97))
58137	26303320	Moreover, the use of cisplatin-based chemotherapy is associated with a dose dependent and, in part, irreversible impairment of fertility.	('cisplatin-based chemotherapy', 'Var', (21, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('fertility', 'CPA', (127, 136))	('impairment of fertility', 'Phenotype', 'HP:0000144', (113, 136))	('men', 'Species', '9606', (119, 122))	('impairment', 'NegReg', (113, 123))
58172	26303320	To confirm the cordycepin-induced caspase signaling cascades in MA-10 cells, the following caspase inhibitors were tested: Z-VAD-FMK (general caspase inhibitor), Z-IETD-FMK (caspase-8 inhibitor), and Z-LEHD-FMK (caspase-9 inhibitor).	('Z-VAD-FMK', 'Var', (123, 132))	('caspase', 'Gene', (91, 98))	('caspase-9', 'Gene', '12371', (212, 221))	('caspase', 'Gene', '12368;12370;12371', (174, 181))	('caspase-9', 'Gene', (212, 221))	('Z-IETD-FMK', 'Var', (162, 172))	('caspase', 'Gene', '12368;12370;12371', (142, 149))	('Z-IETD-FMK', 'Chemical', 'MESH:C403753', (162, 172))	('caspase-8', 'Gene', '12370', (174, 183))	('MA-10', 'Chemical', '-', (64, 69))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (123, 132))	('caspase', 'Gene', '12368;12370;12371', (212, 219))	('caspase', 'Gene', (34, 41))	('Z-LEHD-FMK', 'Chemical', 'MESH:C403754', (200, 210))	('caspase', 'Gene', '12368;12370;12371', (91, 98))	('caspase', 'Gene', (174, 181))	('cordycepin', 'Chemical', 'MESH:C058120', (15, 25))	('caspase', 'Gene', (142, 149))	('caspase-8', 'Gene', (174, 183))	('caspase', 'Gene', (212, 219))	('caspase', 'Gene', '12368;12370;12371', (34, 41))
58173	26303320	MA-10 cells were treated with caspase inhibitors for 1 h and then cordycepin (100 muM) was added and cells were treated for an additional 12 h. The general caspase inhibitor Z-VAD-FMK significantly attenuated cleavage of caspase-3, -8, and -9 (p < 0.05; Fig.	('caspase', 'Gene', '12368;12370;12371', (221, 228))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (174, 183))	('Z-VAD-FMK', 'Var', (174, 183))	('caspase', 'Gene', (156, 163))	('caspase', 'Gene', '12368;12370;12371', (30, 37))	('MA-10', 'Chemical', '-', (0, 5))	('caspase', 'Gene', (30, 37))	('cleavage', 'MPA', (209, 217))	('cordycepin', 'Chemical', 'MESH:C058120', (66, 76))	('attenuated', 'NegReg', (198, 208))	('caspase-3, -8, and -9', 'Gene', '12367;12370;12371', (221, 242))	('caspase', 'Gene', '12368;12370;12371', (156, 163))	('caspase', 'Gene', (221, 228))
58184	26303320	To confirm whether MAPK signaling pathways were directly activated by cordycepin, MA-10 cells were pre-treated with inhibitors of ERK (PD98059), JNK (SP600125), and p38 (SB203580) 1 h, then 100 muM cordycepin was added and cells were treated for an additional 12 h. Addition of inhibitors significantly reduced cordycepin-induced elevation of p-ERK, p-JNK, and p-p38 (p < 0.05; Fig.	('MAPK', 'Gene', '26413;26417', (19, 23))	('cordycepin-induced', 'Disease', (311, 329))	('inhibitors', 'Var', (278, 288))	('p-p38', 'MPA', (361, 366))	('SB203580', 'Chemical', 'MESH:C093642', (170, 178))	('p-ERK', 'Gene', (343, 348))	('elevation', 'PosReg', (330, 339))	('MAPK', 'Gene', (19, 23))	('reduced', 'NegReg', (303, 310))	('ERK', 'Gene', (345, 348))	('SP600125', 'Chemical', 'MESH:C432165', (150, 158))	('ERK', 'Gene', (130, 133))	('cordycepin', 'Chemical', 'MESH:C058120', (311, 321))	('ERK', 'Gene', '26413', (345, 348))	('MA-10', 'Chemical', '-', (82, 87))	('p-ERK', 'Gene', '13666', (343, 348))	('ERK', 'Gene', '26413', (130, 133))	('JNK', 'Gene', (145, 148))	('cordycepin', 'Chemical', 'MESH:C058120', (198, 208))	('JNK', 'Gene', (352, 355))	('PD98059', 'Chemical', 'MESH:C093973', (135, 142))	('cordycepin', 'Chemical', 'MESH:C058120', (70, 80))	('JNK', 'Gene', '26419', (145, 148))	('JNK', 'Gene', '26419', (352, 355))
58187	26303320	Inhibition of p38 partially restored the viability of cordycepin-induced cell death in MA-10 cells (p < 0.01; Fig.	('p38', 'Gene', (14, 17))	('MA-10', 'Chemical', '-', (87, 92))	('cordycepin', 'Chemical', 'MESH:C058120', (54, 64))	('Inhibition', 'Var', (0, 10))
58190	26303320	MA-10 cells were pre-treated with inhibitors of general caspase (Z-VAD-FMK) and p38 (SB203580) 1 h, then 100 muM cordycepin was added and cells were treated for an additional 24 h. Treating MA-10 cells with Z-VAD-FMK and SB203580 did not increase a significant amount of apoptotic cells and change morphology compared to control (p > 0.05; Fig.	('cordycepin', 'Chemical', 'MESH:C058120', (113, 123))	('MA-10', 'Chemical', '-', (0, 5))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (65, 74))	('SB203580', 'Chemical', 'MESH:C093642', (85, 93))	('change', 'Reg', (291, 297))	('MA-10', 'Chemical', '-', (190, 195))	('Z-VAD-FMK', 'Var', (207, 216))	('caspase', 'Gene', '12368;12370;12371', (56, 63))	('SB203580', 'Var', (221, 229))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (207, 216))	('SB203580', 'Chemical', 'MESH:C093642', (221, 229))	('caspase', 'Gene', (56, 63))
58192	26303320	Western blotting for cleaved caspase-3 and PARP demonstrates that the target of cordycepin-induced caspase activation is attenuated when the p38 inhibitor SB203580 is added 1 h prior to cordycepin treatment (p < 0.001; Fig.	('caspase', 'Gene', '12368;12370;12371', (29, 36))	('men', 'Species', '9606', (202, 205))	('caspase', 'Gene', (29, 36))	('attenuated', 'NegReg', (121, 131))	('caspase', 'Gene', (99, 106))	('caspase', 'Gene', '12368;12370;12371', (99, 106))	('SB203580', 'Chemical', 'MESH:C093642', (155, 163))	('SB203580', 'Var', (155, 163))	('cordycepin', 'Chemical', 'MESH:C058120', (186, 196))	('cordycepin', 'Chemical', 'MESH:C058120', (80, 90))
58227	26303320	Moreover, the MTT assay was used to determine whether the blocked p53 signaling could rescue the viability of MA-10 cells treated with cordycepin.	('MTT', 'Chemical', '-', (14, 17))	('rescue', 'PosReg', (86, 92))	('p53', 'Gene', '22060', (66, 69))	('viability', 'CPA', (97, 106))	('MA-10', 'Chemical', '-', (110, 115))	('cordycepin', 'Chemical', 'MESH:C058120', (135, 145))	('blocked', 'Var', (58, 65))	('p53', 'Gene', (66, 69))
58234	26303320	Animals treated with cordycepin exhibited a significant decrease in tumor volume compared with control mice beginning on day 21 (616.5 vs. 1201 mm3; p < 0.05; Fig.	('tumor', 'Disease', (68, 73))	('mice', 'Species', '10090', (103, 107))	('cordycepin', 'Var', (21, 31))	('cordycepin', 'Chemical', 'MESH:C058120', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('decrease', 'NegReg', (56, 64))
58244	26303320	We further showed that caspase inhibitors improved the viability of cordycepin-treated MA-10 cells, confirming that cordycepin activated caspase cascades to induce the apoptosis of MA-10 cells.	('cordycepin', 'Chemical', 'MESH:C058120', (116, 126))	('caspase', 'Gene', (23, 30))	('caspase', 'Gene', '12368;12370;12371', (23, 30))	('cordycepin', 'Var', (116, 126))	('improved', 'PosReg', (42, 50))	('MA-10', 'Chemical', '-', (181, 186))	('cordycepin', 'Chemical', 'MESH:C058120', (68, 78))	('caspase', 'Gene', (137, 144))	('induce', 'PosReg', (157, 163))	('caspase', 'Gene', '12368;12370;12371', (137, 144))	('MA-10', 'Chemical', '-', (87, 92))	('apoptosis', 'CPA', (168, 177))
58247	26303320	Previous studies have shown that p38 is important for induction of apoptosis in human breast cancer cells and colon cancer cells, which supports our current observation.	('colon cancer', 'Disease', (110, 122))	('p38', 'Var', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('human', 'Species', '9606', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('breast cancer', 'Disease', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))
58248	26303320	PI3K/mTOR inhibition increases the effectiveness of therapeutic drugs in several cancers.	('increases', 'PosReg', (21, 30))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('mTOR', 'Gene', (5, 9))	('mTOR', 'Gene', '56717', (5, 9))	('inhibition', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('effectiveness', 'MPA', (35, 48))
58261	26303320	However, knockdown of p53 did not affect p21 or CDK2 levels in cordycepin-treated cells.	('p21', 'Gene', (41, 44))	('CDK2', 'Gene', '12566', (48, 52))	('knockdown', 'Var', (9, 18))	('CDK2', 'Gene', (48, 52))	('p21', 'Gene', '12575', (41, 44))	('p53', 'Gene', (22, 25))	('cordycepin', 'Chemical', 'MESH:C058120', (63, 73))	('p53', 'Gene', '22060', (22, 25))
58281	26303320	Antibodies against cleaved caspase-8 (Asp387), cleaved caspase-9 (Asp353), cleaved caspase-3 (Asp175), cleaved caspase-6 (Asp162), cleaved caspase-7 (Asp198), LC3 I/II, mTOR, phosphorylated mTOR (p-mTOR; Ser2448), AKT, p-AKT (Ser473), ERK, p-ERK (Thr202/Tyr204), JNK, p-JNK (Thr183/Tyr185), p38, p-p38 (Thr180/Tyr182), p53, and p-p53 (Ser15) were purchased from Cell Signaling (Beverly, MA).	('p-ERK', 'Gene', (240, 245))	('ERK', 'Gene', (242, 245))	('JNK', 'Gene', (270, 273))	('caspase-6', 'Gene', '12368', (111, 120))	('JNK', 'Gene', (263, 266))	('ERK', 'Gene', (235, 238))	('mTOR', 'Gene', '56717', (190, 194))	('caspase-9', 'Gene', '12371', (55, 64))	('p53', 'Gene', (319, 322))	('mTOR', 'Gene', '56717', (198, 202))	('JNK', 'Gene', '26419', (263, 266))	('caspase-6', 'Gene', (111, 120))	('JNK', 'Gene', '26419', (270, 273))	('caspase-9', 'Gene', (55, 64))	('p53', 'Gene', '22060', (319, 322))	('caspase-8', 'Gene', (27, 36))	('ERK', 'Gene', '26413', (242, 245))	('mTOR', 'Gene', (169, 173))	('ERK', 'Gene', '26413', (235, 238))	('Thr180/Tyr182', 'Var', (303, 316))	('p-ERK', 'Gene', '13666', (240, 245))	('mTOR', 'Gene', (190, 194))	('mTOR', 'Gene', (198, 202))	('caspase-7', 'Gene', (139, 148))	('p53', 'Gene', (330, 333))	('caspase-8', 'Gene', '12370', (27, 36))	('LC3', 'Gene', '66734', (159, 162))	('LC3', 'Gene', (159, 162))	('caspase-7', 'Gene', '12369', (139, 148))	('p53', 'Gene', '22060', (330, 333))	('mTOR', 'Gene', '56717', (169, 173))
58428	25811459	However, if RBM3 was only related to cisplatin sensitivity, one would have expected a higher risk of relapse in patients with CS1 and low RBM3, receiving adjuvant BEP, which was not observed.	('CS1', 'Gene', (126, 129))	('RBM3', 'Gene', '5935', (138, 142))	('CS1', 'Gene', '1442', (126, 129))	('patients', 'Species', '9606', (112, 120))	('RBM3', 'Gene', (138, 142))	('RBM3', 'Gene', '5935', (12, 16))	('BEP', 'Chemical', 'MESH:C038328', (163, 166))	('low', 'Var', (134, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('RBM3', 'Gene', (12, 16))
58451	25384072	Further, we probed a range of testicular germ cell tumor (TGCT) samples and found PIWIL2 to be predominantly expressed as PL2L60A in most of them.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PIWIL2', 'Gene', (82, 88))	('germ cell tumor', 'Phenotype', 'HP:0100728', (41, 56))	('tumor', 'Disease', (51, 56))	('PL2L60A', 'Var', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
58452	25384072	Importantly, the levels of both PL2L60A mRNA and protein products were found to vary depending on the differentiation subtype of TGCTs, i.e., PL2L60A expression is significantly higher in undifferentiated seminomas and appears to be substantially decreased in mixed and nonseminomatous TGCTs.	('expression', 'MPA', (150, 160))	('decreased', 'NegReg', (247, 256))	('PL2L60A', 'Var', (142, 149))	('nonseminomatous', 'Disease', (270, 285))	('higher', 'PosReg', (178, 184))	('nonseminomatous', 'Disease', 'MESH:C537844', (270, 285))	('undifferentiated seminomas', 'Disease', 'MESH:D018239', (188, 214))	('undifferentiated seminomas', 'Disease', (188, 214))
58460	25384072	Finally, PIWIL2 knockdown in murine bone marrow mesenchymal stem cells has been shown to enhance cell proliferation and decrease expression of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('enhance', 'PosReg', (89, 96))	('murine', 'Species', '10090', (29, 35))	('expression', 'MPA', (129, 139))	('tumor', 'Disease', (143, 148))	('decrease', 'NegReg', (120, 128))	('knockdown', 'Var', (16, 25))	('PIWIL2', 'Gene', (9, 15))	('cell proliferation', 'CPA', (97, 115))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
58470	25384072	Cell lines used in experiments included TERA1 (ATCC HTB-105, testicular embryonal carcinoma), NT2/D1 (ATCC CRL-1973, pluripotent testicular embryonal carcinoma), A549 (ATCC CCL-185, lung carcinoma), T-47D (ATCC HTB-133, mammary gland ductal carcinoma), HeLa (ATCC CCL-2, cervical adenocarcinoma), Raji (ATCC CCL-86, Burkitt's lymphoma), Jurkat (ATCC TIB-152, acute T-cell leukaemia), NGP-127 (neuroblastoma,), IMR-32 (ATCC CCL-127, neuroblastoma), Daudi (ATCC CCL-213, Burkitt's lymphoma), A-431 (ATCC CRL-1555, epidermoid carcinoma), HEK-293 (ATCC CRL-1573, embryonic kidney), Hep G2 (ATCC HB-8065, hepatocellular carcinoma) and HL-60 (ATCC CCL-240, acute promyelocytic leukemia).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('pluripotent testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (117, 159))	('lymphoma', 'Phenotype', 'HP:0002665', (479, 487))	('CCL-2', 'Gene', (460, 465))	('CCL-2', 'Gene', '6347', (264, 269))	('neuroblastoma', 'Phenotype', 'HP:0003006', (432, 445))	('epidermoid carcinoma', 'Disease', (512, 532))	('neuroblastoma', 'Disease', 'MESH:D009447', (432, 445))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (600, 624))	('CCL-2', 'Gene', '6347', (460, 465))	('Hep G2', 'CellLine', 'CVCL:0027', (578, 584))	('embryonic kidney', 'Disease', 'MESH:D007674', (559, 575))	('testicular embryonal carcinoma', 'Disease', (61, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (326, 334))	('testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (61, 91))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (651, 679))	('CCL-2', 'Gene', (642, 647))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('A-431', 'CellLine', 'CVCL:0037', (490, 495))	('pluripotent testicular embryonal carcinoma', 'Disease', (117, 159))	('lung carcinoma', 'Disease', 'MESH:D008175', (182, 196))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (271, 294))	('leukemia', 'Phenotype', 'HP:0001909', (671, 679))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (600, 624))	('HL-60', 'CellLine', 'CVCL:0002', (630, 635))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (651, 679))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (72, 91))	('testicular embryonal carcinoma', 'Disease', 'MESH:D013736', (129, 159))	('acute promyelocytic leukemia', 'Disease', (651, 679))	('CCL-2', 'Gene', '6347', (642, 647))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('RA', 'Chemical', 'MESH:D014212', (42, 44))	('HeLa', 'CellLine', 'CVCL:0030', (253, 257))	('ductal carcinoma', 'Disease', (234, 250))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (512, 532))	('cervical adenocarcinoma', 'Disease', (271, 294))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (234, 250))	('HEK-293', 'CellLine', 'CVCL:0045', (535, 542))	('hepatocellular carcinoma', 'Disease', (600, 624))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (469, 487))	('ATCC HB-8065', 'Var', (586, 598))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (469, 487))	('neuroblastoma', 'Disease', (393, 406))	('Jurkat', 'CellLine', 'CVCL:0065', (337, 343))	('CCL-2', 'Gene', (264, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('ductal carcinoma', 'Disease', 'MESH:D044584', (234, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (316, 334))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (316, 334))	('acute T-cell leukaemia', 'Disease', (359, 381))	("Burkitt's lymphoma", 'Disease', (469, 487))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (140, 159))	('Raji', 'CellLine', 'CVCL:0511', (297, 301))	('neuroblastoma', 'Phenotype', 'HP:0003006', (393, 406))	('acute T-cell leukaemia', 'Disease', 'MESH:D054218', (359, 381))	('embryonic kidney', 'Disease', (559, 575))	('lung carcinoma', 'Disease', (182, 196))	('neuroblastoma', 'Disease', 'MESH:D009447', (393, 406))	('neuroblastoma', 'Disease', (432, 445))	("Burkitt's lymphoma", 'Disease', (316, 334))
58492	25384072	PIWIL2 mRNA expression was knocked down in TERA1 and NT2/D1 expressing PL2L60A and PL2L80A, respectively (Fig.1D).	('RA', 'Chemical', 'MESH:D014212', (45, 47))	('PL2L60A', 'Var', (71, 78))	('knocked down', 'NegReg', (27, 39))	('NT2/D1', 'Gene', (53, 59))	('PIWIL2 mRNA', 'Gene', (0, 11))	('PL2L80A', 'Var', (83, 90))
58493	25384072	In order to identify transcription start and polyadenylation sites for mRNAs corresponding to PL2L60A and PL2L80A, we used TERA1 and NT2/D1 cell lines, respectively.	('PL2L80A', 'Var', (106, 113))	('RA', 'Chemical', 'MESH:D014212', (125, 127))	('PL2L60A', 'Var', (94, 101))
58495	25384072	We identified possible transcription start sites for PL2L60A (TERA1) in exons 1, 4 and 5 and for PL2L80A (NT2/D1) in exons 7 and 11 (Table 1).	('RA', 'Chemical', 'MESH:D014212', (64, 66))	('PL2L60A', 'Gene', (53, 60))	('PL2L80A', 'Var', (97, 104))
58498	25384072	Noticeable promoter activity was only observed in genomic regions upstream of putative transcription start sites in exons 1 and 5 in TERA1 (for PL2L60A) and exon 7 in NT2/D1 (for PL2L80A).	('RA', 'Chemical', 'MESH:D014212', (135, 137))	('PL2L80A', 'Var', (179, 186))	('PL2L60A', 'Var', (144, 151))
58505	25384072	By consolidating results of Western blot assays along with 5' and 3'-RACE experiments, promoter activity and in silico data we could make conclusions on transcriptional and translational boundaries of PL2L60A in TERA1 and PL2L80A in NT2/D1.	('PL2L80A', 'Var', (222, 229))	('RA', 'Chemical', 'MESH:D014212', (214, 216))	('RA', 'Chemical', 'MESH:D014212', (69, 71))	('PL2L60A', 'Var', (201, 208))
58506	25384072	Since the transcription start site for PL2L80A in exon 7 (NT2/D1) appears to be validated in 5'-RACE experiments, promoter activity assays and is in accord with the data on chromatin modifications, DNaseI hypersensitivity clusters and transcription factor binding sites from ENCODE, we assume the PL2L80A mRNA to span exons 7 to 23 (Fig.	('RA', 'Chemical', 'MESH:D014212', (96, 98))	('PL2L80A', 'Var', (297, 304))	('PL2L80A', 'Var', (39, 46))	('hypersensitivity', 'Disease', 'MESH:D004342', (205, 221))	('hypersensitivity', 'Disease', (205, 221))
58510	25384072	Remarkably, both PL2L60A in TERA1 and PL2L80A in NT2/D1 share the same AUG start codon in exon 7, though their mRNAs are transcribed from different start sites in exons 5 and 7, respectively (Fig.	('RA', 'Chemical', 'MESH:D014212', (30, 32))	('PL2L60A', 'Var', (17, 24))	('PL2L80A', 'Var', (38, 45))
58511	25384072	To confirm the transcription start sites of these two isoforms, we performed RT-qPCR on mRNA from the two cell lines with primers for exons immediately downstream of the both transcription start sites: exons 6-8 for PL2L60A in TERA1 and exons 8-9 for PL2L80A in NT2/D1.	('PL2L80A', 'Var', (251, 258))	('RA', 'Chemical', 'MESH:D014212', (229, 231))	('PL2L60A', 'Var', (216, 223))
58521	25384072	Additionally, average values of mRNA abundance for exons 6-8 were about 10 times lower than for exons 8-9 in seminomas, which expressed PL2L60A protein variant.	('mRNA abundance', 'MPA', (32, 46))	('lower', 'NegReg', (81, 86))	('PL2L60A protein', 'Var', (136, 151))	('seminomas', 'Disease', 'MESH:D018239', (109, 118))	('seminomas', 'Disease', (109, 118))
58527	25384072	In NT2/D1, PL2L80A mRNA level significantly decreases and protein isoform expression is undetectable on Day 2 after retinoic acid induction (Fig.	('protein isoform expression', 'MPA', (58, 84))	('retinoic acid', 'Chemical', 'MESH:D014212', (116, 129))	('PL2L80A', 'Var', (11, 18))	('decreases', 'NegReg', (44, 53))	('mRNA level', 'MPA', (19, 29))
58528	25384072	Therefore, these data confirm the assumption that promoter region around exon 7 for PL2L80A (in NT2/D1) and for PL2L60A (in seminomas) is more active in undifferentiated testicular tumors and pluripotent carcinoma cell line and its activity goes down in the course of differentiation.	('active', 'MPA', (143, 149))	('testicular tumors', 'Phenotype', 'HP:0010788', (170, 187))	('pluripotent carcinoma', 'Disease', (192, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('PL2L80A', 'Var', (84, 91))	('undifferentiated testicular tumors', 'Disease', 'MESH:D013736', (153, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('seminomas', 'Disease', 'MESH:D018239', (124, 133))	('seminomas', 'Disease', (124, 133))	('PL2L60A', 'Var', (112, 119))	('more', 'PosReg', (138, 142))	('activity', 'MPA', (232, 240))	('pluripotent carcinoma', 'Disease', 'MESH:D002277', (192, 213))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('undifferentiated testicular tumors', 'Disease', (153, 187))
58532	25384072	PIWIL2 was demonstrated to impact the development of precancerous stem cells into cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('impact', 'Reg', (27, 33))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('PIWIL2', 'Var', (0, 6))
58534	25384072	Furthermore, the knockdown of PIWIL2 in SW620 and SW480 cell lines derived from colon cancer significantly reduced invasive proliferation.	('invasive proliferation', 'CPA', (115, 137))	('PIWIL2', 'Gene', (30, 36))	('SW620', 'CellLine', 'CVCL:0547', (40, 45))	('colon cancer', 'Disease', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('reduced', 'NegReg', (107, 114))	('knockdown', 'Var', (17, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('SW480', 'CellLine', 'CVCL:0546', (50, 55))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))
58535	25384072	Other groups of researchers have provided a certain amount of evidence on PIWIL2 involvement in tumorigenesis by suppressing p53 through STAT3/c-Src, as well as influence of PIWIL2 on upregulation of STAT3, Bcl2 and nuclear expression of NF-kB and activation of STAT3/Bcl-X(L) pathway.	('STAT3', 'Gene', (262, 267))	('STAT3', 'Gene', (137, 142))	('STAT3', 'Gene', '6774', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('upregulation', 'PosReg', (184, 196))	('nuclear expression', 'MPA', (216, 234))	('STAT3', 'Gene', '6774', (137, 142))	('STAT3', 'Gene', '6774', (262, 267))	('NF-kB', 'Protein', (238, 243))	('involvement', 'Reg', (81, 92))	('Bcl-X(L', 'Gene', (268, 275))	('suppressing', 'NegReg', (113, 124))	('p53', 'Gene', '7157', (125, 128))	('tumor', 'Disease', (96, 101))	('Bcl2', 'Gene', (207, 211))	('PIWIL2', 'Var', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('c-Src', 'Gene', (143, 148))	('Bcl2', 'Gene', '596', (207, 211))	('STAT3', 'Gene', (200, 205))	('p53', 'Gene', (125, 128))	('Bcl-X(L)', 'Gene', '598', (268, 276))	('PIWIL2', 'Var', (174, 180))	('c-Src', 'Gene', '6714', (143, 148))
58539	25384072	Further, using RACE experiments and promoter activity luciferase assay, we ascertained and validated the promoter regions for PIWIL2 isoforms in testicular cancer cell lines: for PL2L60A upstream of exon 5 in TERA1 and for PL2L80A upstream of exon 7 in NT2/D1.	('PL2L80A', 'Var', (223, 230))	('testicular cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('RA', 'Chemical', 'MESH:D014212', (211, 213))	('PL2L60A', 'Var', (179, 186))	('RA', 'Chemical', 'MESH:D014212', (15, 17))	('testicular cancer', 'Phenotype', 'HP:0010788', (145, 162))	('testicular cancer', 'Disease', 'MESH:D013736', (145, 162))
58541	25384072	Next, through combining the data from RACE experiments, promoter activity assays, RT-qPCRs and Western blot analyses with specially constructed PIWIL2 short isoforms, we were able to make conclusions on the transcriptional boundaries of PL2L60A in TERA1 and PL2L80A in NT2/D1 cell lines.	('RA', 'Chemical', 'MESH:D014212', (38, 40))	('RA', 'Chemical', 'MESH:D014212', (250, 252))	('PL2L60A', 'Var', (237, 244))	('PL2L80A', 'Var', (258, 265))
58543	25384072	In particular, the absence of the evolutionarily conserved symmetrical dimethylarginines in N-terminal sequence could deprive both PL2L80A and PL2L60A of ability to bind TUDOR domain containing proteins which, in turn, may prevent this isoform from participating in piRNA/PIWI machinery.	('bind', 'Interaction', (165, 169))	('absence', 'NegReg', (19, 26))	('dimethylarginines', 'Var', (71, 88))	('participating', 'MPA', (249, 262))	('PL2L80A', 'Gene', (131, 138))	('deprive', 'NegReg', (118, 125))	('TUDOR domain containing proteins', 'Protein', (170, 202))	('dimethylarginines', 'Chemical', 'MESH:C487735', (71, 88))	('ability', 'MPA', (154, 161))	('proteins', 'Protein', (194, 202))	('prevent', 'NegReg', (223, 230))
58544	25384072	A similar context is described in Drosophila, where piwiNt mutation removing nuclear localization signal from PIWI protein leads to the impaired transposon silencing function but does not affect the maintenance of germ stem cells.	('transposon silencing function', 'MPA', (145, 174))	('nuclear localization signal', 'MPA', (77, 104))	('Drosophila', 'Species', '7227', (34, 44))	('removing', 'NegReg', (68, 76))	('mutation', 'Var', (59, 67))	('piwiNt', 'Gene', (52, 58))	('impaired', 'NegReg', (136, 144))
58609	29093004	In addition to the current study finding a significant relation between cannabis use and testicular cancer, our prior work drawing upon the same Swedish conscript cohort found that cannabis use was significantly associated with the development of lung cancer.	('testicular cancer', 'Disease', (89, 106))	('lung cancer', 'Disease', (247, 258))	('cannabis use', 'Var', (181, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('associated with', 'Reg', (212, 227))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('testicular cancer', 'Phenotype', 'HP:0010788', (89, 106))	('testicular cancer', 'Disease', 'MESH:D013736', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('lung cancer', 'Disease', 'MESH:D008175', (247, 258))	('men', 'Species', '9606', (239, 242))
58619	29093004	Aberration in both steroid hormone levels and gonadotropin levels suggests that cannabinoids may cause a general perturbation to the hypothalamic-pituitary-gonadal axis which could result in tumorigenesis.	('hypothalamic-pituitary-gonadal axis', 'Disease', 'MESH:D007029', (133, 168))	('tumorigenesis', 'CPA', (191, 204))	('steroid hormone', 'Chemical', 'MESH:D013256', (19, 34))	('cannabinoids', 'Chemical', 'MESH:D002186', (80, 92))	('result in', 'Reg', (181, 190))	('hypothalamic-pituitary-gonadal axis', 'Disease', (133, 168))	('perturbation', 'MPA', (113, 125))	('Aberration', 'Var', (0, 10))
58878	19237718	All testicular tumors were identified by ICDO-2 site codes (testis: C620-C621 and C629) and categorized by ICDO-2 histology codes (seminoma: 9060-9063, embryonal: 9070-9073, teratocarcinoma: 9081, mixed germ cell tumor: 9085, and carcinoma not otherwise specified: 8010).	('carcinoma', 'Disease', 'MESH:D002277', (180, 189))	('germ cell tumor', 'Phenotype', 'HP:0100728', (203, 218))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('teratocarcinoma', 'Disease', 'MESH:D018243', (174, 189))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('carcinoma', 'Disease', (230, 239))	('teratocarcinoma', 'Disease', (174, 189))	('testicular tumors', 'Disease', (4, 21))	('seminoma', 'Disease', (131, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('C629', 'Var', (82, 86))	('carcinoma', 'Disease', (180, 189))	('seminoma', 'Disease', 'MESH:D018239', (131, 139))	('testicular tumors', 'Phenotype', 'HP:0010788', (4, 21))	('tumor', 'Disease', (15, 20))	('carcinoma', 'Disease', 'MESH:D002277', (230, 239))	('testicular tumors', 'Disease', 'MESH:D013736', (4, 21))	('testicular tumor', 'Phenotype', 'HP:0010788', (4, 20))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('C620-C621', 'Var', (68, 77))
58945	19237718	Prior work by us and others suggests that certain severe forms of male infertility are associated with faulty DNA repair.	('faulty', 'Var', (103, 109))	('associated', 'Reg', (87, 97))	('infertility', 'Phenotype', 'HP:0000789', (71, 82))	('male infertility', 'Disease', 'MESH:D007248', (66, 82))	('male infertility', 'Phenotype', 'HP:0003251', (66, 82))	('male infertility', 'Disease', (66, 82))
58946	19237718	Faulty DNA repair has classically been associated with tumorigenesis, in human and animal models, and could underlie the association of infertility and testicular cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('testicular cancer', 'Disease', 'MESH:D013736', (152, 169))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('testicular cancer', 'Disease', (152, 169))	('tumor', 'Disease', (55, 60))	('human', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('infertility', 'Phenotype', 'HP:0000789', (136, 147))	('associated', 'Reg', (39, 49))	('Faulty DNA', 'Var', (0, 10))	('infertility', 'Disease', 'MESH:D007247', (136, 147))	('infertility', 'Disease', (136, 147))	('testicular cancer', 'Phenotype', 'HP:0010788', (152, 169))
58958	29928359	These data suggested that the anti-PD-1/PD-L1 immunotherapy and the anti-angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('testicular cancer', 'Phenotype', 'HP:0010788', (171, 188))	('testicular cancer', 'Disease', 'MESH:D013736', (171, 188))	('anti-PD-1/PD-L1', 'Var', (30, 45))	('testicular cancer', 'Disease', (171, 188))
59037	29928359	Nitzsche et al showed that blocking VEGFR2 with the antiangiogenic compound HP-14 inhibited growth of platinum sensible and -resistant TGCT cells and suppressed tumor angiogenesis.	('suppressed', 'NegReg', (150, 160))	('inhibited', 'NegReg', (82, 91))	('blocking', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('growth', 'CPA', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('platinum', 'Chemical', 'MESH:D010984', (102, 110))	('tumor', 'Disease', (161, 166))	('VEGFR2', 'Gene', (36, 42))
59044	29928359	The presence of PD-1 presenting tumor infiltrating lymphocytes (TILs) may have strong prognostic and predictive features in different types of tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('PD-1', 'Gene', (16, 20))
59050	29928359	The morbid tumor vascularity usually creates a more immune suppressive microenvironment in different types of cancer.	('morbid', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
59054	29928359	Our data suggests that both the anti-PD-1/PD-L1 immunotherapy and the anti-angiogenic therapy might be a promising option in the treatment of testicular cancer.	('testicular cancer', 'Disease', (142, 159))	('anti-PD-1/PD-L1', 'Var', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('testicular cancer', 'Phenotype', 'HP:0010788', (142, 159))	('testicular cancer', 'Disease', 'MESH:D013736', (142, 159))
59062	22201807	The appreciation for TE modification of mammalian gene expression gained significant interest after the discoveries that the majority of transposable elements either carry cis-acting elements in their sequence that are recognized by the mammalian transcriptional or RNA processing machineries or have high propensity for accrual of these cis-signals via mutations long after the completion of the integration process.	('cis-acting elements', 'MPA', (172, 191))	('mutations', 'Var', (354, 363))	('mammalian', 'Species', '9606', (40, 49))	('transposable', 'Gene', (137, 149))	('mammalian', 'Species', '9606', (237, 246))
59063	22201807	The potential for TEs to modify normal gene expression even when they are located outside of the gene boundaries is consistent with associations between non-coding DNA and human disease.	('TEs', 'Var', (18, 21))	('normal gene expression', 'MPA', (32, 54))	('associations', 'Interaction', (132, 144))	('human', 'Species', '9606', (172, 177))	('modify', 'Reg', (25, 31))
59068	22201807	While this group of retroelements exhibits relatively high activity in the mouse genome (based on the frequency of disease-causing germ-line mutations), there are no reports of congenital human diseases associated with the insertion of the human endogenous LTR elements.	('activity', 'MPA', (59, 67))	('human', 'Species', '9606', (188, 193))	('human', 'Species', '9606', (240, 245))	('insertion', 'Var', (223, 232))	('mouse', 'Species', '10090', (75, 80))	('congenital human diseases', 'Disease', (177, 202))
59071	22201807	Although the ORF1 protein is not required for Alu mobilization, retrotransposition of Alu elements is significantly enhanced in the presence of ORF1.	('Alu', 'Chemical', '-', (86, 89))	('enhanced', 'PosReg', (116, 124))	('ORF1', 'Gene', (144, 148))	('presence', 'Var', (132, 140))	('retrotransposition of Alu elements', 'CPA', (64, 98))	('Alu', 'Chemical', '-', (46, 49))	('ORF1', 'Gene', '55354', (13, 17))	('ORF1', 'Gene', (13, 17))	('ORF1', 'Gene', '55354', (144, 148))
59083	22201807	Human diseases caused by L1, Alu, and SVA insertional mutagenesis range from hemophilia and X-linked Duchenne muscular dystrophy to cystic fibrosis and breast cancer (reviewed in), supporting the random nature of the integration process.	('Human', 'Species', '9606', (0, 5))	('cystic fibrosis', 'Disease', 'MESH:D003550', (132, 147))	('hemophilia', 'Disease', 'MESH:D006467', (77, 87))	('insertional mutagenesis', 'Var', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('Alu', 'Chemical', '-', (29, 32))	('breast cancer', 'Disease', (152, 165))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (110, 128))	('caused', 'Reg', (15, 21))	('X-linked Duchenne muscular dystrophy', 'Disease', (92, 128))	('hemophilia', 'Disease', (77, 87))	('cystic fibrosis', 'Disease', (132, 147))	('X-linked Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (92, 128))
59090	22201807	Insertions of transposable elements within intronic sequences can interfere with normal gene expression through the introduction of functional (i) promoters and their regulatory elements, (ii) polyadenylation (pA) signals, and (iii) splice donor (SD) and acceptor (SA) sites.	('normal gene expression', 'MPA', (81, 103))	('Insertions', 'Var', (0, 10))	('donor', 'Species', '9606', (240, 245))	('interfere', 'NegReg', (66, 75))	('polyadenylation', 'MPA', (193, 208))
59095	22201807	L1 elements have been proposed to potentially influence the selective expression of monoallelically-expressed genes due to the enrichment of evolutionarily more recent LINE-1 elements in the regions surrounding these genes in human and mouse.	('influence', 'Reg', (46, 55))	('human', 'Species', '9606', (226, 231))	('elements', 'Var', (3, 11))	('selective expression', 'MPA', (60, 80))	('mouse', 'Species', '10090', (236, 241))
59100	22201807	likely maintaining functional sense and antisense promoters) L1 insertions are reported to specifically decrease the expression of primary transcripts in human cell lines from the alleles containing these integration events relative to the corresponding alleles without L1.	('insertions', 'Var', (64, 74))	('expression', 'MPA', (117, 127))	('human', 'Species', '9606', (154, 159))	('decrease', 'NegReg', (104, 112))
59101	22201807	The presence of the full-length mouse L1 in an intron of a mini-gene reporter system convincingly demonstrated the debilitating effect of the full-length L1 inserted in the forward orientation on normal gene expression (up to 10-fold reduction).	('mouse', 'Species', '10090', (32, 37))	('normal gene expression', 'MPA', (196, 218))	('reduction', 'NegReg', (234, 243))	('inserted', 'Var', (157, 165))
59102	22201807	In the same experimental system, mouse L1 insertion in the reverse orientation did not significantly impact transcript production.	('insertion', 'Var', (42, 51))	('transcript production', 'MPA', (108, 129))	('mouse', 'Species', '10090', (33, 38))
59104	22201807	Skipping of the L1-containing exon produces a mRNA for the membrane-bound form of the attractin protein.	('attractin', 'Gene', '8455', (86, 95))	('Skipping', 'Var', (0, 8))	('mRNA for the membrane-bound form of', 'MPA', (46, 81))	('attractin', 'Gene', (86, 95))
59107	22201807	In addition, the expression of fusion transcripts between L1 and the proto-oncogene cMet has been induced with demethylation agents in colon cancer and leukemia cell lines.	('colon cancer', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('induced', 'Reg', (98, 105))	('expression', 'MPA', (17, 27))	('cMet', 'Gene', (84, 88))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('leukemia', 'Disease', 'MESH:D007938', (152, 160))	('fusion transcripts', 'Var', (31, 49))	('leukemia', 'Disease', (152, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('cMet', 'Gene', '4233', (84, 88))
59113	22201807	However, deamination of CpG islands within Alu sequences inserted near promoters of human genes can generate active transcription binding sites and is known to skew the programmed regulation of native promoters.	('Alu', 'Chemical', '-', (43, 46))	('human', 'Species', '9606', (84, 89))	('skew', 'Reg', (160, 164))	('active transcription', 'MPA', (109, 129))	('deamination', 'Var', (9, 20))
59128	22201807	Alu exonization appears to be influenced by the sequences within Alu itself, for example the deletion of the left arm of Alu shifts the inclusion of the Alu right arm from alternative to constitutive splicing.	('Alu', 'Chemical', '-', (121, 124))	('Alu', 'Chemical', '-', (65, 68))	('Alu', 'Chemical', '-', (153, 156))	('Alu', 'Chemical', '-', (0, 3))	('inclusion', 'MPA', (136, 145))	('deletion', 'Var', (93, 101))	('Alu', 'Gene', (121, 124))
59139	22201807	SVA elements are a more recently formed retrotranspositionally active family of elements that have contributed to human disease through insertional mutagenesis.	('insertional mutagenesis', 'Var', (136, 159))	('human', 'Species', '9606', (114, 119))	('contributed', 'Reg', (99, 110))
59157	22201807	HERV expression has also been associated with a number of autoimmune disorders such as multiple sclerosis, psoriasis and systemic lupus erythematosus.	('associated', 'Reg', (30, 40))	('multiple sclerosis', 'Disease', 'MESH:D009103', (87, 105))	('psoriasis', 'Phenotype', 'HP:0003765', (107, 116))	('systemic lupus erythematosus', 'Disease', (121, 149))	('autoimmune disorders', 'Disease', (58, 78))	('expression', 'Var', (5, 15))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (121, 149))	('HERV', 'Protein', (0, 4))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (58, 78))	('multiple sclerosis', 'Disease', (87, 105))	('autoimmune disorders', 'Disease', 'MESH:D001327', (58, 78))	('psoriasis', 'Disease', 'MESH:D011565', (107, 116))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (121, 149))	('psoriasis', 'Disease', (107, 116))
59168	22201807	The insertion of the PiggyBac transposable element PGBD3 into intron 5 of the Cockayne syndrome Group B (CSB) gene is an interesting example of the potential for both outcomes.	('Cockayne syndrome Group B', 'Gene', (78, 103))	('CSB', 'Gene', '2074', (105, 108))	('PGBD3', 'Gene', '267004', (51, 56))	('insertion', 'Var', (4, 13))	('CSB', 'Gene', (105, 108))	('Cockayne syndrome Group B', 'Gene', '2074', (78, 103))	('PGBD3', 'Gene', (51, 56))
59173	22201807	Mutations in the CSB chromatin remodeling protein are linked to CS, a devastating form of progeria.	('CSB', 'Gene', (17, 20))	('linked', 'Reg', (54, 60))	('CSB', 'Gene', '2074', (17, 20))	('Mutations', 'Var', (0, 9))
59175	22201807	Disruption of the binding site of this transposon-derived repressor by a single nucleotide substitution in intron 3 of the insulin-like growth factor 2 (IGF2) gene results in increased muscle growth and reduced fat deposition in pigs.	('single nucleotide substitution', 'Var', (73, 103))	('insulin-like growth factor 2', 'Gene', (123, 151))	('increased muscle growth', 'Phenotype', 'HP:0003712', (175, 198))	('pigs', 'Species', '9823', (229, 233))	('reduced', 'NegReg', (203, 210))	('muscle growth', 'CPA', (185, 198))	('reduced fat deposition', 'Phenotype', 'HP:0040063', (203, 225))	('IGF2', 'Gene', (153, 157))	('fat deposition', 'MPA', (211, 225))	('insulin-like growth factor 2', 'Gene', '396916', (123, 151))	('IGF2', 'Gene', '396916', (153, 157))	('increased', 'PosReg', (175, 184))	('Disruption', 'Var', (0, 10))
59188	26713853	Alternative splicing of pre-mRNAs can generate multiple mRNA isoforms from a single gene, and it has been shown that more than half of human and mouse genes use alternative polyadenylation (APA) sites to produce multiple isoforms with different poly(A) sites.	('mouse', 'Species', '10090', (145, 150))	('poly(A)', 'Chemical', 'MESH:D011061', (245, 252))	('human', 'Species', '9606', (135, 140))	('mRNA isoforms', 'MPA', (56, 69))	('Alternative splicing', 'Var', (0, 20))	('generate', 'Reg', (38, 46))
59190	26713853	The poly(A) sites include post-transcriptional regulatory elements in the mature transcript that may significantly change mRNA stability, localization, or translation, thereby impacting the protein sequences and the amount of protein derived from that mRNA.	('change', 'Reg', (115, 121))	('poly(A) sites', 'Var', (4, 17))	('localization', 'MPA', (138, 150))	('translation', 'MPA', (155, 166))	('protein sequences', 'MPA', (190, 207))	('amount of protein derived', 'MPA', (216, 241))	('poly(A)', 'Chemical', 'MESH:D011061', (4, 11))	('impacting', 'NegReg', (176, 185))	('mRNA stability', 'MPA', (122, 136))
59207	26713853	PCR was then performed to amplify the cDNA and to introduce two mutations into the poly(A).	('introduce', 'Reg', (50, 59))	('mutations', 'Var', (64, 73))	('poly(A)', 'Chemical', 'MESH:D011061', (83, 90))	('cDNA', 'Gene', (38, 42))
59252	26713853	The poly(A)s in mRNA and lncRNA genes were supported by similar cis elements.	('poly(A)s', 'Chemical', 'MESH:D011061', (4, 12))	('poly(A)s', 'Var', (4, 12))	('lncRNA genes', 'Gene', (25, 37))	('mRNA', 'Gene', (16, 20))
59290	26713853	The 3'UTR shortened genes was more than the lengthened genes in GSCs vs. ESCs or GSCs vs. MEFs (Fig 2C).	('ESCs', 'Disease', (73, 77))	('genes', 'Var', (20, 25))	('GSCs', 'Disease', (64, 68))	('GSCs', 'Disease', (81, 85))	('MEFs', 'CellLine', 'CVCL:9115', (90, 94))
59304	26713853	For example, the loss of testis-specific Cstf64 in mice caused male infertility resulting from spermatogenesis defects.	('Cstf64', 'Gene', '108062', (41, 47))	('loss of testis-', 'Phenotype', 'HP:0012870', (17, 32))	('spermatogenesis defects', 'CPA', (95, 118))	('mice', 'Species', '10090', (51, 55))	('caused', 'Reg', (56, 62))	('male infertility', 'Phenotype', 'HP:0003251', (63, 79))	('male infertility', 'Disease', 'MESH:D007248', (63, 79))	('infertility', 'Phenotype', 'HP:0000789', (68, 79))	('male infertility', 'Disease', (63, 79))	('Cstf64', 'Gene', (41, 47))	('loss', 'Var', (17, 21))	('infertility resulting from spermatogenesis', 'Phenotype', 'HP:0008669', (68, 110))
59309	26713853	The idea of APA regulation may be striking the collective imagination in that it was recently found that knocking down CFIm25, a repressor of proximal APA sites, could enhance tumorigenesis whereas its overexpression reduced tumor properties.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('enhance', 'PosReg', (168, 175))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (176, 181))	('knocking down', 'Var', (105, 118))	('tumor', 'Disease', (225, 230))	('CFIm25', 'Gene', (119, 125))	('reduced', 'NegReg', (217, 224))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
59341	23662100	In the same study, small interfering RNA-mediated knockdown of APP also resulted in decreased cancer cell growth.	('APP', 'Gene', (63, 66))	('decreased cancer', 'Disease', (84, 100))	('knockdown', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('decreased cancer', 'Disease', 'MESH:D009369', (84, 100))
59391	20535293	showed superior recurrence-free survival (98% vs.79%) with primary chemotherapy followed by RPLND compared to RPLND alone, with no difference in cancer-specific survival.	('cancer', 'Disease', (145, 151))	('recurrence-free survival', 'CPA', (16, 40))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('RPLND', 'Var', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('superior', 'PosReg', (7, 15))
59403	20535293	Based on this data, for compliant patients with completely resected retroperitoneal metastases, observation with salvage chemotherapy at relapse is commonly recommended for patients with pathologic N1 disease whereas two cycles of adjuvant chemotherapy is administered to noncompliant patients or those with pathologic N2 or N3 disease.	('patients', 'Species', '9606', (173, 181))	('men', 'Species', '9606', (162, 165))	('retroperitoneal metastases', 'Disease', 'MESH:D009362', (68, 94))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (285, 293))	('pathologic', 'Var', (187, 197))	('retroperitoneal metastases', 'Disease', (68, 94))
59407	20535293	The initial trials for advanced germ cell tumors used cisplatin combined with vinblastine and bleomycin, which were already established as active agents in testicular cancer.	('cisplatin', 'Var', (54, 63))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('testicular cancer', 'Disease', (156, 173))	('bleomycin', 'Chemical', 'MESH:D001761', (94, 103))	('vinblastine', 'Chemical', 'MESH:D014747', (78, 89))	('germ cell tumors', 'Phenotype', 'HP:0100728', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('testicular cancer', 'Phenotype', 'HP:0010788', (156, 173))	('testicular cancer', 'Disease', 'MESH:D013736', (156, 173))
59416	20535293	Grade 2 or higher dermatologic (7% vs. 2%) and neurologic side effects (16% vs. 3%) were more frequent in the BEP group without major differences in pulmonary toxicity (4% vs. 2%), although routine pulmonary function testing was not employed.	('pulmonary toxicity', 'Disease', 'MESH:D008171', (149, 167))	('neurologic', 'Disease', (47, 57))	('BEP', 'Chemical', 'MESH:C038328', (110, 113))	('pulmonary toxicity', 'Disease', (149, 167))	('dermatologic', 'Disease', (18, 30))	('BEP', 'Var', (110, 113))
59439	20535293	Minimizing the dissection boundaries to avoid nerve damage (using smaller, modified templates) unnecessarily increases the risk of unresected disease, which can threaten oncologic control.	('unresected disease', 'Disease', (131, 149))	('nerve damage', 'Disease', 'MESH:D004194', (46, 58))	('Minimizing', 'Var', (0, 10))	('nerve damage', 'Disease', (46, 58))
59476	34007386	published a case report of a 41-year-old patient with a history of a left radical orchiectomy and subsequent lesions in his liver and brain who presented with a lump, but no pain, in his left thigh 7 years after the diagnosis of testicular cancer.	('pain', 'Disease', 'MESH:D010146', (174, 178))	('pain', 'Disease', (174, 178))	('lesions', 'Var', (109, 116))	('testicular cancer', 'Phenotype', 'HP:0010788', (229, 246))	('testicular cancer', 'Disease', 'MESH:D013736', (229, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('patient', 'Species', '9606', (41, 48))	('testicular cancer', 'Disease', (229, 246))	('pain', 'Phenotype', 'HP:0012531', (174, 178))
59478	34007386	Excision of the tumor eliminated his symptoms with no recurrence during 10-months' follow-up.	('eliminated', 'NegReg', (22, 32))	('symptoms', 'MPA', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('Excision', 'Var', (0, 8))
59562	33050470	The IC50 of cisplatin for NCCIT-P was 2.92 microM, 10-times lower compared to that of NCCIT-R (31.59 microM); for 2102Ep-P it was 3.26 microM, four-times lower compared to that of 2102Ep-R (15.61 microM); for NT2-P it was 0.92 microM, three-times lower compared to that of NT2-R (3.31 microM).	('NCCIT-R', 'Chemical', '-', (86, 93))	('NT2-R', 'Chemical', '-', (273, 278))	('NT2-P', 'Chemical', '-', (209, 214))	('2102Ep-P', 'Var', (114, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (12, 21))	('NCCIT-P', 'Chemical', '-', (26, 33))	('2102Ep-R', 'Chemical', '-', (180, 188))	('2102Ep-P', 'Chemical', '-', (114, 122))	('lower', 'NegReg', (60, 65))
59575	33050470	Finally, we demonstrated that treatment with belinostat and panobinostat at 24 h led to a remarkable increase in lysine acetylation levels, increased acetylation of histone H3, and decreased HDAC1 protein expression (Figure S6B).	('HDAC1', 'Gene', (191, 196))	('men', 'Species', '9606', (35, 38))	('belinostat', 'Chemical', 'MESH:C487081', (45, 55))	('panobinostat', 'Var', (60, 72))	('lysine acetylation levels', 'MPA', (113, 138))	('acetylation', 'MPA', (150, 161))	('increase', 'PosReg', (101, 109))	('HDAC1', 'Gene', '3065', (191, 196))	('histone H3', 'Protein', (165, 175))	('panobinostat', 'Chemical', 'MESH:D000077767', (60, 72))	('lysine', 'Chemical', 'MESH:D008239', (113, 119))	('increased', 'PosReg', (140, 149))	('decreased', 'NegReg', (181, 190))
59578	33050470	We observed that at 5, 10, and 20 nM concentrations of belinostat, an effect on cell viability was, indeed, not apparent (on the contrary, cells were actually proliferating), but subsequent treatment with cisplatin 10 microM considerably reduced cell viability, compared to the absence of effect when the same dose of cisplatin was given in the absence of belinostat pre-treatment (illustration of protocol and graphical representation in Figure S7).	('cisplatin', 'Var', (205, 214))	('belinostat', 'Chemical', 'MESH:C487081', (55, 65))	('men', 'Species', '9606', (376, 379))	('reduced', 'NegReg', (238, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (205, 214))	('belinostat', 'Chemical', 'MESH:C487081', (356, 366))	('cisplatin', 'Chemical', 'MESH:D002945', (318, 327))	('cell viability', 'CPA', (246, 260))	('men', 'Species', '9606', (195, 198))
59587	33050470	Changes in the expression of these enzymes have been reported in several cancers and, importantly, inhibitors have been used effectively as cancer treatment, including repurposed drugs (e.g., antifungal trichostatin A (TSA)) or drugs used for treating epilepsy (e.g., valproic acid or carbamazepine), as well as the more recently developed inhibitors, some already approved by the FDA and others on clinical trial.	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('trichostatin A', 'Chemical', 'MESH:C012589', (203, 217))	('epilepsy', 'Phenotype', 'HP:0001250', (252, 260))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', (73, 79))	('epilepsy', 'Disease', (252, 260))	('TSA', 'Chemical', 'MESH:C012589', (219, 222))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carbamazepine', 'Chemical', 'MESH:D002220', (285, 298))	('men', 'Species', '9606', (152, 155))	('expression', 'MPA', (15, 25))	('cancer', 'Disease', (140, 146))	('valproic acid', 'Chemical', 'MESH:D014635', (268, 281))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Changes', 'Var', (0, 7))	('epilepsy', 'Disease', 'MESH:D004827', (252, 260))
59599	33050470	The same is again supported by our in vitro results, disclosing an upregulation of some HDAC isoforms in NCCIT-R, compared to NCCIT-P, both at the mRNA and protein level (Figure 3).	('NCCIT-R', 'Var', (105, 112))	('HDAC', 'Gene', (88, 92))	('upregulation', 'PosReg', (67, 79))	('HDAC', 'Gene', '9734', (88, 92))	('NCCIT-R', 'Chemical', '-', (105, 112))	('NCCIT-P', 'Chemical', '-', (126, 133))
59600	33050470	The differential expression of HDAC11 is particularly interesting and deserves to be explored in further studies, given the recently reported effect of HDAC11-specific inhibitors in eliminating treatment-resistant lung adenocarcinoma cells by targeting SOX2, which is amplified in the NCCIT cell line.	('HDAC11', 'Gene', '79885', (152, 158))	('men', 'Species', '9606', (199, 202))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (214, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('HDAC11', 'Gene', (152, 158))	('inhibitors', 'Var', (168, 178))	('lung adenocarcinoma', 'Disease', (214, 233))	('HDAC11', 'Gene', '79885', (31, 37))	('SOX2', 'Gene', '6657', (253, 257))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (214, 233))	('SOX2', 'Gene', (253, 257))	('eliminating', 'NegReg', (182, 193))	('HDAC11', 'Gene', (31, 37))
59611	33050470	The similar effect on distinct cell lines, with different p53 status (mutated for NCCIT and wild-type for the remainder), suggests that the mechanism is independent of p53.	('p53', 'Gene', '7157', (168, 171))	('p53', 'Gene', (58, 61))	('p53', 'Gene', (168, 171))	('mutated', 'Var', (70, 77))	('p53', 'Gene', '7157', (58, 61))
59623	33050470	Moreover, we intend to validate these findings and to explore in more detail if and how HDACs may be involved in cisplatin-resistance, through the knock-down of specific HDAC isoforms using CRISPR-Cas9 technology.	('knock-down', 'Var', (147, 157))	('HDAC', 'Gene', (170, 174))	('HDAC', 'Gene', (88, 92))	('HDAC', 'Gene', '9734', (170, 174))	('HDAC', 'Gene', '9734', (88, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('involved', 'Reg', (101, 109))
59626	33050470	Despite our data supporting the p53-independent mechanism, it is worth exploring p53 downstream targets, including NOXA and PUMA, and other family members (p63/p73), as these can be epigenetically regulated (including restored expression of p63 in TGCT cell lines).	('p63', 'Gene', (241, 244))	('PUMA', 'Gene', '27113', (124, 128))	('expression', 'MPA', (227, 237))	('p73', 'Gene', '7161', (160, 163))	('NOXA', 'Gene', (115, 119))	('p53', 'Gene', (32, 35))	('p73', 'Gene', (160, 163))	('p53', 'Gene', '7157', (32, 35))	('epigenetically regulated', 'Var', (182, 206))	('p53', 'Gene', (81, 84))	('p63', 'Gene', (156, 159))	('p53', 'Gene', '7157', (81, 84))	('NOXA', 'Gene', '5366', (115, 119))	('p63', 'Gene', '8626', (241, 244))	('p63', 'Gene', '8626', (156, 159))	('PUMA', 'Gene', (124, 128))
59699	33050470	Cell viability after 72 h of exposure to cisplatin in NCCIT-R (A), NCCIT-P (B), 2102Ep-R (C), 2102Ep-P (D), NT2-R (E), and NT2-P (F), Figure S4: Barplots with cell viability studies after treatment with several doses of belinostat and panobinostat, per time point (24, 48, and 72 h), across cisplatin-resistant cell lines.	('2102Ep-P', 'Chemical', '-', (94, 102))	('belinostat', 'Chemical', 'MESH:C487081', (220, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('NT2-P', 'Chemical', '-', (123, 128))	('NCCIT-P', 'Chemical', '-', (67, 74))	('men', 'Species', '9606', (193, 196))	('2102Ep-R', 'Var', (80, 88))	('2102Ep-P', 'Var', (94, 102))	('NCCIT-R', 'Chemical', '-', (54, 61))	('panobinostat', 'Chemical', 'MESH:D000077767', (235, 247))	('cisplatin', 'Chemical', 'MESH:D002945', (291, 300))	('2102Ep-R', 'Chemical', '-', (80, 88))	('NT2-R', 'Chemical', '-', (108, 113))
59707	26459559	Rare inactivating PDE11A variants associated with testicular germ cell tumors Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('testicular cancer', 'Phenotype', 'HP:0010788', (251, 268))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', (231, 237))	('variants', 'Var', (25, 33))	('familial adrenocortical tumors', 'Disease', (207, 237))	('associated with', 'Reg', (191, 206))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('familial adrenocortical tumors', 'Disease', 'MESH:C565972', (207, 237))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('PDE11A', 'Gene', (168, 174))	('PDE11A', 'Gene', '50940', (168, 174))	('PDE11A', 'Gene', (18, 24))	('PDE11A', 'Gene', '50940', (18, 24))	('germ cell tumors', 'Phenotype', 'HP:0100728', (61, 77))	('germ cell tumor', 'Phenotype', 'HP:0100728', (61, 76))	('mutations', 'Var', (100, 109))	('associated', 'Reg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('familial testicular cancer', 'Disease', (242, 268))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('familial testicular cancer', 'Disease', 'MESH:D013736', (242, 268))
59709	26459559	In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk.	('tumor', 'Disease', (68, 73))	('germ cell tumor', 'Phenotype', 'HP:0100728', (58, 73))	('PDE11A', 'Gene', (189, 195))	('PDE11A', 'Gene', '50940', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('familial TGCT', 'Disease', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('variants', 'Var', (177, 185))
59710	26459559	To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls.We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic.	('PDE11A', 'Gene', '50940', (53, 59))	('missense', 'Var', (189, 197))	('variants', 'Var', (176, 184))	('PDE11A', 'Gene', (169, 175))	('PDE11A', 'Gene', '50940', (169, 175))	('PDE11A', 'Gene', (53, 59))	('patients', 'Species', '9606', (97, 105))
59711	26459559	Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037).	('common', 'Reg', (125, 131))	('p.K568R', 'Var', (61, 68))	('p.F258Y', 'Var', (21, 28))	('p.R545X', 'Var', (48, 55))	('p.F258Y', 'Mutation', 'rs1438588949', (21, 28))	('p.V820M', 'Var', (39, 46))	('p.G291R', 'Mutation', 'rs767064669', (30, 37))	('p.K568R', 'Mutation', 'rs148955609', (61, 68))	('p.G291R', 'Var', (30, 37))	('p.R545X', 'Mutation', 'rs374570863', (48, 55))	('p.V820M', 'Mutation', 'rs140269105', (39, 46))
59714	26459559	This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.	('PDE11A', 'Gene', (352, 358))	('testicular cancer', 'Disease', (178, 195))	('PDE11A', 'Gene', '50940', (53, 59))	('associated', 'Reg', (262, 272))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('variants', 'Var', (359, 367))	('familial TGCT', 'Disease', (72, 85))	('TGCT', 'Disease', (278, 282))	('variants', 'Var', (221, 229))	('testicular cancer', 'Phenotype', 'HP:0010788', (178, 195))	('PDE11A', 'Gene', '50940', (352, 358))	('testicular cancer', 'Disease', 'MESH:D013736', (178, 195))	('variants', 'Var', (60, 68))	('associated', 'Reg', (390, 400))	('PDE11A', 'Gene', (53, 59))
59718	26459559	The International Testicular Cancer Linkage Consortium performed a genome-wide genetic linkage study, which suggested that the combined action of multiple common genetic variants, each with small effect sizes relative to classical, highly penetrant Mendelian traits, may explain a significant fraction of this familial aggregation.	('Testicular Cancer', 'Disease', (18, 35))	('Testicular Cancer', 'Disease', 'MESH:D013736', (18, 35))	('variants', 'Var', (170, 178))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Testicular Cancer', 'Phenotype', 'HP:0010788', (18, 35))
59720	26459559	A candidate gene study found that germline mutations in isoform 4 of PDE11A were associated with familial/bilateral testicular cancer.	('testicular cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))	('germline mutations', 'Var', (34, 52))	('PDE11A', 'Gene', (69, 75))	('PDE11A', 'Gene', '50940', (69, 75))	('associated', 'Reg', (81, 91))
59721	26459559	PDE11A is an important regulator of cyclic AMP signaling in steroidogenic tissue such as the testis, and germline mutations in this gene have been associated with familial adrenocortical tumors.	('associated', 'Reg', (147, 157))	('germline mutations', 'Var', (105, 123))	('familial adrenocortical tumors', 'Disease', (163, 193))	('familial adrenocortical tumors', 'Disease', 'MESH:C565972', (163, 193))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('PDE11A', 'Gene', (0, 6))	('PDE11A', 'Gene', '50940', (0, 6))	('cyclic AMP', 'Chemical', 'MESH:D000242', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
59724	26459559	Furthermore, the Pde11a knockout mouse features male infertility, a known TGCT risk factor.	('Pde11a', 'Gene', '241489', (17, 23))	('Pde11a', 'Gene', (17, 23))	('male infertility', 'Disease', 'MESH:D007248', (48, 64))	('features', 'Reg', (39, 47))	('male infertility', 'Phenotype', 'HP:0003251', (48, 64))	('male infertility', 'Disease', (48, 64))	('mouse', 'Species', '10090', (33, 38))	('infertility', 'Phenotype', 'HP:0000789', (53, 64))	('knockout', 'Var', (24, 32))
59725	26459559	Interestingly, alterations in the cAMP pathway have also been observed in non-germ cell-derived testicular tumors, such as somatic alterations in Leydig cell hyperplasia and McCune-Albright syndrome, and associated with germline alterations in PRKAR1A that underlie Carney complex-associated Sertoli cell tumors; these mutations underscore the possible importance of the cAMP pathway in testicular tissue.	('PRKAR1A', 'Gene', '5573', (244, 251))	('non-germ', 'Disease', (74, 82))	('alterations', 'Reg', (15, 26))	('cAMP', 'Chemical', 'MESH:D000242', (34, 38))	('testicular tumors', 'Disease', 'MESH:D013736', (96, 113))	('testicular tumors', 'Phenotype', 'HP:0010788', (96, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('alterations', 'Var', (131, 142))	('associated', 'Reg', (204, 214))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('Sertoli cell tumors', 'Phenotype', 'HP:0100619', (292, 311))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Leydig cell hyperplasia', 'Phenotype', 'HP:0010791', (146, 169))	('tumors', 'Disease', (107, 113))	('cAMP', 'Chemical', 'MESH:D000242', (371, 375))	('PRKAR1A', 'Gene', (244, 251))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (174, 198))	('tumors', 'Disease', (305, 311))	('Leydig cell hyperplasia', 'Disease', (146, 169))	('Leydig cell hyperplasia', 'Disease', 'MESH:D007984', (146, 169))	('testicular tumors', 'Disease', (96, 113))	('alterations', 'Var', (229, 240))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('McCune-Albright syndrome', 'Disease', (174, 198))	('tumors', 'Disease', 'MESH:D009369', (305, 311))
59726	26459559	Studies of adrenal, prostate, and testicular cancer have suggested that PDE11A missense mutations may represent susceptibility modifiers rather than direct, sufficient causes of these tumors.	('testicular cancer', 'Disease', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('missense mutations', 'Var', (79, 97))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('PDE11A', 'Gene', '50940', (72, 78))	('testicular cancer', 'Phenotype', 'HP:0010788', (34, 51))	('testicular cancer', 'Disease', 'MESH:D013736', (34, 51))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('PDE11A', 'Gene', (72, 78))
59727	26459559	Finally, the detection of increased methylation of specific CpG islands in the promoter region of PDE11A argues that diminished PDE11A function is a TGCT risk factor, because CpG methylation correlates with decreased mRNA expression.	('PDE11A', 'Gene', '50940', (98, 104))	('PDE11A', 'Gene', '50940', (128, 134))	('decreased', 'NegReg', (207, 216))	('PDE11A', 'Gene', (98, 104))	('methylation', 'Var', (179, 190))	('CpG', 'Var', (175, 178))	('mRNA expression', 'MPA', (217, 232))	('TGCT', 'Disease', (149, 153))	('methylation', 'MPA', (36, 47))	('diminished', 'NegReg', (117, 127))	('PDE11A', 'Gene', (128, 134))	('increased', 'PosReg', (26, 35))	('expression', 'Species', '29278', (222, 232))	('function', 'MPA', (135, 143))
59729	26459559	This represents a significant expansion from our previous study of PDE11A variants, which examined only cases from 64 TGCT families; in the new analysis we examine individuals from 90 families.	('variants', 'Var', (74, 82))	('PDE11A', 'Gene', (67, 73))	('PDE11A', 'Gene', '50940', (67, 73))
59730	26459559	Here, we evaluated PDE11A variants in both sporadic and familial cases compared with an unrelated healthy male population.	('PDE11A', 'Gene', '50940', (19, 25))	('PDE11A', 'Gene', (19, 25))	('variants', 'Var', (26, 34))
59731	26459559	We have uncovered additional rare, deleterious PDE11A variants that may contribute to TGCT carcinogenesis, refining the current understanding of the relationship between PDE11A and testicular cancer risk and extending our prior work to suggest that PDE11A variants maybe involved in not only familial but also sporadic TGCT development.	('familial', 'Disease', (292, 300))	('involved', 'Reg', (271, 279))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('carcinogenesis', 'Disease', (91, 105))	('testicular cancer', 'Disease', 'MESH:D013736', (181, 198))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))	('PDE11A', 'Gene', '50940', (170, 176))	('PDE11A', 'Gene', (170, 176))	('PDE11A', 'Gene', '50940', (249, 255))	('variants', 'Var', (256, 264))	('PDE11A', 'Gene', (249, 255))	('contribute', 'Reg', (72, 82))	('variants', 'Var', (54, 62))	('testicular cancer', 'Disease', (181, 198))	('PDE11A', 'Gene', (47, 53))	('PDE11A', 'Gene', '50940', (47, 53))	('TGCT', 'Disease', (86, 90))	('men', 'Species', '9606', (331, 334))	('testicular cancer', 'Phenotype', 'HP:0010788', (181, 198))
59735	26459559	The 94 familial case samples in this study that were previously analyzed for PDE11A mutations were excluded from the primary analysis.	('mutations', 'Var', (84, 93))	('PDE11A', 'Gene', (77, 83))	('PDE11A', 'Gene', '50940', (77, 83))
59742	26459559	For transfection experiments, the PDE11A open reading frame was cloned into the pCR3.1 plasmid, and the newly identified mutations p.(R545X) and p.(K568R) were introduced into the construct using the QuikChange Lightning Site-Directed Mutagenesis kit (Agilent, Santa Clara, CA, USA).	('PDE11A', 'Gene', '50940', (34, 40))	('p.(K568R)', 'Mutation', 'rs148955609', (145, 154))	('p.(R545X', 'Var', (131, 139))	('PDE11A', 'Gene', (34, 40))	('p.(R545X)', 'Mutation', 'rs374570863', (131, 140))	('men', 'Species', '9606', (23, 26))	('p.(K568R', 'Var', (145, 153))
59745	26459559	Cells were transfected with 6 mg of plasmid DNA expressing either WT or the mutated form of PDE11A, then harvested 48 h after transfection.	('PDE11A', 'Gene', '50940', (92, 98))	('mutated', 'Var', (76, 83))	('PDE11A', 'Gene', (92, 98))
59751	26459559	Protein levels were determined by western blot using the antibodies for PDE11A, c-KIT, and KITLG (stem cell factor (SCF)/kit-ligand), using specific rabbit polyclonal antibodies (ab116556 for PDE11A, ab5506 for c-KIT, and ab52603 for KITLG; Abcam, Cambridge, MA, USA), following standard procedures.	('KITLG', 'Gene', (234, 239))	('KITLG', 'Gene', (91, 96))	('KITLG', 'Gene', '4254', (234, 239))	('c-KIT', 'Gene', (211, 216))	('SCF', 'Gene', '4254', (116, 119))	('ab116556', 'Var', (179, 187))	('c-KIT', 'Gene', '3815', (211, 216))	('KITLG', 'Gene', '4254', (91, 96))	('PDE11A', 'Gene', (192, 198))	('PDE11A', 'Gene', '50940', (192, 198))	('PDE11A', 'Gene', '50940', (72, 78))	('stem cell factor', 'Gene', (98, 114))	('PDE11A', 'Gene', (72, 78))	('stem cell factor', 'Gene', '4254', (98, 114))	('SCF', 'Gene', (116, 119))	('kit-ligand', 'Gene', '4254', (121, 131))	('rabbit', 'Species', '9986', (149, 155))	('ab52603', 'Var', (222, 229))	('kit-ligand', 'Gene', (121, 131))	('c-KIT', 'Gene', (80, 85))	('c-KIT', 'Gene', '3815', (80, 85))
59754	26459559	We identified 55 PDE11A variants in all 716 subjects: 20 missense variants, four splice variants, two nonsense variants, seven synonymous changes, and 22 intronic variants.	('PDE11A', 'Gene', '50940', (17, 23))	('PDE11A', 'Gene', (17, 23))	('missense variants', 'Var', (57, 74))	('variants', 'Var', (24, 32))
59755	26459559	Nine of the novel missense variants were in PDE11A isoform 4, and one was in isoform 3.	('PDE11A', 'Gene', '50940', (44, 50))	('missense variants', 'Var', (18, 35))	('PDE11A', 'Gene', (44, 50))
59756	26459559	Several rare PDE11A variants were found only in the TGCT cases (Table 2).	('PDE11A', 'Gene', (13, 19))	('variants', 'Var', (20, 28))	('PDE11A', 'Gene', '50940', (13, 19))
59757	26459559	We did not observe the previously reported F258Y or G291R variants in our validation study; of note, these variants have not been observed in the Exome Aggregation Consortium (ExaC) database (Table 2) or in controls from our previous study.	('F258Y', 'Var', (43, 48))	('G291R', 'Mutation', 'rs767064669', (52, 57))	('F258Y', 'Mutation', 'rs1438588949', (43, 48))	('G291R', 'Var', (52, 57))
59760	26459559	In addition, we detected a novel missense variant, K568R (CADD score=19.8), and novel nonsense variant, R545X (CADD score=23.2), that were only present in TGCT cases: K568R was in a white familial seminoma case and R545X was in an African-American sporadic seminoma case (ExaC minor allele frequency (MAF) African: 0.0097%).	('familial seminoma', 'Disease', 'MESH:D018239', (188, 205))	('K568R', 'Var', (51, 56))	('sporadic seminoma', 'Disease', 'MESH:D018239', (248, 265))	('sporadic seminoma', 'Phenotype', 'HP:0100617', (248, 265))	('K568R', 'Mutation', 'rs148955609', (167, 172))	('sporadic seminoma', 'Disease', (248, 265))	('R545X', 'Mutation', 'rs374570863', (104, 109))	('R545X', 'Var', (215, 220))	('K568R', 'Var', (167, 172))	('K568R', 'Mutation', 'rs148955609', (51, 56))	('familial seminoma', 'Disease', (188, 205))	('R545X', 'Mutation', 'rs374570863', (215, 220))
59763	26459559	The frequency of the intronic variant at Chr2:178634135 (NM_016953.3: c.1738-34G>T) was significantly increased in the validation TGCT cases (MAF=1.0%, P=0.01), particularly among the sporadic cases (MAF=1.7%, P=0.008); it was not detected in controls or in.	('Chr2:178634135', 'Gene', (41, 55))	('TGCT', 'Disease', (130, 134))	('MAF=1', 'Gene', '84232', (142, 147))	('MAF=1', 'Gene', '84232', (200, 205))	('MAF=1', 'Gene', (142, 147))	('c.1738-34G>T', 'SUBSTITUTION', 'None', (70, 82))	('c.1738-34G>T', 'Var', (70, 82))	('MAF=1', 'Gene', (200, 205))	('increased', 'PosReg', (102, 111))
59764	26459559	Table 3 lists the variants observed in white participants significantly associated with specific case subgroups in the stratified analyses, excluding the case samples in.	('associated', 'Reg', (72, 82))	('variants', 'Var', (18, 26))	('participants', 'Species', '9606', (45, 57))
59766	26459559	A splice site variant (chr2:178769917; NM_016953.3:c.1072-3C>T) had a significantly reduced frequency in sporadic cases only (MAF=8.3%) compared with controls (MAF=14.8%; P=0.04).	('NM_016953.3:c.1072-3C>T', 'Mutation', 'rs13012088', (39, 62))	('reduced', 'NegReg', (84, 91))	('MAF=1', 'Gene', '84232', (160, 165))	('c.1072-3C>T', 'Var', (51, 62))	('MAF=1', 'Gene', (160, 165))
59768	26459559	There were six PDE11A variants (R184Q, Q279E, N298, I552T, S570P, and Y644C) uncovered by our sequencing that were not significantly different between white cases and controls (Supplementary Table 3, see section on supplementary data given at the end of this article).	('PDE11A', 'Gene', (15, 21))	('Q279E', 'Mutation', 'rs780674695', (39, 44))	('PDE11A', 'Gene', '50940', (15, 21))	('S570P', 'Mutation', 'rs149795546', (59, 64))	('men', 'Species', '9606', (183, 186))	('R184Q', 'Mutation', 'rs6433711', (32, 37))	('Y644C', 'Mutation', 'rs758194850', (70, 75))	('R184Q', 'Var', (32, 37))	('Q279E', 'Var', (39, 44))	('N298', 'Var', (46, 50))	('men', 'Species', '9606', (221, 224))	('I552T', 'Var', (52, 57))	('I552T', 'Mutation', 'rs138427178', (52, 57))	('S570P', 'Var', (59, 64))	('Y644C', 'Var', (70, 75))
59769	26459559	Eight additional nonsignificant variants were identified and previously reported (R52T, A349T, R307X, D609N, Y727C, R804H, R867G, and R878V) (Supplementary Table 3).	('A349T', 'Mutation', 'rs77477862', (88, 93))	('Y727C', 'Var', (109, 114))	('Y727C', 'Mutation', 'rs17400325', (109, 114))	('R804H', 'Var', (116, 121))	('R307X', 'Mutation', 'rs76308115', (95, 100))	('R878V', 'Mutation', 'p.R878V', (134, 139))	('R867G', 'Mutation', 'rs61306957', (123, 128))	('men', 'Species', '9606', (148, 151))	('A349T', 'Var', (88, 93))	('D609N', 'Var', (102, 107))	('R804H', 'Mutation', 'rs75127279', (116, 121))	('R307X', 'Var', (95, 100))	('R867G', 'Var', (123, 128))	('R52T', 'Mutation', 'rs77972073', (82, 86))	('D609N', 'Mutation', 'rs77934668', (102, 107))	('R52T', 'Var', (82, 86))	('R878V', 'Var', (134, 139))
59770	26459559	We used cell line studies to characterize the cAMP levels and PDE activity of the two new variants (p.K568R and p.R545X) identified in this study.	('cAMP', 'Chemical', 'MESH:D000242', (46, 50))	('p.R545X', 'Mutation', 'rs374570863', (112, 119))	('p.K568R', 'Var', (100, 107))	('cAMP levels', 'MPA', (46, 57))	('p.R545X', 'Var', (112, 119))	('PDE activity', 'MPA', (62, 74))	('p.K568R', 'Mutation', 'rs148955609', (100, 107))
59771	26459559	Transfection experiments were performed using HEK293 cell lines and expression vectors harboring the p.R545X and p.K568R variants.	('HEK293', 'CellLine', 'CVCL:0045', (46, 52))	('p.K568R', 'Mutation', 'rs148955609', (113, 120))	('p.R545X', 'Var', (101, 108))	('expression vectors', 'Species', '29278', (68, 86))	('men', 'Species', '9606', (19, 22))	('p.R545X', 'Mutation', 'rs374570863', (101, 108))	('p.K568R', 'Var', (113, 120))
59772	26459559	We detected higher cAMP levels in the cell lines for each PDE11A mutation relative to WT, suggesting a reduced ability of these mutant PDE11A proteins to degrade cAMP (Fig.	('proteins', 'Protein', (142, 150))	('cAMP', 'Chemical', 'MESH:D000242', (19, 23))	('degrade', 'NegReg', (154, 161))	('higher', 'PosReg', (12, 18))	('reduced', 'NegReg', (103, 110))	('PDE11A', 'Gene', '50940', (58, 64))	('cAMP', 'MPA', (162, 166))	('mutant', 'Var', (128, 134))	('PDE11A', 'Gene', (58, 64))	('mutation', 'Var', (65, 73))	('cAMP levels', 'MPA', (19, 30))	('PDE11A', 'Gene', '50940', (135, 141))	('cAMP', 'Chemical', 'MESH:D000242', (162, 166))	('PDE11A', 'Gene', (135, 141))
59773	26459559	Post-transfection changes in PDE activity were negatively correlated with cAMP levels: PDE activity was lower vs WT PDE11A-transfected HEK293 cells for both mutation-bearing constructs (Fig.	('PDE11A', 'Gene', (116, 122))	('PDE11A', 'Gene', '50940', (116, 122))	('cAMP', 'Chemical', 'MESH:D000242', (74, 78))	('lower', 'NegReg', (104, 109))	('HEK293', 'CellLine', 'CVCL:0045', (135, 141))	('mutation-bearing', 'Var', (157, 173))	('PDE activity', 'MPA', (87, 99))
59774	26459559	A western blot showed lower PDE11A levels in the p.K568R HEK293 lysate cell line compared with WT (Fig.	('HEK293', 'CellLine', 'CVCL:0045', (57, 63))	('p.K568R', 'Var', (49, 56))	('PDE11A', 'Gene', (28, 34))	('PDE11A', 'Gene', '50940', (28, 34))	('p.K568R', 'Mutation', 'rs148955609', (49, 56))	('lower', 'NegReg', (22, 27))
59775	26459559	In the p.R545X HEK293 lysate cell line the expected 100 kDa band for PDE11A was not detected; instead, we observed a smaller band (~60 kDa), indicating a smaller protein product as a result of this premature stop codon (Fig.	('premature stop codon', 'Var', (198, 218))	('smaller', 'NegReg', (154, 161))	('HEK293', 'CellLine', 'CVCL:0045', (15, 21))	('protein product', 'MPA', (162, 177))	('p.R545X', 'Mutation', 'rs374570863', (7, 14))	('PDE11A', 'Gene', (69, 75))	('PDE11A', 'Gene', '50940', (69, 75))	('p.R545X', 'Var', (7, 14))
59776	26459559	No difference was seen for c-Kit and KITLG levels by immunoblot in p.K568R- and p.R545X-transfected cell lines compared with the WT PDE11A transfected cell line (Fig.	('KITLG', 'Gene', '4254', (37, 42))	('p.K568R', 'Mutation', 'rs148955609', (67, 74))	('KITLG', 'Gene', (37, 42))	('c-Kit', 'Gene', (27, 32))	('PDE11A', 'Gene', '50940', (132, 138))	('c-Kit', 'Gene', '3815', (27, 32))	('p.R545X-transfected', 'Var', (80, 99))	('p.K568R-', 'Var', (67, 75))	('PDE11A', 'Gene', (132, 138))	('p.R545X', 'Mutation', 'rs374570863', (80, 87))
59777	26459559	In our combined studies, we have identified five rare missense and nonsense PDE11A variants that present only in TGCT cases: p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R.	('p.K568R', 'Var', (165, 172))	('p.G291R', 'Var', (134, 141))	('p.R545X', 'Var', (152, 159))	('p.G291R', 'Mutation', 'rs767064669', (134, 141))	('PDE11A', 'Gene', (76, 82))	('p.F258Y', 'Var', (125, 132))	('PDE11A', 'Gene', '50940', (76, 82))	('p.V820M', 'Var', (143, 150))	('p.K568R', 'Mutation', 'rs148955609', (165, 172))	('p.V820M', 'Mutation', 'rs140269105', (143, 150))	('p.F258Y', 'Mutation', 'rs1438588949', (125, 132))	('p.R545X', 'Mutation', 'rs374570863', (152, 159))
59778	26459559	The two variants detected in our replication cohort, p.R545X and p.K568R, had not been previously reported.	('p.K568R', 'Var', (65, 72))	('p.R545X', 'Mutation', 'rs374570863', (53, 60))	('p.K568R', 'Mutation', 'rs148955609', (65, 72))	('p.R545X', 'Var', (53, 60))
59779	26459559	Furthermore, we have shown that the two newly detected mutations in our current case series, K568R and R545X, resulted in reduced PDE activity and increased cAMP levels using cell lines.	('K568R', 'Var', (93, 98))	('R545X', 'Var', (103, 108))	('increased', 'PosReg', (147, 156))	('R545X', 'Mutation', 'rs374570863', (103, 108))	('cAMP', 'Chemical', 'MESH:D000242', (157, 161))	('PDE activity', 'MPA', (130, 142))	('K568R', 'Mutation', 'rs148955609', (93, 98))	('reduced', 'NegReg', (122, 129))	('cAMP levels', 'MPA', (157, 168))
59780	26459559	The other three rare variants (p.F258Y, p.G291R, and p.V820M), observed only in the TGCT cases, had been shown previously to be functionally inactivating mutations.	('p.V820M', 'Var', (53, 60))	('p.F258Y', 'Var', (31, 38))	('p.G291R', 'Mutation', 'rs767064669', (40, 47))	('p.G291R', 'Var', (40, 47))	('p.F258Y', 'Mutation', 'rs1438588949', (31, 38))	('p.V820M', 'Mutation', 'rs140269105', (53, 60))	('TGCT', 'Disease', (84, 88))
59781	26459559	Our findings confirm that the two missense changes detected in our prior study but not in this one, F258Y and G291R, were only observed in TGCT cases; furthermore, they were absent from our 353 controls, as was the case in our prior report.	('F258Y', 'Mutation', 'rs1438588949', (100, 105))	('G291R', 'Var', (110, 115))	('G291R', 'Mutation', 'rs767064669', (110, 115))	('F258Y', 'Var', (100, 105))	('TGCT', 'Disease', (139, 143))
59783	26459559	Our results further confirm the V820M variant previously associated with testicular cancer, as it was observed in one additional case in our study but not in our controls.	('V820M', 'Mutation', 'rs140269105', (32, 37))	('testicular cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('testicular cancer', 'Phenotype', 'HP:0010788', (73, 90))	('testicular cancer', 'Disease', 'MESH:D013736', (73, 90))	('V820M', 'Var', (32, 37))	('associated', 'Reg', (57, 67))
59786	26459559	In the latter study, the variants as a group (missense and nonsense) were significantly more common in TGCT cases vs only the endocrine-negative control group, which consisted of volunteers of mostly European descent who had been screened clinically and biochemically and found to have no endocrine disorders.	('endocrine disorders', 'Disease', 'MESH:D004700', (289, 308))	('common', 'Reg', (93, 99))	('endocrine disorders', 'Phenotype', 'HP:0000818', (289, 308))	('TGCT', 'Disease', (103, 107))	('missense', 'Var', (46, 54))	('nonsense', 'Var', (59, 67))	('endocrine disorders', 'Disease', (289, 308))
59787	26459559	We did not detect a significant change in expression of KITLG in relation to our newly identified PDE11A mutations, p.R545X and p.K568R.	('p.R545X', 'Var', (116, 123))	('p.K568R', 'Mutation', 'rs148955609', (128, 135))	('PDE11A', 'Gene', '50940', (98, 104))	('expression', 'Species', '29278', (42, 52))	('p.R545X', 'Mutation', 'rs374570863', (116, 123))	('PDE11A', 'Gene', (98, 104))	('p.K568R', 'Var', (128, 135))	('KITLG', 'Gene', '4254', (56, 61))	('KITLG', 'Gene', (56, 61))
59788	26459559	Our previous study had shown that the other rare PDE11A mutations - p.F258Y, p.G291R, and p.V820M - resulted in an increased expression of KITLG.	('KITLG', 'Gene', '4254', (139, 144))	('p.V820M', 'Mutation', 'rs140269105', (90, 97))	('p.F258Y', 'Var', (68, 75))	('p.F258Y', 'Mutation', 'rs1438588949', (68, 75))	('increased', 'PosReg', (115, 124))	('p.G291R', 'Var', (77, 84))	('expression', 'Species', '29278', (125, 135))	('KITLG', 'Gene', (139, 144))	('p.G291R', 'Mutation', 'rs767064669', (77, 84))	('expression', 'MPA', (125, 135))	('p.V820M -', 'Var', (90, 99))	('PDE11A', 'Gene', (49, 55))	('PDE11A', 'Gene', '50940', (49, 55))
59790	26459559	Thus, we cannot exclude the possibility that expression of PDE11A p.R545X and p.K568R mutants may also be associated with the modulation of the KITLG signaling in testicular cancer cells.	('p.R545X', 'Var', (66, 73))	('p.K568R', 'Var', (78, 85))	('testicular cancer', 'Disease', 'MESH:D013736', (163, 180))	('testicular cancer', 'Phenotype', 'HP:0010788', (163, 180))	('associated', 'Reg', (106, 116))	('modulation', 'Reg', (126, 136))	('expression', 'Species', '29278', (45, 55))	('p.K568R', 'Mutation', 'rs148955609', (78, 85))	('p.R545X', 'Mutation', 'rs374570863', (66, 73))	('PDE11A', 'Gene', (59, 65))	('testicular cancer', 'Disease', (163, 180))	('PDE11A', 'Gene', '50940', (59, 65))	('KITLG', 'Gene', '4254', (144, 149))	('KITLG', 'Gene', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
59791	26459559	While the current analysis examined the relationship between PDE11A variation and testicular cancer in nearly twice the number of bilateral/familial cases as our first study, and for the first time in a cohort of sporadic TGCT cases, there are several limitations of this study.	('PDE11A', 'Gene', '50940', (61, 67))	('PDE11A', 'Gene', (61, 67))	('variation', 'Var', (68, 77))	('testicular cancer', 'Phenotype', 'HP:0010788', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('testicular cancer', 'Disease', 'MESH:D013736', (82, 99))	('testicular cancer', 'Disease', (82, 99))
59796	26459559	Finally, it is possible that PDE11A haplotypes (i.e., variants in cis with those we identified) might have an influence on susceptibility to testicular cancer; given the high frequency of common SNPs in PDE11A, this is a possibility.	('testicular cancer', 'Disease', 'MESH:D013736', (141, 158))	('susceptibility', 'Reg', (123, 137))	('PDE11A', 'Gene', (203, 209))	('PDE11A', 'Gene', '50940', (203, 209))	('testicular cancer', 'Disease', (141, 158))	('PDE11A', 'Gene', '50940', (29, 35))	('variants', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('influence', 'Reg', (110, 119))	('PDE11A', 'Gene', (29, 35))	('testicular cancer', 'Phenotype', 'HP:0010788', (141, 158))
59798	26459559	In summary, this study refines our understanding of which specific variants in PDE11A are most likely to be disease associated.	('PDE11A', 'Gene', (79, 85))	('variants', 'Var', (67, 75))	('PDE11A', 'Gene', '50940', (79, 85))
59799	26459559	We determined that although not all exonic PDE11A variants (as a group) are associated with TGCT risk, it appears that a select subset of rare missense and nonsense variants are associated with risk.	('PDE11A', 'Gene', (43, 49))	('exonic', 'Var', (36, 42))	('nonsense variants', 'Var', (156, 173))	('missense', 'Var', (143, 151))	('associated', 'Reg', (178, 188))	('associated', 'Reg', (76, 86))	('variants', 'Var', (50, 58))	('PDE11A', 'Gene', '50940', (43, 49))	('TGCT', 'Disease', (92, 96))
59800	26459559	These variants were shown to be functionally inactivating and may have a role in TGCT pathogenesis ultimately through increased cAMP levels.	('variants', 'Var', (6, 14))	('TGCT', 'Disease', (81, 85))	('cAMP levels', 'MPA', (128, 139))	('increased', 'PosReg', (118, 127))	('cAMP', 'Chemical', 'MESH:D000242', (128, 132))
59801	26459559	It is possible that the effect of PDE11A sequence variants in such a highly polymorphic gene is amplified or mitigated by the presence of other variants that are present in cis in the sequence; we did not study this effect here.	('PDE11A', 'Gene', (34, 40))	('PDE11A', 'Gene', '50940', (34, 40))	('variants', 'Var', (50, 58))
59802	26459559	We have extended our earlier work (conducted specifically in familial TGCT) to the broader context of sporadic TGCT, documenting that inactivating PDE11A variants occur in both TGCT subsets.	('variants', 'Var', (154, 162))	('men', 'Species', '9606', (121, 124))	('PDE11A', 'Gene', '50940', (147, 153))	('PDE11A', 'Gene', (147, 153))	('inactivating', 'NegReg', (134, 146))
59803	26459559	These data suggest that certain inactivating PDE11A variants are significantly associated with TGCT risk and provide further support for the hypothesis that inactivating variants in PDE11A are uncommonly, but reproducibly, associated with TGCT risk.	('associated', 'Reg', (79, 89))	('inactivating', 'Var', (32, 44))	('TGCT', 'Disease', (95, 99))	('associated', 'Reg', (223, 233))	('PDE11A', 'Gene', '50940', (45, 51))	('PDE11A', 'Gene', (182, 188))	('variants', 'Var', (52, 60))	('PDE11A', 'Gene', '50940', (182, 188))	('PDE11A', 'Gene', (45, 51))	('TGCT', 'Disease', (239, 243))
59804	26459559	Further careful examination of these specific PDE11A variants in relation to TGCT etiology is warranted.	('PDE11A', 'Gene', (46, 52))	('TGCT', 'Disease', (77, 81))	('variants', 'Var', (53, 61))	('PDE11A', 'Gene', '50940', (46, 52))
59818	15208620	Up to 1992, the histology of testicular cancers as in the Cancer Registry (WHO/HS/CANC/24.1 Histology Code) was used, to define seminoma (pathology codes 066) and teratoma (826, also including embryonal tumours).	('embryonal tumours', 'Disease', 'MESH:D009373', (193, 210))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('testicular cancer', 'Phenotype', 'HP:0010788', (29, 46))	('teratoma', 'Phenotype', 'HP:0009792', (163, 171))	('seminoma', 'Disease', 'MESH:D018239', (128, 136))	('embryonal tumours', 'Disease', (193, 210))	('teratoma', 'Disease', 'MESH:D013724', (163, 171))	('testicular cancers', 'Phenotype', 'HP:0010788', (29, 47))	('testicular cancers', 'Disease', 'MESH:D013736', (29, 47))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('testicular cancers', 'Disease', (29, 47))	('seminoma', 'Disease', (128, 136))	('826', 'Var', (173, 176))	('teratoma', 'Disease', (163, 171))
60012	21790653	Alteration of signals from the niche can produce drastic changes in the behavior and morphology of spermatogonial stem cells, allowing them to develop in many different tissues without prior genetic modifications.	('develop', 'CPA', (143, 150))	('man', 'Species', '9606', (154, 157))	('Alteration', 'Var', (0, 10))	('changes', 'Reg', (57, 64))	('behavior', 'MPA', (72, 80))	('allowing', 'Reg', (126, 134))
60029	21790653	Conversely, a Gdnf knockout model develops a Sertoli cell-only phenotype.	('Sertoli', 'Disease', (45, 52))	('knockout', 'Var', (19, 27))	('Sertoli cell', 'Phenotype', 'HP:0100619', (45, 57))	('Gdnf', 'Gene', (14, 18))	('Gdnf', 'Gene', '2668', (14, 18))
60031	21790653	In one pathway, phosphorylation of RET and SRC-kinase family proteins (SFKs) followed by phosphatidylinositol 3-kinase (PI3K) phosphorylation, activates the AKT pathway and finally Mycn gene expression (Figure 3A).	('phosphorylation', 'Var', (16, 31))	('phosphatidylinositol 3-kinase', 'MPA', (89, 118))	('AKT', 'Gene', '207', (157, 160))	('Mycn', 'Gene', '4613', (181, 185))	('AKT', 'Gene', (157, 160))	('activates', 'PosReg', (143, 152))	('Mycn', 'Gene', (181, 185))
60070	21790653	A mutation in the FGFR3 gene was evident in a number of spermatocytic seminomas under investigation.	('FGFR3', 'Gene', '2261', (18, 23))	('mutation', 'Var', (2, 10))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (56, 79))	('spermatocytic seminomas', 'Disease', (56, 79))	('spermatocytic seminoma', 'Phenotype', 'HP:0100617', (56, 78))	('FGFR3', 'Gene', (18, 23))	('evident', 'Reg', (33, 40))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (56, 79))
60074	21790653	Alternatively, GDNF can activate the canonical RAS/ERK1/2 pathway, which results in phosphorylation and activation of transcription factors such as CREB-1, ATF-1, CREM-1 and c-FOS (Figure 3B).	('CREB-1', 'Gene', '1385', (148, 154))	('activation', 'PosReg', (104, 114))	('CREM-1', 'Gene', (163, 169))	('ERK1/2', 'Gene', (51, 57))	('c-FOS', 'Gene', '2353', (174, 179))	('activate', 'PosReg', (24, 32))	('ATF-1', 'Gene', (156, 161))	('ERK1/2', 'Gene', '5595;5594', (51, 57))	('GDNF', 'Var', (15, 19))	('ATF-1', 'Gene', '466', (156, 161))	('c-FOS', 'Gene', (174, 179))	('CREB-1', 'Gene', (148, 154))	('phosphorylation', 'MPA', (84, 99))
60078	21790653	In addition, 57% (15/26) of these tumors had an elevated expression of HRAS, and about 19% (5/26) carried a mutation in the HRAS gene.	('expression', 'MPA', (57, 67))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('HRAS', 'Gene', '3265', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('HRAS', 'Gene', (124, 128))	('HRAS', 'Gene', '3265', (71, 75))	('mutation', 'Var', (108, 116))	('HRAS', 'Gene', (71, 75))	('elevated', 'PosReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
60249	33568653	High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes.	('mutations', 'Var', (45, 54))	('SSV', 'Chemical', '-', (13, 16))	('SSV', 'Disease', (13, 16))	('histone H3.3', 'Gene', (56, 68))	('H3F3C', 'Gene', (74, 79))	('transcription', 'MPA', (99, 112))	('mutations', 'Var', (80, 89))	('histone H3.3', 'Gene', '3020', (56, 68))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('H3F3C', 'Gene', '440093', (74, 79))
60255	33568653	All classes of somatic structural variants (SSVs):including tandem duplications, insertions, deletions, inversions, and translocations:can potentially alter the regulation of specific genes through several possible mechanisms, including gene fusion, promoter element disruption, enhancer hijacking, disruption of topologically associated domains (TADs), and altered DNA methylation.	('variants', 'Var', (34, 42))	('disruption', 'Reg', (299, 309))	('DNA methylation', 'MPA', (366, 381))	('tandem duplications', 'Var', (60, 79))	('altered', 'Reg', (358, 365))	('disruption', 'Reg', (267, 277))	('enhancer hijacking', 'PosReg', (279, 297))	('gene', 'CPA', (237, 241))	('TADs', 'Disease', (347, 351))	('deletions', 'Var', (93, 102))	('promoter', 'MPA', (250, 258))	('TADs', 'Disease', 'None', (347, 351))	('alter', 'Reg', (151, 156))	('regulation', 'MPA', (161, 171))	('specific genes', 'Gene', (175, 189))	('SSV', 'Chemical', '-', (44, 47))	('insertions', 'Var', (81, 91))
60256	33568653	Also, cancers harboring a high overall structural variation burden may exhibit an altered molecular profile reflective of extensive DNA damage.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('molecular profile', 'MPA', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('altered', 'Reg', (82, 89))	('structural variation', 'Var', (39, 59))
60274	33568653	Here, a high SSV burden is associated with TP53 mutations, histone H3.3 gene H3F3C mutations, and increased expression of DNA damage response genes.	('mutations', 'Var', (83, 92))	('DNA damage response genes', 'Gene', (122, 147))	('SSV', 'Chemical', '-', (13, 16))	('SSV burden', 'Disease', (13, 23))	('histone H3.3', 'Gene', '3020', (59, 71))	('H3F3C', 'Gene', (77, 82))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (108, 118))	('TP53', 'Gene', '7157', (43, 47))	('histone H3.3', 'Gene', (59, 71))	('TP53', 'Gene', (43, 47))	('H3F3C', 'Gene', '440093', (77, 82))	('mutations', 'Var', (48, 57))
60284	33568653	In line with previous observations in adult cancers, here, genomic rearrangements could be associated with widespread CNA patterns in pediatric brain tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('widespread CNA patterns', 'Disease', (107, 130))	('adult cancers', 'Disease', (38, 51))	('brain tumors', 'Disease', 'MESH:D001932', (144, 156))	('brain tumors', 'Phenotype', 'HP:0030692', (144, 156))	('genomic rearrangements', 'Var', (59, 81))	('brain tumors', 'Disease', (144, 156))	('brain tumor', 'Phenotype', 'HP:0030692', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('adult cancers', 'Disease', 'MESH:D009369', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associated', 'Reg', (91, 101))
60285	33568653	When we considered the set of all SSV-gene associations involving an SSV breakpoint falling within 1 Mb of gene start site for a given tumor, we found these associations to be highly enriched for gene-level amplification or deletion, though more so for the former.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (69, 72))	('tumor', 'Disease', (135, 140))	('falling', 'Phenotype', 'HP:0002527', (84, 91))	('deletion', 'Var', (224, 232))	('fall', 'Phenotype', 'HP:0002527', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
60286	33568653	While a significant proportion of SSVs associated with gene amplification involved tandem duplication SSVs as might be expected, all classes of SSV were involved with altered CNA patterns (Supplementary Fig.	('SSV', 'Chemical', '-', (102, 105))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (144, 147))	('CNA patterns', 'MPA', (175, 187))	('gene amplification', 'Var', (55, 73))	('involved with altered', 'Reg', (153, 174))	('SSVs', 'Disease', (34, 38))	('tandem duplication', 'Var', (83, 101))	('involved', 'Reg', (74, 82))
60287	33568653	The intra-chromosomal, non-translocation SSVs associated with CNA showed enrichment for SSVs of larger DNA sizes (>100 kb, Supplementary Fig.	('CNA', 'Disease', (62, 65))	('non-translocation', 'Var', (23, 40))	('SSV', 'Chemical', '-', (41, 44))	('SSV', 'Chemical', '-', (88, 91))
60293	33568653	SSV patterns:together with patterns of CNA, insertion/deletion of nucleotide bases (indels), and Single Nucleotide Variants (SNVs):revealed both concordant and discordant patterns among tumors from the same patient.	('SSV', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('insertion/deletion', 'Var', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('patient', 'Species', '9606', (207, 214))
60299	33568653	In principle, SSVs with breakpoints nearby a gene could lead to altered cis-regulation, e.g., by enhancer hijacking or altered DNA methylation, and SSV breakpoints within a gene could result in gene disruption or a gene fusion (Fig.	('result in', 'Reg', (184, 193))	('lead to altered', 'Reg', (56, 71))	('SSV', 'Var', (148, 151))	('SSV', 'Chemical', '-', (14, 17))	('DNA methylation', 'MPA', (127, 142))	('enhancer', 'PosReg', (97, 105))	('breakpoints', 'Var', (24, 35))	('SSV', 'Chemical', '-', (148, 151))	('cis-regulation', 'MPA', (72, 86))	('altered', 'Reg', (119, 126))	('gene', 'CPA', (194, 198))	('gene fusion', 'CPA', (215, 226))
60328	33568653	For particular genes of interest, including oncogenes TERT and MYB and tumor suppressor gene NF1, the relative expression changes in tumors harboring an SSV breakpoint were more dramatic as compared to tumors with CNA (Fig.	('TERT', 'Gene', '7015', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SSV', 'Chemical', '-', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NF1', 'Gene', '4763', (93, 96))	('tumor', 'Disease', (202, 207))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MYB', 'Gene', '4602', (63, 66))	('NF1', 'Gene', (93, 96))	('MYB', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (133, 139))	('breakpoint', 'Var', (157, 167))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TERT', 'Gene', (54, 58))
60333	33568653	Similarly, SSV breakpoints involving gene overexpression were enriched (p < 1E-15, chi-squared test) for putative enhancer translocation events, with the rearrangement bringing an enhancer within 500 kb of the gene (Fig.	('enhancer', 'PosReg', (180, 188))	('SSV', 'Chemical', '-', (11, 14))	('rearrangement', 'Var', (154, 167))
60350	33568653	We found a highly significant degree of overlapping gene-to-tumor associations involving predicted fusions using RNA-seq chimeric reads, gene overexpression, and SSVs breakpoint falling within the boundary of a gene (Supplementary Fig.	('SSVs breakpoint falling', 'Disease', 'MESH:D002303', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SSVs breakpoint falling', 'Disease', (162, 185))	('fall', 'Phenotype', 'HP:0002527', (178, 182))	('fusions', 'Var', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('falling', 'Phenotype', 'HP:0002527', (178, 185))	('tumor', 'Disease', (60, 65))
60353	33568653	This set of 1208 fusion calls with the highest level of support involved 974 distinct gene fusions, 368 tumors, and 331 patients (Supplementary Data 4), as well as the majority of gene body-associated SSV breakpoints with overexpression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overexpression', 'PosReg', (222, 236))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (91, 98))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('SSV', 'Chemical', '-', (201, 204))	('patients', 'Species', '9606', (120, 128))
60354	33568653	Of the 368 tumors, 182 had fusions both detectable in two or more tumors and including a known cancer-associated gene by COSMIC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (95, 101))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('fusions', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
60361	33568653	Alterations considered were gene fusion, SSV-mediated altered cis-regulation or gene disruption (taking from the genes significant for 1 Mb region), SNV or indel, and deep deletion or high-level amplification (Supplementary Data 5).	('high-level amplification', 'Var', (184, 208))	('SSV', 'Chemical', '-', (41, 44))	('deep deletion', 'Var', (167, 180))	('gene fusion', 'Var', (28, 39))	('cis-regulation', 'MPA', (62, 76))	('SNV', 'Var', (149, 152))	('altered', 'Reg', (54, 61))	('gene', 'CPA', (80, 84))	('indel', 'Var', (156, 161))
60366	33568653	Some tumor types showed particularly high enrichment for alterations affecting a specific pathway (Fig.	('alterations', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (5, 10))
60367	33568653	RTK-related alterations showed enrichment within PLGG; p53/Rb-related alterations, within PHGG; alterations involving chromatin modifiers, TERT, and MYC family, within MBL; SWI/SNF alterations, within ATRT; Wnt/beta-catenin alterations, within CRANIO; and HIPPO pathway alterations, within MNG.	('alterations', 'Var', (70, 81))	('MBL', 'Disease', (168, 171))	('TERT', 'Gene', '7015', (139, 143))	('p53', 'Gene', (55, 58))	('MBL', 'Disease', 'MESH:C563602', (168, 171))	('p53', 'Gene', '7157', (55, 58))	('RTK', 'Gene', '5979', (0, 3))	('MYC', 'Gene', (149, 152))	('beta-catenin', 'Gene', (211, 223))	('SWI/SNF', 'Gene', (173, 180))	('HIPPO pathway', 'Pathway', (256, 269))	('beta-catenin', 'Gene', '1499', (211, 223))	('MYC', 'Gene', '4609', (149, 152))	('RTK', 'Gene', (0, 3))	('TERT', 'Gene', (139, 143))
60388	33568653	We searched for genes with inactivating SNVs or indels correlated with high SSV burden, with 17 genes being significant (Fig.	('high SSV burden', 'Disease', (71, 86))	('indels', 'Var', (48, 54))	('SNVs', 'Var', (40, 44))	('SSV', 'Chemical', '-', (76, 79))
60391	33568653	TP53 hotspot SNVs and inactivating SNVs and indels, along with single-copy loss, were associated with higher SSV burden, in both the CBTTC pediatric brain and TCGA adult pan-cancer cohorts (Fig.	('SSV', 'Chemical', '-', (109, 112))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('higher', 'PosReg', (102, 108))	('cancer', 'Disease', (174, 180))	('pan', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('SNVs', 'Var', (13, 17))	('inactivating', 'Var', (22, 34))	('pan', 'Gene', '51816', (170, 173))	('SSV', 'Disease', (109, 112))
60393	33568653	TP53 mutation also corresponded to increases in detected SNVs and indels, in addition to SSV burden (Supplementary Figs.	('SNVs', 'MPA', (57, 61))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('increases', 'PosReg', (35, 44))	('indels', 'MPA', (66, 72))	('SSV burden', 'MPA', (89, 99))	('mutation', 'Var', (5, 13))	('SSV', 'Chemical', '-', (89, 92))
60394	33568653	6b), with mutation and copy loss events mostly occurring in PHGG and MBL tumors.	('occurring', 'Reg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MBL tumors', 'Disease', 'MESH:C563602', (69, 79))	('MBL tumors', 'Disease', (69, 79))	('PHGG', 'Disease', (60, 64))	('copy loss', 'Var', (23, 32))
60404	33568653	A survey of Histone H3 genes showed frequent mutations in H3F3A and H3F3C across CBTTC tumors (Supplementary Fig.	('H3F3C', 'Gene', '440093', (68, 73))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('H3F3A', 'Gene', '3020', (58, 63))	('H3F3A', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('H3F3C', 'Gene', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
60405	33568653	While H3F3A mutations are commonly associated with pediatric brain tumors, particularly with PHGG and DIPG, H3F3C, which also encodes for an H3.3 histone component, appears to be much less studied in the context of cancer, including pediatric brain cancer.	('H3F3C', 'Gene', (108, 113))	('brain cancer', 'Phenotype', 'HP:0030692', (243, 255))	('cancer', 'Disease', (249, 255))	('brain tumors', 'Disease', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('brain cancer', 'Disease', 'MESH:D001932', (243, 255))	('H3F3A', 'Gene', '3020', (6, 11))	('cancer', 'Disease', (215, 221))	('H3F3C', 'Gene', '440093', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('H3F3A', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (61, 72))	('brain cancer', 'Disease', (243, 255))	('brain tumors', 'Disease', 'MESH:D001932', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('brain tumors', 'Phenotype', 'HP:0030692', (61, 73))
60407	33568653	7b), with no hypermutated tumors having H3F3C mutations.	('mutations', 'Var', (46, 55))	('H3F3C', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('H3F3C', 'Gene', '440093', (40, 45))	('tumors', 'Disease', (26, 32))
60408	33568653	While H3F3A mutations in CBTTC tumors primarily involved the known K28M/K27M hotspot (n = 30 tumors), followed by the G35R/G34R hotspot (n = 4), H3F3C mutations followed another distinctive pattern.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('H3F3C', 'Gene', (145, 150))	('K27M', 'Var', (72, 76))	('G35R', 'SUBSTITUTION', 'None', (118, 122))	('H3F3A', 'Gene', '3020', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('K28M', 'SUBSTITUTION', 'None', (67, 71))	('involved', 'Reg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('G34R', 'SUBSTITUTION', 'None', (123, 127))	('G34R', 'Var', (123, 127))	('H3F3A', 'Gene', (6, 11))	('H3F3C', 'Gene', '440093', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (93, 99))	('K28M', 'Var', (67, 71))	('CBTTC', 'Disease', (25, 30))	('mutations', 'Var', (12, 21))	('G35R', 'Var', (118, 122))	('K27M', 'SUBSTITUTION', 'None', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (93, 99))
60409	33568653	All nine impacted tumors (three PLGG, two EPMT, and one each for ATRT, MNG, PHGG, and SARCNOS; two progressive, two recurrent, and one second malignancy) had nucleotide changes involving both K37 duplication and N79K amino acid change (Fig.	('K37', 'Gene', '8688', (192, 195))	('N79K', 'Mutation', 'rs768711923', (212, 216))	('N79K amino acid change', 'Var', (212, 234))	('malignancy', 'Disease', 'MESH:D009369', (142, 152))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('malignancy', 'Disease', (142, 152))	('K37', 'Gene', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
60410	33568653	Two of the nine tumors also harbored amino acid changes L104F and V89I.	('L104F', 'Mutation', 'rs765335762', (56, 61))	('L104F', 'Var', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('V89I', 'Mutation', 'rs148314204', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('V89I', 'Var', (66, 70))
60411	33568653	H3F3C mutations were mutually exclusive with TP53 alterations (Fig.	('TP53', 'Gene', (45, 49))	('H3F3C', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (45, 49))	('H3F3C', 'Gene', '440093', (0, 5))	('mutations', 'Var', (6, 15))
60415	33568653	We went on to survey whole-exome sequencing data from 10,224 TCGA adult cancers for H3F3C mutations.	('adult cancers', 'Disease', 'MESH:D009369', (66, 79))	('H3F3C', 'Gene', (84, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('H3F3C', 'Gene', '440093', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('adult cancers', 'Disease', (66, 79))
60416	33568653	Of all TCGA tumors, 49:representing many different tissues of origin:harbored a mutation in H3F3C (Fig.	('H3F3C', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('H3F3C', 'Gene', '440093', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
60419	33568653	The TCGA H3F3C mutations did not show the same tight hotspot pattern found in CBTTC tumors, although TCGA mutations did include G35R (two patients), N79K (one patient), and V89I (four patients).	('V89I', 'Mutation', 'rs148314204', (173, 177))	('G35R', 'Var', (128, 132))	('N79K', 'Mutation', 'rs768711923', (149, 153))	('V89I', 'Var', (173, 177))	('TCGA', 'Gene', (101, 105))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patient', 'Species', '9606', (184, 191))	('G35R', 'Mutation', 'rs748979871', (128, 132))	('H3F3C', 'Gene', '440093', (9, 14))	('patient', 'Species', '9606', (138, 145))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('patient', 'Species', '9606', (159, 166))	('N79K', 'Var', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (138, 146))	('H3F3C', 'Gene', (9, 14))
60422	33568653	Aspects of this phenomenon, as observed in both PCAWG and CBTTC cohorts, include: hundreds of genes recurrently impacted, SSV breakpoints as far as 1 Mb from the gene contributing to deregulation, rearrangements involving widespread CNA patterns, many more genes with increased over decreased expression associated with SSV breakpoints, and overexpressed and under-expressed genes respectively representing known oncogenes and tumor suppressor genes.	('SSV', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (427, 432))	('SSV', 'Chemical', '-', (320, 323))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('tumor', 'Disease', (427, 432))	('rearrangements', 'Var', (197, 211))	('expression', 'MPA', (293, 303))	('increased over', 'PosReg', (268, 282))	('impacted', 'Reg', (112, 120))
60437	33568653	For a given patient, the overall numbers of SSVs and other somatic mutations tend to increase in a recurrent or progressive tumor as compared to the primary tumor.	('tumor', 'Disease', (157, 162))	('recurrent', 'CPA', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SSVs', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patient', 'Species', '9606', (12, 19))	('increase', 'PosReg', (85, 93))	('SSV', 'Chemical', '-', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
60442	33568653	DNA mutation correlates of high SSV burden included mutations in TP53 and histone H3.3 genes.	('mutations', 'Var', (52, 61))	('histone H3.3', 'Gene', '3020', (74, 86))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('histone H3.3', 'Gene', (74, 86))	('SSV', 'Chemical', '-', (32, 35))
60443	33568653	Our TP53-related findings would be consistent with those of an adult pan-cancer study of TCGA data, in which TP53 mutational status was associated with global increases in DNA copy number instability and somatic SNV/indel frequency.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pan', 'Gene', '51816', (69, 72))	('TP53', 'Gene', (4, 8))	('pan', 'Gene', (69, 72))	('increases', 'PosReg', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (109, 113))	('DNA copy number instability', 'MPA', (172, 199))	('mutational status', 'Var', (114, 131))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (4, 8))
60444	33568653	Other studies have also linked TP53 mutation with increased numbers of chromosome rearrangements in pediatric cancers.	('cancers', 'Disease', (110, 117))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('chromosome rearrangements', 'MPA', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('mutation', 'Var', (36, 44))
60445	33568653	While H3F3A mutations are commonly associated with pediatric brain cancers, H3F3C appears to be much less studied in cancer, including pediatric brain cancer.	('brain cancer', 'Disease', (145, 157))	('brain cancer', 'Phenotype', 'HP:0030692', (61, 73))	('brain cancer', 'Disease', 'MESH:D001932', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('H3F3A', 'Gene', '3020', (6, 11))	('H3F3C', 'Gene', '440093', (76, 81))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (117, 123))	('brain cancer', 'Phenotype', 'HP:0030692', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('H3F3A', 'Gene', (6, 11))	('brain cancer', 'Disease', 'MESH:D001932', (145, 157))	('brain cancers', 'Disease', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('brain cancers', 'Disease', 'MESH:D001932', (61, 74))	('H3F3C', 'Gene', (76, 81))
60446	33568653	Interestingly, a search of the PeCan (https://pecan.stjude.cloud/) and PedCBioportal (https://pedcbioportal.kidsfirstdrc.org/) databases:representing more than 1000 additional pediatric brain tumors:did not uncover additional cases of H3F3C hotspot mutation.	('mutation', 'Var', (249, 257))	('brain tumors', 'Disease', 'MESH:D001932', (186, 198))	('brain tumors', 'Phenotype', 'HP:0030692', (186, 198))	('H3F3C', 'Gene', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('brain tumor', 'Phenotype', 'HP:0030692', (186, 197))	('brain tumors', 'Disease', (186, 198))	('PeCan', 'Species', '32201', (31, 36))	('H3F3C', 'Gene', '440093', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('pecan', 'Species', '32201', (46, 51))
60447	33568653	This may be because mutations in CBTTC cohort were few and spread among multiple histologic types and involving progressive or recurrent or second malignancy cases.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('CBTTC', 'Gene', (33, 38))	('malignancy', 'Disease', (147, 157))	('spread', 'Reg', (59, 65))	('mutations', 'Var', (20, 29))	('involving', 'Reg', (102, 111))
60448	33568653	At the same time, the observations in adult tumors would suggest that alteration of histone H3.3 genes (including H3F3C) may cumulatively involve many patients, with the functional impact not being limited to hotspot mutations.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('H3F3C', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('histone H3.3', 'Gene', (84, 96))	('patients', 'Species', '9606', (151, 159))	('H3F3C', 'Gene', '440093', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('alteration', 'Var', (70, 80))	('histone H3.3', 'Gene', '3020', (84, 96))	('involve', 'Reg', (138, 145))
60465	33568653	Manta algorithm classified each SSV call as one of the following: tandem duplications, insertions, deletions, inversions, and translocations.	('deletions', 'Var', (99, 108))	('insertions', 'Var', (87, 97))	('SSV', 'Chemical', '-', (32, 35))
60474	33568653	This aspect would include treating SSV breakpoints representing different classes (tandem duplications, insertions, deletions, inversions, and translocations) and insert sizes the same in the integration with gene expression.	('deletions', 'Var', (116, 125))	('insertions', 'Var', (104, 114))	('SSV', 'Chemical', '-', (35, 38))
60497	33568653	We considered all inactivating SNVs (nonstop/nonsense) and indels in putative tumor suppressor genes (e.g., TP53) in the analyses.	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('nonstop/nonsense', 'Var', (37, 53))	('tumor', 'Disease', (78, 83))
60499	33568653	At both the gene and pathway levels, we tabulated somatic alterations in the following order: SNV or indel, gene fusion, deep deletion (approximating homozygous loss), high-level amplification (approximating five or more copies), and SSV (for oncogenes, breakpoint falling with 1 Mb of gene and associated with expression >0.4 SD from median for the given tumor; for tumor suppressors, breakpoint falling within the gene body and expression < -0.4 SD).	('fall', 'Phenotype', 'HP:0002527', (397, 401))	('expression', 'MPA', (311, 321))	('tumor', 'Disease', (367, 372))	('deep deletion', 'Var', (121, 134))	('SSV', 'Var', (234, 237))	('SSV', 'Chemical', '-', (234, 237))	('falling', 'Phenotype', 'HP:0002527', (265, 272))	('falling', 'Phenotype', 'HP:0002527', (397, 404))	('high-level amplification', 'Var', (168, 192))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('gene fusion', 'Var', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('SNV', 'Var', (94, 97))	('fall', 'Phenotype', 'HP:0002527', (265, 269))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (356, 361))
60507	33568653	For CBTTC datasets, we constructed a [gene x tumor] matrix, involving 567 genes with nonsense/nonstop/indel mutations in at least three tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('nonsense/nonstop/indel mutations', 'Var', (85, 117))	('x tumor', 'Disease', 'MESH:C562844', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('x tumor', 'Disease', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
60732	28555838	Given our observation that patients with TGCT exhibited an average 30% increase in the size of the CD4+ and CD8+ T-cell memory pool at the time of presentation, we next went on to assess the effect of treatment on the proportion of naive and memory T cells.	('patients', 'Species', '9606', (27, 35))	('CD8', 'Gene', (108, 111))	('increase', 'PosReg', (71, 79))	('CD4', 'Gene', (99, 102))	('TGCT', 'Var', (41, 45))	('CD8', 'Gene', '925', (108, 111))	('men', 'Species', '9606', (206, 209))	('CD4', 'Gene', '920', (99, 102))
60784	28555838	PBMCs (5 x 105) were resuspended in 100 muL MACS buffer (PBS, 0.5% BSA, 2 mM EDTA), and surface stained with fluorochrome-conjugated antibodies on ice for 30 min to identify memory T-cell subsets (CD3-APCCy7, CD4-PerCPCy5.5, CD8-AmCyan, CCR7-PE and CD45RA-efluor450).	('CD4', 'Gene', '920', (209, 212))	('CD8', 'Gene', (225, 228))	('CD8', 'Gene', '925', (225, 228))	('CCR7', 'Gene', '1236', (237, 241))	('PBS', 'Chemical', 'MESH:D007854', (57, 60))	('CD45', 'Gene', (249, 253))	('CCR7', 'Gene', (237, 241))	('MACS', 'Gene', '4082', (44, 48))	('CD45', 'Gene', '5788', (249, 253))	('MACS', 'Gene', (44, 48))	('CD4', 'Gene', (249, 252))	('EDTA', 'Chemical', 'MESH:D004492', (77, 81))	('CD4', 'Gene', (209, 212))	('CD3-APCCy7', 'Var', (197, 207))	('CD4', 'Gene', '920', (249, 252))
60810	28555838	Cells were surface stained with CD3-APC-Cy7, CD4-FITC and CD8-PC5 on ice for 30 min, then washed twice before cytometric analysis.	('CD8', 'Gene', (58, 61))	('CD4', 'Gene', (45, 48))	('CD4', 'Gene', '920', (45, 48))	('CD8', 'Gene', '925', (58, 61))	('CD3-APC-Cy7', 'Var', (32, 43))
60877	25103095	Delays in diagnosis can dramatically impact survival with 5-year median relative survivals dropping from 99% for cancer confined to the testis to 74% for metastatic disease.	('impact', 'Reg', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('metastatic', 'Disease', (154, 164))	('survival', 'MPA', (44, 52))	('cancer', 'Disease', (113, 119))	('Delays', 'Var', (0, 6))	('dropping', 'NegReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
61005	33632159	Cannabinoids have been detected in seminal fluid and have been linked with DNA nicking and fragmentation, abnormal sperm nuclear size, gross abnormalities of sperm morphology including sperm fragmentation, disordered DNA packing and re-packing, disorders of protamine synthesis, histone-protamine substitution and major disruption of sperm DNA methylation.	('fragmentation', 'CPA', (91, 104))	('abnormal', 'Var', (106, 114))	('disruption', 'NegReg', (320, 330))	('linked', 'Reg', (63, 69))	('men', 'Species', '9606', (195, 198))	('sperm fragmentation', 'CPA', (185, 204))	('DNA nicking', 'Disease', (75, 86))	('histone-protamine substitution', 'MPA', (279, 309))	('disorders', 'Var', (245, 254))	('men', 'Species', '9606', (95, 98))	('Cannabinoids', 'Chemical', 'MESH:D002186', (0, 12))	('sperm nuclear size', 'CPA', (115, 133))	('sperm DNA', 'CPA', (334, 343))	('protamine synthesis', 'MPA', (258, 277))	('disordered DNA packing', 'CPA', (206, 228))
61019	33632159	Micronucleus disruption releases double stranded DNA into the cytoplasm where it potently stimulates the cytoplasmic GMP-AMP - STimulator of INterferon Gamma (cGAS-STING) pathway which further intracytoplasmically stimulates inflammation via interferon-gamma and innate immune signalling and destabilizes the genome.	('stimulates', 'PosReg', (214, 224))	('STING', 'Gene', (164, 169))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('cGAS', 'Gene', (159, 163))	('interferon-gamma', 'Gene', (242, 258))	('disruption', 'Var', (13, 23))	('inflammation', 'Disease', (225, 237))	('GMP-AMP', 'Chemical', '-', (117, 124))	('STING', 'Gene', '340061', (164, 169))	('genome', 'CPA', (309, 315))	('double stranded', 'Var', (33, 48))	('cGAS', 'Gene', '115004', (159, 163))	('innate immune signalling', 'Pathway', (263, 287))	('stimulates', 'PosReg', (90, 100))	('interferon-gamma', 'Gene', '3458', (242, 258))	('destabilizes', 'NegReg', (292, 304))
61116	22941667	Current evidence suggests that maldevelopment of the primordial germ cells gives rise to testicular carcinoma in situ (CIS), which is the recognized dormant precursor of TGCT.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('testicular carcinoma', 'Disease', 'MESH:D013736', (89, 109))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (89, 109))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (100, 117))	('maldevelopment', 'Var', (31, 45))	('CIS', 'Phenotype', 'HP:0030075', (119, 122))	('testicular carcinoma', 'Disease', (89, 109))	('men', 'Species', '9606', (41, 44))	('gives rise to', 'Reg', (75, 88))
61123	22941667	The International Classification of Diseases for the Oncology third edition (ICD-O-3) was used to classify histologic subtypes of TGCTs (topography code: C62) into seminoma (9060-9062, 9064) and nonseminoma (9065-9102).	('seminoma', 'Disease', (198, 206))	('nonseminoma', 'Disease', (195, 206))	('seminoma', 'Disease', 'MESH:D018239', (164, 172))	('nonseminoma', 'Disease', 'None', (195, 206))	('Oncology', 'Phenotype', 'HP:0002664', (53, 61))	('9065-9102', 'Var', (208, 217))	('9064', 'Var', (185, 189))	('TGCTs', 'Disease', (130, 135))	('seminoma', 'Disease', 'MESH:D018239', (198, 206))	('seminoma', 'Disease', (164, 172))	('9060-9062', 'Var', (174, 183))
61170	18719707	Substantial roles for RNAi in regulating endogenous gene expression have been difficult to ascertain because Drosophila melanogaster and Caenorhabditis elegans mutants that selectively inactivate RNAi seem to be normal and fertile.	('Caenorhabditis elegans', 'Species', '6239', (137, 159))	('mutants', 'Var', (160, 167))	('RNAi', 'Gene', (196, 200))
61182	18719707	Nematodes also lack conventional piRNAs, as the Piwi homologue PRG-1 contains '21U' RNAs.	('Piwi', 'Gene', (48, 52))	("'21U' RNAs", 'Var', (78, 88))	('Piwi', 'Gene', '34521', (48, 52))
61185	18719707	This was most clear in C. elegans, because many RNAi-defective mutants also deregulate transposons.	('RNAi-defective', 'Gene', (48, 62))	('mutants', 'Var', (63, 70))	('transposons', 'Protein', (87, 98))	('deregulate', 'Reg', (76, 86))	('C. elegans', 'Species', '6239', (23, 33))
61186	18719707	A conundrum for mammalian piRNA studies was that although multiple mouse Piwi-gene mutants exhibit testicular defects, transposon activation and sterility, corresponding mutant ovaries were normal and functional.	('ovaries', 'Disease', (177, 184))	('testicular defects', 'CPA', (99, 117))	('Piwi', 'Gene', (73, 77))	('mutants', 'Var', (83, 90))	('ovaries', 'Disease', 'MESH:D010051', (177, 184))	('transposon activation', 'CPA', (119, 140))	('sterility', 'CPA', (145, 154))	('mammalian', 'Species', '9606', (16, 25))	('mouse', 'Species', '10090', (67, 72))	('Piwi', 'Gene', '34521', (73, 77))
61192	18719707	1c), and the depletion or mutation of either DCR2 or AGO2 elevates TE transcript levels.	('TE transcript levels', 'MPA', (67, 87))	('AGO2', 'Gene', (53, 57))	('mutation', 'Var', (26, 34))	('DCR2', 'Gene', '36993', (45, 49))	('elevates', 'PosReg', (58, 66))	('depletion', 'MPA', (13, 22))	('DCR2', 'Gene', (45, 49))
61197	18719707	The levels of the 3'-overlapping transcripts Pdzd 11 and Kif4 increased modestly in mouse Dicer mutants, consistent with an autoregulatory activity of the siRNAs generated by this cis-NAT.	('increased', 'PosReg', (62, 71))	('Kif4', 'Gene', '16571', (57, 61))	('Pdzd 11', 'Gene', '72621', (45, 52))	('NAT', 'Gene', '14312', (184, 187))	('Dicer', 'Gene', (90, 95))	('Dicer', 'Gene', '42693', (90, 95))	('mouse', 'Species', '10090', (84, 89))	('NAT', 'Gene', (184, 187))	('Kif4', 'Gene', (57, 61))	('Pdzd 11', 'Gene', (45, 52))	('mutants', 'Var', (96, 103))
61208	18719707	Small-RNA cloning from mouse oocytes revealed an unexpected class of 'functional' pseudogenes.	('pseudogenes', 'Var', (82, 93))	('mouse', 'Species', '10090', (23, 28))	("'functional'", 'PosReg', (69, 81))
61209	18719707	Multiple genes with antisense-transcribed pseudogenes were inferred to anneal with their complementary progenitors (as trans-NATs) and be diced into siRNAs.	('NAT', 'Gene', '14312', (125, 128))	('anneal', 'CPA', (71, 77))	('pseudogenes', 'Var', (42, 53))	('NAT', 'Gene', (125, 128))	('antisense-transcribed pseudogenes', 'Var', (20, 53))
61213	18719707	In at least one case : histone deacetylase-1 (Hdac1) : siRNAs derived exclusively from sense-antisense pseudogene duplexes, which were inferred to repress functional Hdac1 trancripts.	('histone deacetylase-1 (Hdac1', 'Gene', '38565', (23, 51))	('Hdac1', 'Gene', (46, 51))	('Hdac1', 'Gene', '38565', (166, 171))	('sense-antisense', 'Var', (87, 102))	('Hdac1', 'Gene', '38565', (46, 51))	('Hdac1', 'Gene', (166, 171))
61214	18719707	Earlier functional tests showed that long dsRNA does not activate protein kinase R or the interferon response in oocytes, as it does in most other mammalian cells.	('interferon', 'CPA', (90, 100))	('mammalian', 'Species', '9606', (147, 156))	('long dsRNA', 'Var', (37, 47))	('protein kinase R', 'Enzyme', (66, 82))
61222	18719707	However, hp-CG18854 is a pseudogene with substantial homology to CG8289, which encodes a chromodomain protein, and elevated hp-CG 18854 could repress CG8289 in trans.	('hp-CG', 'Chemical', '-', (124, 129))	('CG8289', 'Gene', '32741', (65, 71))	('CG8289', 'Gene', (65, 71))	('hp-CG', 'Var', (124, 129))	('CG8289', 'Gene', '32741', (150, 156))	('hp-CG', 'Chemical', '-', (9, 14))	('hp-CG18854', 'Chemical', '-', (9, 19))	('CG8289', 'Gene', (150, 156))	('hp-CG18854', 'Var', (9, 19))
61223	18719707	Curiously, several candidate hpRNA loci were identified in mouse, including a long-inverted repeat pseudogene of the Ran GTPase-activating protein-1 (Rangap1) gene.	('Ran GTPase-activating protein-1', 'Gene', (117, 148))	('mouse', 'Species', '10090', (59, 64))	('Ran GTPase-activating protein-1', 'Gene', '19387', (117, 148))	('long-inverted repeat', 'Var', (78, 98))	('Rangap1', 'Gene', (150, 157))
61229	18719707	For example, unlike Dcr2 mutants, r2d2 mutants reveal its requirement for early development and female fertility.	('Dcr2', 'Gene', (20, 24))	('r2d2', 'Gene', '34066', (34, 38))	('Dcr2', 'Gene', '36993', (20, 24))	('mutants', 'Var', (39, 46))	('r2d2', 'Gene', (34, 38))	('female fertility', 'CPA', (96, 112))
61233	18719707	Finally, loqs functions in inverted-repeat RNA-mediated silencing.	('loqs', 'Gene', '34751', (9, 13))	('loqs', 'Gene', (9, 13))	('inverted-repeat', 'Var', (27, 42))
61234	18719707	Despite its original classification as a core component of the miRNA pathway, loqs-null mutants have only modest defects in the maturation of many miRNAs.	('mutants', 'Var', (88, 95))	('maturation', 'MPA', (128, 138))	('loqs', 'Gene', '34751', (78, 82))	('loqs', 'Gene', (78, 82))
61246	18719707	Conversely, how do co-expressed mammalian cis-NATs, and co-expressed pseudogene-gene complementary pairs, avoid triggering an interferon response outside of oocytes?	('pseudogene-gene', 'Var', (69, 84))	('cis-NATs', 'Chemical', '-', (42, 50))	('interferon response', 'MPA', (126, 145))	('avoid', 'NegReg', (106, 111))	('mammalian', 'Species', '9606', (32, 41))
61254	18719707	The recent papers do show deregulation of retrotransposon transcripts, pseudogene-complementary transcripts and some cis-NAT pairs in Dicer and/or Ago mutants, and thus their regulation by endo-siRNAs is plausible, although this remains to be shown directly Evidence for direct siRNA-mediated target regulation was only explicitly shown for some hpRNAs in D. melanogaster, and such evidence would be desirable for other classes of endo-siRNAs.	('NAT', 'Gene', '14312', (121, 124))	('mutants', 'Var', (151, 158))	('D. melanogaster', 'Species', '7227', (356, 371))	('NAT', 'Gene', (121, 124))	('deregulation', 'MPA', (26, 38))	('pseudogene-complementary', 'Gene', (71, 95))	('Dicer', 'Gene', (134, 139))	('Dicer', 'Gene', '42693', (134, 139))	('retrotransposon transcripts', 'Gene', (42, 69))
61257	18719707	It is relevant to note, therefore, that D. melanogaster Dcr2 mutants exhibit abnormal nucleolar morphology, whereas Ago2 mutants were reported to have chromosome segregation defects.	('chromosome segregation defects', 'CPA', (151, 181))	('Ago2', 'Gene', '39683', (116, 120))	('Dcr2', 'Gene', (56, 60))	('nucleolar morphology', 'CPA', (86, 106))	('D. melanogaster', 'Species', '7227', (40, 55))	('mutants', 'Var', (61, 68))	('Ago2', 'Gene', (116, 120))	('Dcr2', 'Gene', '36993', (56, 60))
61266	30305294	Traditional genome-wide association studies have identified single nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss.	('WFS1', 'Gene', (105, 109))	('hearing loss', 'Disease', 'MESH:D034381', (144, 156))	('ACYP2', 'Gene', '98', (95, 100))	('WFS1', 'Gene', '7466', (105, 109))	('hearing loss', 'Phenotype', 'HP:0000365', (144, 156))	('associated', 'Reg', (110, 120))	('ACYP2', 'Gene', (95, 100))	('hearing loss', 'Disease', (144, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('single nucleotide polymorphisms', 'Var', (60, 91))
61283	30305294	Thus, pharmacogenomics has elucidated genetic variability as a key determinant in both therapeutic benefit and potential toxicities likely to be experienced during cisplatin-based chemotherapy.	('toxicities', 'Disease', (121, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))	('toxicities', 'Disease', 'MESH:D064420', (121, 131))	('genetic variability', 'Var', (38, 57))
61286	30305294	ototoxicity and nephrotoxicity) are primarily due to cisplatin; therefore the genetic variants identified are most likely associated with cisplatin exposure.	('associated', 'Reg', (122, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('ototoxicity and nephrotoxicity', 'Disease', 'MESH:D006311', (0, 30))	('variants', 'Var', (86, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))
61288	30305294	Cisplatin is associated with irreversible, bilateral sensorineural hearing loss that occurs at a much higher rate than other ototoxic drugs.	('bilateral sensorineural hearing', 'Phenotype', 'HP:0008619', (43, 74))	('ototoxic', 'Disease', 'MESH:D006311', (125, 133))	('sensorineural hearing loss', 'Disease', 'MESH:D006319', (53, 79))	('hearing loss', 'Phenotype', 'HP:0000365', (67, 79))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('sensorineural hearing', 'Phenotype', 'HP:0000407', (53, 74))	('Cisplatin', 'Var', (0, 9))	('sensorineural hearing loss', 'Disease', (53, 79))	('ototoxic', 'Disease', (125, 133))
61290	30305294	In addition, approximately 40% of cisplatin-treated patients experience some degree of tinnitus, which occurs at a significantly higher rate than either the general population (15%), or in comparable cancer patients not given cisplatin-based chemotherapy (12%).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('patients', 'Species', '9606', (207, 215))	('tinnitus', 'Disease', (87, 95))	('cisplatin-treated', 'Var', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tinnitus', 'Disease', 'MESH:D014012', (87, 95))	('tinnitus', 'Phenotype', 'HP:0000360', (87, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))	('patients', 'Species', '9606', (52, 60))
61300	30305294	Not only did STS treatment reduce grade 1 or higher hearing loss incidence by 48% (18 of 55 children (33%) in the cisplatin-STS group experienced hearing loss compared to 29 of 46 (63%) in the cisplatin-alone group; relative risk, 0.52; 95% confidence interval [CI]: 0.33 to 0.81; p=0.002), but cisplatin-STS conferred overall and event-free survival rates comparable to those who did not receive the protective agent.	('hearing loss', 'Phenotype', 'HP:0000365', (146, 158))	('STS', 'Chemical', 'MESH:C017717', (124, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('hearing loss', 'Disease', 'MESH:D034381', (146, 158))	('hearing loss', 'Disease', 'MESH:D034381', (52, 64))	('cisplatin-STS', 'Var', (295, 308))	('reduce', 'NegReg', (27, 33))	('men', 'Species', '9606', (22, 25))	('children', 'Species', '9606', (92, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('hearing loss', 'Phenotype', 'HP:0000365', (52, 64))	('STS', 'Chemical', 'MESH:C017717', (305, 308))	('cisplatin', 'Chemical', 'MESH:D002945', (295, 304))	('hearing loss', 'Disease', (146, 158))	('STS', 'Chemical', 'MESH:C017717', (13, 16))	('hearing loss', 'Disease', (52, 64))
61308	30305294	In a study  that utilized a platform containing primarily single nucleotide polymorphisms (SNPs) in metabolizing genes, genetic variants in TPMT (rs12201199) and COMT (rs9332377) were identified that prompted the FDA to revise their label recommendations in 2012 for pediatric patients given cisplatin.	('men', 'Species', '9606', (244, 247))	('rs12201199', 'Mutation', 'rs12201199', (146, 156))	('rs9332377', 'Mutation', 'rs9332377', (168, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (292, 301))	('rs12201199', 'Var', (146, 156))	('TPMT', 'Gene', (140, 144))	('rs9332377', 'Var', (168, 177))	('COMT', 'Gene', '1312', (162, 166))	('TPMT', 'Gene', '7172', (140, 144))	('patients', 'Species', '9606', (277, 285))	('S', 'Chemical', 'MESH:D013455', (91, 92))	('COMT', 'Gene', (162, 166))
61309	30305294	However, the modification was rescinded in 2015 due to conflicting evidence of association between TPMT genetic variants and cisplatin-induced hearing loss provided by two replication studies and a meta-analysis.	('TPMT', 'Gene', (99, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('hearing loss', 'Phenotype', 'HP:0000365', (143, 155))	('association', 'Interaction', (79, 90))	('TPMT', 'Gene', '7172', (99, 103))	('hearing loss', 'Disease', (143, 155))	('variants', 'Var', (112, 120))	('hearing loss', 'Disease', 'MESH:D034381', (143, 155))
61315	30305294	The first GWAS of CAO in 238 pediatric brain tumor patients identified an association with a genetic variant in ACYP2 (rs1872328, hazard ratio (HR)=4.5, 95% CI 2.63-7.69, p=3.9 x 10-8), and results were replicated in a second cohort of 68 pediatric patients.	('rs1872328', 'Var', (119, 128))	('brain tumor', 'Disease', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (249, 257))	('brain tumor', 'Disease', 'MESH:D001932', (39, 50))	('rs1872328', 'Mutation', 'rs1872328', (119, 128))	('brain tumor', 'Phenotype', 'HP:0030692', (39, 50))	('ACYP2', 'Gene', (112, 117))	('patients', 'Species', '9606', (51, 59))	('S', 'Chemical', 'MESH:D013455', (13, 14))	('association', 'Interaction', (74, 85))	('ACYP2', 'Gene', '98', (112, 117))
61316	30305294	Further, increased ACYP2 expression highly correlated with cisplatin sensitivity in lymphoblastoid cell lines in vitro (p=6.5 x 10-5), but the genotype at the SNP rs1872328 position was not associated with cisplatin sensitivity in vitro, nor was it related to expression of ACYP2 and other genes 300 kb within this index SNP.	('ACYP2', 'Gene', '98', (274, 279))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('cisplatin sensitivity', 'MPA', (59, 80))	('expression', 'MPA', (25, 35))	('S', 'Chemical', 'MESH:D013455', (159, 160))	('increased', 'PosReg', (9, 18))	('ACYP2', 'Gene', (19, 24))	('ACYP2', 'Gene', (274, 279))	('S', 'Chemical', 'MESH:D013455', (321, 322))	('rs1872328', 'Var', (163, 172))	('rs1872328', 'Mutation', 'rs1872328', (163, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('ACYP2', 'Gene', '98', (19, 24))
61320	30305294	The first GWAS of CAO in adult-onset cancer in 511 testicular cancer survivors identified a genome-wide significant SNP (rs62283056; p=1.4 x 10-8) in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein).	('testicular cancer', 'Disease', 'MESH:D013736', (51, 68))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('Mendelian deafness', 'Disease', 'MESH:D003638', (170, 188))	('S', 'Chemical', 'MESH:D013455', (13, 14))	('S', 'Chemical', 'MESH:D013455', (196, 197))	('testicular cancer', 'Disease', (51, 68))	('cancer', 'Disease', (62, 68))	('testicular cancer', 'Phenotype', 'HP:0010788', (51, 68))	('WFS1', 'Gene', (194, 198))	('rs62283056;', 'Var', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rs62283056', 'Mutation', 'rs62283056', (121, 131))	('WFS1', 'Gene', '7466', (194, 198))	('deafness', 'Phenotype', 'HP:0000365', (180, 188))	('Mendelian deafness', 'Disease', (170, 188))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
61325	30305294	In a meta-analysis of this GWAS and the GWAS that initially identified ACYP2, rs62283056 in WFS1 remained the top signal.	('ACYP2', 'Gene', '98', (71, 76))	('WFS1', 'Gene', (92, 96))	('S', 'Chemical', 'MESH:D013455', (94, 95))	('rs62283056', 'Var', (78, 88))	('WFS1', 'Gene', '7466', (92, 96))	('rs62283056', 'Mutation', 'rs62283056', (78, 88))	('ACYP2', 'Gene', (71, 76))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('S', 'Chemical', 'MESH:D013455', (30, 31))
61326	30305294	However, the meta-analysis did not support the ACYP2 variant rs1872328 as being significantly associated with adult-onset cancer CAO.	('rs1872328', 'Mutation', 'rs1872328', (61, 70))	('ACYP2', 'Gene', '98', (47, 52))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('ACYP2', 'Gene', (47, 52))	('associated', 'Reg', (94, 104))	('rs1872328', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
61328	30305294	Cisplatin-based therapy is associated with peripheral neuropathy (manifested as tingling, numbness, weakness, or burning pain) that occurs in about 36-38% of patients.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (43, 64))	('weakness', 'Disease', (100, 108))	('weakness', 'Disease', 'MESH:D018908', (100, 108))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (43, 64))	('peripheral neuropathy', 'Disease', (43, 64))	('numbness', 'Disease', 'MESH:D006987', (90, 98))	('tingling', 'Disease', (80, 88))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('tingling', 'Phenotype', 'HP:0003401', (80, 88))	('numbness', 'Disease', (90, 98))	('burning pain', 'Disease', 'MESH:D010146', (113, 125))	('patients', 'Species', '9606', (158, 166))	('Cisplatin-based therapy', 'Var', (0, 23))	('burning pain', 'Disease', (113, 125))	('neuropathy', 'Phenotype', 'HP:0009830', (54, 64))
61344	30305294	RPRD1B is of particular interest because defects in its expression or knockdown have been shown to inhibit DNA repair mechanisms that resolve cisplatin-induced lesions.	('defects', 'Var', (41, 48))	('knockdown', 'Var', (70, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('inhibit', 'NegReg', (99, 106))	('RPRD1B', 'Gene', (0, 6))	('DNA repair mechanisms', 'MPA', (107, 128))	('RPRD1B', 'Gene', '58490', (0, 6))
61345	30305294	Further, RPRD1B knockdown in human breast carcinoma cells potentiates cisplatin sensitivity.	('RPRD1B', 'Gene', '58490', (9, 15))	('RPRD1B', 'Gene', (9, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('breast carcinoma', 'Disease', (35, 51))	('knockdown', 'Var', (16, 25))	('breast carcinoma', 'Disease', 'MESH:D001943', (35, 51))	('cisplatin sensitivity', 'MPA', (70, 91))	('human', 'Species', '9606', (29, 34))	('breast carcinoma', 'Phenotype', 'HP:0003002', (35, 51))	('potentiates', 'PosReg', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
61350	30305294	Further, cisplatin induces acute kidney injury in approximately 20-30% of patients, while hypomagnesemia manifests in 40-100%.	('cisplatin', 'Var', (9, 18))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (90, 104))	('acute kidney injury', 'Disease', 'MESH:D058186', (27, 46))	('acute kidney injury', 'Disease', (27, 46))	('patients', 'Species', '9606', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('hypomagnesemia', 'Disease', 'MESH:C537153', (90, 104))	('acute kidney', 'Phenotype', 'HP:0001919', (27, 39))	('hypomagnesemia', 'Disease', (90, 104))	('induces', 'Reg', (19, 26))
61352	30305294	A SNP in ERCC1 (8092C>A/rs3212986) has been shown to be significantly associated with a reduced risk of cisplatin-induced nephrotoxicity in two separate candidate gene studies, as well as rs1051740 in EPHX1.	('EPHX1', 'Gene', (201, 206))	('rs3212986', 'Mutation', 'rs3212986', (24, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('8092C>A', 'Mutation', 'rs3212986', (16, 23))	('8092C>A/rs3212986', 'Var', (16, 33))	('ERCC1', 'Gene', (9, 14))	('S', 'Chemical', 'MESH:D013455', (2, 3))	('nephrotoxicity', 'Disease', (122, 136))	('rs1051740', 'Var', (188, 197))	('EPHX1', 'Gene', '2052', (201, 206))	('ERCC1', 'Gene', '2067', (9, 14))	('nephrotoxicity', 'Disease', 'MESH:D007674', (122, 136))	('reduced', 'NegReg', (88, 95))	('rs1051740', 'Mutation', 'rs1051740', (188, 197))
61353	30305294	In addition, two cation transporters vital for cisplatin renal uptake (OCT2/SLC22A2 and CTR1/SLC31A1; Table 1) have SNPs associated with renoprotection and maintenance of estimated glomular filtration rate (rs596881 (OCT2); rs12686377 and rs7851395 (CTR1.	('estimated glomular filtration rate', 'MPA', (171, 205))	('S', 'Chemical', 'MESH:D013455', (93, 94))	('OCT2', 'Gene', '6582', (217, 221))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('SLC22A2', 'Gene', '6582', (76, 83))	('S', 'Chemical', 'MESH:D013455', (76, 77))	('SLC31A1', 'Gene', '1317', (93, 100))	('CTR1', 'Gene', (250, 254))	('rs596881', 'Mutation', 'rs596881', (207, 215))	('SLC31A1', 'Gene', (93, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('OCT2', 'Gene', (217, 221))	('rs12686377', 'Var', (224, 234))	('SLC22A2', 'Gene', (76, 83))	('OCT2', 'Gene', '6582', (71, 75))	('CTR1', 'Gene', '1317', (250, 254))	('renoprotection', 'CPA', (137, 151))	('rs7851395', 'Var', (239, 248))	('CTR1', 'Gene', (88, 92))	('rs12686377', 'Mutation', 'rs12686377', (224, 234))	('rs7851395', 'Mutation', 'rs7851395', (239, 248))	('CTR1', 'Gene', '1317', (88, 92))	('rs596881', 'Var', (207, 215))	('OCT2', 'Gene', (71, 75))
61354	30305294	As do many antineoplastic agents, cisplatin can profoundly impact hematopoiesis.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('hematopoiesis', 'Disease', (66, 79))	('cisplatin', 'Var', (34, 43))	('hematopoiesis', 'Disease', 'MESH:C536227', (66, 79))	('impact', 'Reg', (59, 65))
61362	30305294	Two SNPs (rs13014982 and rs9909179) exhibited associations with myelosuppression in the discovery and replication sets, but did not reach genome-wide significance in the discovery set.	('myelosuppression', 'Disease', 'MESH:D001855', (64, 80))	('rs13014982', 'Mutation', 'rs13014982', (10, 20))	('rs13014982', 'Var', (10, 20))	('rs9909179', 'Mutation', 'rs9909179', (25, 34))	('associations', 'Reg', (46, 58))	('myelosuppression', 'Disease', (64, 80))	('rs9909179', 'Var', (25, 34))	('S', 'Chemical', 'MESH:D013455', (4, 5))
61364	30305294	rs13014982 is located in a gene desert at 2q24.3 (within 500 kb of FIGN), limiting its potential genetic significance, but rs9909179 was determined via GTEx to be a plausible eQTL for HS3ST3A1 in blood (p=0.03), an enzyme involved in heparan sulfate biosynthesis, which may be important in hematopoiesis.	('HS3ST3A1', 'Gene', (184, 192))	('rs9909179', 'Mutation', 'rs9909179', (123, 132))	('hematopoiesis', 'Disease', 'MESH:C536227', (290, 303))	('rs13014982', 'Var', (0, 10))	('HS3ST3A1', 'Gene', '9955', (184, 192))	('rs9909179', 'Var', (123, 132))	('hematopoiesis', 'Disease', (290, 303))	('rs13014982', 'Mutation', 'rs13014982', (0, 10))
61372	30305294	Importantly, severe emesis in Yakuts was independently associated with two polymorphisms in the CYP2E1 gene, but was only associated with the GSTT1-null genotype in Eastern European Russians.	('polymorphisms', 'Var', (75, 88))	('emesis', 'Disease', 'MESH:D014839', (20, 26))	('associated', 'Reg', (55, 65))	('CYP2E1', 'Gene', (96, 102))	('emesis', 'Phenotype', 'HP:0002013', (20, 26))	('emesis', 'Disease', (20, 26))	('GSTT1', 'Gene', '2952', (142, 147))	('GSTT1', 'Gene', (142, 147))	('CYP2E1', 'Gene', '1571', (96, 102))
61378	30305294	GWAS have the potential to identify causal SNPs in genes agnostically, but require large cohorts of patients treated with the same regimen and uniformly phenotyped for toxicity.	('SNPs', 'Var', (43, 47))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('toxicity', 'Disease', (168, 176))	('men', 'Species', '9606', (135, 138))	('patients', 'Species', '9606', (100, 108))	('S', 'Chemical', 'MESH:D013455', (43, 44))	('S', 'Chemical', 'MESH:D013455', (3, 4))
61382	30305294	As such, genetic variants that are associated with varying levels of cisplatin sensitivity in European-based studies may not be relevant in patients of other genetic ancestries, thereby promoting a gap in health disparities.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('health disparities', 'MPA', (205, 223))	('patients', 'Species', '9606', (140, 148))	('variants', 'Var', (17, 25))
61406	30305294	CAO: cisplatin-associated ototoxicity eQTL: expression quantitative trait loci GTEx: Genotype-Tissue Expression GWAS: genome-wide association study NSCLC: non-small cell lung carcinoma SNP: single nucleotide polymorphism STS: sodium thiosulfate	('S', 'Chemical', 'MESH:D013455', (223, 224))	('S', 'Chemical', 'MESH:D013455', (115, 116))	('S', 'Chemical', 'MESH:D013455', (149, 150))	('NSCLC', 'Disease', (148, 153))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (155, 184))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (155, 184))	('S', 'Chemical', 'MESH:D013455', (221, 222))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('non-small cell lung carcinoma', 'Disease', (155, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (5, 14))	('ototoxicity', 'Disease', 'MESH:D006311', (26, 37))	('STS', 'Chemical', 'MESH:C017717', (221, 224))	('single nucleotide polymorphism', 'Var', (190, 220))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (159, 184))	('sodium thiosulfate', 'Chemical', 'MESH:C017717', (226, 244))	('S', 'Chemical', 'MESH:D013455', (185, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('ototoxicity', 'Disease', (26, 37))
61445	23623488	Nonseminoma without mixed germ cell tumors included codes 9065, 9070-9072, 9080-9084, and 9100-9102 while code 9085 identified mixed germ cell cancers.	('germ cell tumor', 'Phenotype', 'HP:0100728', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('9100-9102', 'Var', (90, 99))	('Nonseminoma', 'Disease', 'None', (0, 11))	('cell cancers', 'Disease', (138, 150))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('Nonseminoma', 'Disease', (0, 11))	('9070-9072', 'Var', (64, 73))	('cell cancers', 'Disease', 'MESH:C538614', (138, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('9080-9084', 'Var', (75, 84))	('germ cell tumors', 'Phenotype', 'HP:0100728', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('germ cell cancer', 'Phenotype', 'HP:0100728', (133, 149))	('codes 9065', 'Var', (52, 62))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
61446	23623488	Specific nonseminoma entities included embryonal carcinoma (9070), yolk sac tumors (9071), malignant teratoma (9080-9084, 9102), and choriocarcinoma (9100-9101).	('9071', 'Var', (84, 88))	('9080-9084', 'Var', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('nonseminoma entities', 'Disease', (9, 29))	('teratoma', 'Phenotype', 'HP:0009792', (101, 109))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('9070', 'Var', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('choriocarcinoma', 'Disease', 'MESH:D002822', (133, 148))	('tumors', 'Disease', (76, 82))	('choriocarcinoma', 'Disease', (133, 148))	('nonseminoma entities', 'Disease', 'None', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (39, 58))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('malignant teratoma', 'Disease', (91, 109))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (39, 58))	('embryonal carcinoma', 'Disease', (39, 58))	('malignant teratoma', 'Disease', 'MESH:D013724', (91, 109))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (133, 148))
61543	31704139	In this National Cancer Database analysis, PTS was a predictor of OS in CS IA seminoma.	('PTS', 'Var', (43, 46))	('CS IA seminoma', 'Disease', (72, 86))	('Cancer', 'Disease', (17, 23))	('CS IA seminoma', 'Disease', 'MESH:D018239', (72, 86))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))
61613	31704139	Individuals with large T1 seminomas managed with adjuvant radiation or chemotherapy vs. observation had a 41% decrease in overall mortality translating into a 3.5% and 4.5% absolute improvement in OS at 5 and 10 years, respectively.	('mortality', 'Disease', 'MESH:D003643', (130, 139))	('men', 'Species', '9606', (189, 192))	('large T1', 'Var', (17, 25))	('mortality', 'Disease', (130, 139))	('seminomas', 'Disease', (26, 35))	('decrease', 'NegReg', (110, 118))	('seminomas', 'Disease', 'MESH:D018239', (26, 35))	('improvement', 'PosReg', (182, 193))
61615	31704139	originally used a 4 cm cut-point to demonstrate a non-significant difference in 5-year relapse-free rates: 88% vs. 73% for <=4 cm vs. >4 cm tumors, respectively (P = 0.12).	('<=4', 'Var', (123, 126))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('relapse-free', 'CPA', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
61620	31704139	first reported primary tumor size as an independent prognosticator in a Danish cohort of 261 men with 4-year relapse-free survivals of 94, 82 and 64% for tumors <3, >=3 to <6 and >=6 cm, respectively (P < 0.001).	('tumors', 'Disease', (154, 160))	('>=6 cm', 'Var', (179, 185))	('>=3 to <6', 'Var', (165, 174))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('men', 'Species', '9606', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (154, 159))
61670	30456189	The presence of a positive lymph node in the retroperitoneum elevates the disease to stage II, in which additional treatment is needed and active surveillance is no longer an option.	('presence', 'Var', (4, 12))	('elevates', 'PosReg', (61, 69))	('men', 'Species', '9606', (120, 123))
61736	30456189	The risk of secondary malignancies cannot be ignored by urologists caring for these patients, however, with MRIs costing over twice the cost of CT, the burden on the healthcare system must also be acknowledged when following these men.	('malignancies', 'Disease', 'MESH:D009369', (22, 34))	('patients', 'Species', '9606', (84, 92))	('malignancies', 'Disease', (22, 34))	('men', 'Species', '9606', (231, 234))	('MRIs', 'Var', (108, 112))
61835	18622385	Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors Alterations in methylation of CpG dinucleotides at the 5 position of deoxycytidine residues (5mC) are a hallmark of cancer cells, including testicular germ cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('nonseminomatous male germ cell tumors', 'Disease', (88, 125))	('CpG', 'Gene', (156, 159))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (156, 173))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Alterations', 'Var', (126, 137))	('seminoma', 'Disease', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cell tumors', 'Disease', (282, 293))	('seminoma', 'Disease', 'MESH:D018239', (91, 99))	('cell tumors', 'Disease', 'MESH:D005935', (114, 125))	('neoplasia', 'Disease', 'MESH:D009369', (53, 62))	('cell tumors', 'Disease', 'MESH:D005935', (282, 293))	('germ cell tumors', 'Phenotype', 'HP:0100728', (109, 125))	('germ cell tumors', 'Phenotype', 'HP:0100728', (277, 293))	('deoxycytidine', 'Chemical', 'MESH:D003841', (195, 208))	('seminoma', 'Disease', (67, 75))	('nonseminomatous male germ cell tumors', 'Disease', 'MESH:C537844', (88, 125))	('neoplasia', 'Disease', (53, 62))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (43, 62))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('seminoma', 'Disease', 'MESH:D018239', (67, 75))	('germ cell tumor', 'Phenotype', 'HP:0100728', (109, 124))	('neoplasia', 'Phenotype', 'HP:0002664', (53, 62))	('germ cell tumor', 'Phenotype', 'HP:0100728', (277, 292))	('cancer', 'Disease', (242, 248))	('methylation', 'MPA', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('5mC', 'Chemical', '-', (219, 222))
61838	18622385	Smiraglia et al have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have undergone 5mC erasure, and nonseminomas arise from IGCNU cells derived from primordial germ cells that have already undergone de novo methylation after the original erasure of methylation and contain normal 5mC levels.	('5mC', 'Chemical', '-', (331, 334))	('nonseminomas', 'Disease', (151, 163))	('nonseminomas', 'Disease', 'None', (151, 163))	('seminomas', 'Disease', 'MESH:D018239', (46, 55))	('seminomas', 'Disease', (46, 55))	('methylation', 'Var', (258, 269))	('5mC', 'Chemical', '-', (134, 137))	('seminomas', 'Disease', 'MESH:D018239', (154, 163))	('seminomas', 'Disease', (154, 163))
61848	18622385	Although genetic changes, such as gain of the short arm of chromosome 12, are very common in testicular germ cell tumors, epigenetic changes may also be important in initiating these tumors.	('epigenetic changes', 'Var', (122, 140))	('gain', 'PosReg', (34, 38))	('cell tumors', 'Disease', 'MESH:D005935', (109, 120))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('germ cell tumors', 'Phenotype', 'HP:0100728', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('germ cell tumor', 'Phenotype', 'HP:0100728', (104, 119))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Disease', (183, 189))	('cell tumors', 'Disease', (109, 120))	('short arm', 'Phenotype', 'HP:0009824', (46, 55))
61850	18622385	Somatic hypermethylation of deoxycytidine within CpG islands in the promoter regions of genes is associated with transcriptional silencing, whereas hypomethylation of CpG islands may result in gene activation.	('activation', 'PosReg', (198, 208))	('hypermethylation', 'Var', (8, 24))	('gene', 'MPA', (193, 197))	('silencing', 'NegReg', (129, 138))	('deoxycytidine', 'Chemical', 'MESH:D003841', (28, 41))	('hypomethylation', 'Var', (148, 163))	('transcriptional', 'MPA', (113, 128))
61854	18622385	Two autosomal loci showed a similar trend: seminomas were relatively hypomethylated, whereas nonseminomas were either normally methylated or hypermethylated.	('seminomas', 'Disease', 'MESH:D018239', (96, 105))	('seminomas', 'Disease', (96, 105))	('hypomethylated', 'Var', (69, 83))	('nonseminomas', 'Disease', (93, 105))	('seminomas', 'Disease', 'MESH:D018239', (43, 52))	('nonseminomas', 'Disease', 'None', (93, 105))	('seminomas', 'Disease', (43, 52))
61859	18622385	However, little is known regarding the timing of events of epigenetic changes occurring early during development of testicular germ cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('germ cell tumor', 'Phenotype', 'HP:0100728', (127, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cell tumors', 'Disease', (132, 143))	('epigenetic changes', 'Var', (59, 77))	('cell tumors', 'Disease', 'MESH:D005935', (132, 143))	('germ cell tumors', 'Phenotype', 'HP:0100728', (127, 143))
61880	18622385	M. SssI treatment resulted in a marked increase in staining (data not shown), which was fully dependent upon the addition of the methyl donor, S-adenosyl-methionine (data not shown).	('treatment', 'Var', (8, 17))	('M. SssI', 'Var', (0, 7))	('donor', 'Species', '9606', (136, 141))	('increase', 'PosReg', (39, 47))	('staining', 'MPA', (51, 59))	('S-adenosyl-methionine', 'Chemical', 'MESH:D012436', (143, 164))
61881	18622385	This shows that our primary and secondary reagents can access methylated DNA within seminoma cells if indeed 5mC is present.	('methylated', 'Var', (62, 72))	('seminoma', 'Disease', (84, 92))	('seminoma', 'Disease', 'MESH:D018239', (84, 92))	('5mC', 'Chemical', '-', (109, 112))
61917	18622385	This in situ analysis was critical for our finding of profound hypomethylation in IGCNU and seminoma, as we were able to evaluate the relative methylation status of both the neoplastic cells and the nontumor host cells (eg, tumor-infiltrating lymphocytes).	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (202, 207))	('seminoma', 'Disease', (92, 100))	('tumor', 'Disease', (224, 229))	('hypomethylation', 'Var', (63, 78))	('IGCNU', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('seminoma', 'Disease', 'MESH:D018239', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
61923	18622385	And, IGCNU or seminoma cells that differentiate into any other male testicular germ cell tumor type undergo de novo CpG methylation in an apparent attempt to recapitulate the process of normal development (Figure 5).	('seminoma', 'Disease', 'MESH:D018239', (14, 22))	('methylation', 'Var', (120, 131))	('germ cell tumor', 'Phenotype', 'HP:0100728', (79, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('seminoma', 'Disease', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
61944	24516397	Combination of immunofluorescent visualization of the proteins of synaptonemal complexes with whole-chromosome DNA FISH on pachytene spreads revealed that heterosubspecific, unlike consubspecific, homologous chromosomes are predisposed to asynapsis in F1 hybrid male and female meiosis.	('heterosubspecific', 'Var', (155, 172))	('predisposed', 'Reg', (224, 235))	('asynapsis', 'CPA', (239, 248))	('pachytene', 'Chemical', '-', (123, 132))
61947	24516397	We propose that meiotic asynapsis in intersubspecific hybrids is a consequence of cis-acting mismatch between homologous chromosomes modulated by the trans-acting Hstx2 and Prdm9 hybrid male sterility genes.	('Prdm9', 'Gene', '213389', (173, 178))	('meiotic asynapsis', 'CPA', (16, 33))	('mismatch', 'Var', (93, 101))	('Hstx2', 'Gene', (163, 168))	('Prdm9', 'Gene', (173, 178))
61953	24516397	The repeated introgressions of Mmm genes into Mmd genome and vice versa across their hybrid zone indicate incomplete reproductive isolation between both young subspecies.	('reproductive isolation', 'CPA', (117, 139))	('Mmd', 'Gene', (46, 49))	('introgressions', 'Var', (13, 27))	('Mmm genes', 'Gene', (31, 40))	('Mmd', 'Gene', '67468', (46, 49))
61955	24516397	We identified the first hybrid sterility gene in mice, hybrid sterility 1 - Hst1 - as a polymorphic variant on Chr 17 between two laboratory strains, C57BL10/Sn and C3H/Di, both predominantly of Mmd origin (at that time still linkage group IX).	('Mmd', 'Gene', '67468', (195, 198))	('mice', 'Species', '10090', (49, 53))	('Hst1', 'Gene', '109727', (76, 80))	('rat', 'Species', '10116', (134, 137))	('Hst1', 'Gene', (76, 80))	('Mmd', 'Gene', (195, 198))	('C3H/Di', 'Var', (165, 171))	('C57BL10/Sn', 'Var', (150, 160))
61956	24516397	When mated with Mmm wild mice trapped in Central Bohemia near Prague, these crosses produced sterile or fertile male hybrids, depending on their Hst1 alleles.	('mice', 'Species', '10090', (25, 29))	('Hst1', 'Gene', (145, 149))	('Central Bohemia', 'Disease', (41, 56))	('Central Bohemia', 'Disease', 'MESH:D012607', (41, 56))	('Hst1', 'Gene', '109727', (145, 149))	('crosses', 'Var', (76, 83))
61973	24516397	The Hstx1 locus mapped within the interval spanned by DXMit76 and DXMit143 (Fig.	('Hstx1', 'Gene', (4, 9))	('Hstx1', 'Gene', '100036139', (4, 9))	('DXMit143', 'Var', (66, 74))	('DXMit76', 'Var', (54, 61))
61974	24516397	To further localize Hstx1, we phenotyped all four B6.PWD-Chr X partial consomics and found a high percentage of abnormal sperm cells in B6.PWD-Chr X.1s compared to other three partial consomics and B6 males (p<0.05 t-test, Fig.	('sperm cells', 'CPA', (121, 132))	('Hstx1', 'Gene', '100036139', (20, 25))	('B6.PWD-Chr', 'Var', (136, 146))	('Hstx1', 'Gene', (20, 25))
61978	24516397	Of these, seven protein-coding genes, namely cancer/testis antigen 2 (Ctag2), RIKEN cDNA 4930447F04 gene (4930447F04Rik), SLIT and NTRK-like family, member 2 (Slitrk2), RIKEN cDNA 4933436I01 gene (4933436I01Rik), fragile X mental retardation syndrome 1 homolog (Fmr1), fragile X mental retardation 1 neighbor (Fmr1nb) and AF4/FMR2 family member 2 (Aff2) show high expression in adult testis.	('Slitrk2', 'Gene', '245450', (159, 166))	('Slitrk2', 'Gene', (159, 166))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Aff2', 'Gene', (348, 352))	('Fmr1nb', 'Gene', (310, 316))	('fragile X mental retardation syndrome 1', 'Gene', '14265', (213, 252))	('Ctag2', 'Gene', (70, 75))	('4933436I01Rik', 'Var', (197, 210))	('Fmr1nb', 'Gene', '207854', (310, 316))	('fragile X mental retardation 1 neighbor', 'Disease', (269, 308))	('SLIT and NTRK-like family, member 2', 'Gene', '245450', (122, 157))	('Ctag2', 'Gene', '70062', (70, 75))	('4930447F04Rik', 'Var', (106, 119))	('Aff2', 'Gene', '14266', (348, 352))	('AF4/FMR2 family member 2', 'Gene', (322, 346))	('mental retardation', 'Phenotype', 'HP:0001249', (223, 241))	('Fmr1', 'Gene', (262, 266))	('cancer', 'Disease', (45, 51))	('AF4/FMR2 family member 2', 'Gene', '14266;17355', (322, 346))	('Fmr1', 'Gene', '14265', (262, 266))	('Fmr1', 'Gene', (310, 314))	('mental retardation', 'Phenotype', 'HP:0001249', (279, 297))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Fmr1', 'Gene', '14265', (310, 314))	('fragile X mental retardation syndrome 1', 'Gene', (213, 252))	('fragile X mental retardation 1 neighbor', 'Disease', 'MESH:D005600', (269, 308))
61979	24516397	Of them, Aff2 is expressed pre-meiotically in spermatogonia, Fmr1 and Fmr1nb show expression in early prophase I, and Ctag2, 4930447F04Rik and Slitrk2 are expressed in meiotic and postmeiotic cells.	('4930447F04Rik', 'Var', (125, 138))	('Slitrk2', 'Gene', (143, 150))	('Fmr1', 'Gene', '14265', (70, 74))	('Fmr1', 'Gene', (61, 65))	('Aff2', 'Gene', '14266', (9, 13))	('Fmr1nb', 'Gene', '207854', (70, 76))	('Ctag2', 'Gene', '70062', (118, 123))	('Fmr1', 'Gene', '14265', (61, 65))	('Ctag2', 'Gene', (118, 123))	('Fmr1nb', 'Gene', (70, 76))	('Slitrk2', 'Gene', '245450', (143, 150))	('Aff2', 'Gene', (9, 13))	('Fmr1', 'Gene', (70, 74))
61983	24516397	Of the remaining genes, Aff2 carries five, Fmr1nb and Slitrk2 carry two, 4930447F04Rik and Ctag2 carry one, and Fmr1 does not carry any non-synonymous substitution.	('Slitrk2', 'Gene', (54, 61))	('Aff2', 'Gene', '14266', (24, 28))	('Fmr1', 'Gene', (43, 47))	('Fmr1nb', 'Gene', (43, 49))	('Fmr1', 'Gene', (112, 116))	('Aff2', 'Gene', (24, 28))	('Fmr1', 'Gene', '14265', (43, 47))	('Slitrk2', 'Gene', '245450', (54, 61))	('Fmr1', 'Gene', '14265', (112, 116))	('Ctag2', 'Gene', (91, 96))	('Ctag2', 'Gene', '70062', (91, 96))	('4930447F04Rik', 'Var', (73, 86))	('Fmr1nb', 'Gene', '207854', (43, 49))
61987	24516397	Three of the candidates for the Hstx1/2 locus, Ctag2, 4933436I01Rik and Fmr1nb, displayed an elevated rate of protein evolution (Table 1).	('Fmr1nb', 'Gene', (72, 78))	('Hstx1/2', 'Gene', '100036139', (32, 39))	('Hstx1/2', 'Gene', (32, 39))	('4933436I01Rik', 'Var', (54, 67))	('Fmr1nb', 'Gene', '207854', (72, 78))	('protein evolution', 'MPA', (110, 127))	('rat', 'Species', '10116', (102, 105))	('Ctag2', 'Gene', (47, 52))	('Ctag2', 'Gene', '70062', (47, 52))	('elevated', 'PosReg', (93, 101))
61989	24516397	The ability of Hstx2B6 to rescue the meiotic arrest of MmmxMmd F1 hybrids is subject to intrasubspecific Mmm polymorphisms.	('meiotic arrest', 'CPA', (37, 51))	('Mmd', 'Gene', (59, 62))	('polymorphisms', 'Var', (109, 122))	('Mmd', 'Gene', '67468', (59, 62))
61991	24516397	To map the STUS/PWD autosomal allelic variants that ensure full intrameiotic arrest in males carrying Mmm Chr XB6, we genotyped 84 test-cross males from crosses of B6 females with (PWDxSTUS)F1 or (STUSxPWD)F1 males.	('intrameiotic arrest', 'Disease', (64, 83))	('intrameiotic arrest', 'Disease', 'MESH:D006323', (64, 83))	('variants', 'Var', (38, 46))
62001	24516397	In contrast, (B6.PWD-Chr X.1xPWD) males carrying Hstx2B6 were semifertile, with partial meiotic arrest at late pachytene stage.	('Hstx2B6', 'Var', (49, 56))	('semifertile', 'Disease', (62, 73))	('pachytene', 'Chemical', '-', (111, 120))	('semifertile', 'Disease', 'None', (62, 73))
62002	24516397	Only 34% of pachynemas showed asynapsis of one or two pairs of autosomes (Fig.	('pachynemas', 'Disease', (12, 22))	('asynapsis', 'Var', (30, 39))	('pachynemas', 'Disease', 'None', (12, 22))
62013	24516397	Moreover 46.5% and 44% of oocytes of (B6.PWD-Chr X.1xPWD)F1 and (B6.PWD-Chr X.1sxPWD)F1 hybrids showed asynaptic autosomes (Fig.	('B6.PWD-Chr', 'Var', (65, 75))	('hybrids', 'Var', (88, 95))	('PWD-Chr X.1xPWD)F1', 'Disease', 'MESH:D005171', (41, 59))	('asynaptic autosomes', 'CPA', (103, 122))
62018	24516397	The finding indicated a cis-type of asynapsis control based on some kind of mismatch between orthologous chromosomes of Mmm and Mmd origin.	('mismatch', 'Var', (76, 84))	('Mmd', 'Gene', '67468', (128, 131))	('Mmd', 'Gene', (128, 131))
62024	24516397	Nevertheless, the partial PWD homozygosity was sufficient to reduce Chr X asynapsis from 64% down to 5.6% of pachytene oocytes (Table 2).	('partial PWD homozygosity', 'Var', (18, 42))	('reduce', 'NegReg', (61, 67))	('Chr X asynapsis', 'CPA', (68, 83))	('pachytene', 'Chemical', '-', (109, 118))
62026	24516397	To explain Haldane's rule of hybrid sterility, the dominance theory posits the recessive nature of X-linked variants that disrupt gametogenesis in hemizygous (XY) but not in homozygous (XX) sex.	('Haldane', 'Chemical', '-', (11, 18))	('variants', 'Var', (108, 116))	('gametogenesis', 'CPA', (130, 143))	('disrupt', 'NegReg', (122, 129))
62035	24516397	Using the position on Chr X, spermatogenic expression, and dN:dS ratio Good and coworkers predicted nine candidate genes for X-linked hybrid sterility, three of which (Ctag2, 4933436I01Rik and Fmr1nb) also occur in the present list of Hstx1/2 candidates.	('Ctag2', 'Gene', (168, 173))	('Ctag2', 'Gene', '70062', (168, 173))	('Fmr1nb', 'Gene', (193, 199))	('dN', 'Chemical', '-', (59, 61))	('Hstx1/2', 'Gene', '100036139', (235, 242))	('Hstx1/2', 'Gene', (235, 242))	('dS', 'Chemical', 'MESH:D003903', (62, 64))	('4933436I01Rik', 'Var', (175, 188))	('Fmr1nb', 'Gene', '207854', (193, 199))	('rat', 'Species', '10116', (65, 68))
62038	24516397	Among the candidate genes in the region, Fmr1nb and 4933436I01Rik are expressed in the appropriate cell type during germ cell differentiation and display two and seven non-synonymous substitutions, respectively.	('Fmr1nb', 'Gene', (41, 47))	('4933436I01Rik', 'Var', (52, 65))	('Fmr1nb', 'Gene', '207854', (41, 47))
62043	24516397	The Hstx1/Hstx2 critical region is flanked by amplicons 4930527E24Rik and Xlr (amplicons 7 and 9 in).	('Hstx1', 'Gene', (4, 9))	('4930527E24Rik', 'Var', (56, 69))	('Hstx1', 'Gene', '100036139', (4, 9))
62060	24516397	Null mutations of Sycp1, Hormad1 or Mei4, the candidate genes regulating the Hstx2-controlled asymmetry of HS, also cause asynapsis.	('asynapsis', 'Disease', (122, 131))	('Hormad1', 'Gene', '67981', (25, 32))	('cause', 'Reg', (116, 121))	('Sycp1', 'Gene', (18, 23))	('Hormad1', 'Gene', (25, 32))	('Mei4', 'Gene', (36, 40))	('Null mutations', 'Var', (0, 14))	('Sycp1', 'Gene', '20957', (18, 23))	('Mei4', 'Gene', '75033', (36, 40))
62073	24516397	Full sterility and complete meiotic block is associated with the Prdm9PWD/B6 Hstx2PWD genotype only, while the substitution of Hstx2PWD for Hstx2B6 on otherwise F1 hybrid background reduces the incidence of cells with asynapsis to the level found in female meiosis.	('Prdm9', 'Gene', (65, 70))	('reduces', 'NegReg', (182, 189))	('Full sterility', 'CPA', (0, 14))	('Prdm9', 'Gene', '213389', (65, 70))	('cells with asynapsis', 'CPA', (207, 227))	('meiotic block', 'Disease', (28, 41))	('substitution', 'Var', (111, 123))	('meiotic block', 'Disease', 'MESH:D006327', (28, 41))
62118	22272939	CIS has previously been shown to induce lipid peroxidation (LP) with a concomitant decrease in the level of testicular anti-oxidants.	('lipid', 'Chemical', 'MESH:D008055', (40, 45))	('lipid peroxidation', 'MPA', (40, 58))	('level of testicular anti-oxidants', 'MPA', (99, 132))	('decrease', 'NegReg', (83, 91))	('CIS', 'Var', (0, 3))
62158	22272939	The weights of testes and epididymes, expressed relative to the body weight, in rats after CIS administration were found to be significantly decreased, compared with the control group (Table 1).	('rat', 'Species', '10116', (103, 106))	('CIS administration', 'Var', (91, 109))	('rat', 'Species', '10116', (80, 83))	('decreased', 'NegReg', (141, 150))	('rats', 'Species', '10116', (80, 84))
62172	22272939	The result of NNC on TA parameters has particularly interesting interpretation as it showed aggregation of GB treated samples with N cluster (cluster 2*) except for CIS + L which mainly aggregated with the CIS group in cluster 1* (Table 3).	('aggregation', 'MPA', (92, 103))	('GB', 'Species', '3311', (107, 109))	('N cluster', 'Var', (131, 140))
62180	22272939	While CIS is one of the leading anticancer drugs in the chemotherapy treatment of variety of cancer types, it induces a testicular damage, sperm dysfunction, germ cell apoptosis and abnormalities in Lyedig cells in rats.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('testicular damage', 'Disease', (120, 137))	('abnormalities in Lyedig cells', 'CPA', (182, 211))	('testicular damage', 'Disease', 'MESH:D013733', (120, 137))	('germ cell apoptosis', 'CPA', (158, 177))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('CIS', 'Var', (6, 9))	('sperm dysfunction', 'Disease', 'MESH:D009845', (139, 156))	('induces', 'Reg', (110, 117))	('sperm dysfunction', 'Disease', (139, 156))	('rats', 'Species', '10116', (215, 219))
62196	20823885	CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure.	('acetylation', 'MPA', (128, 139))	('H3K4 methylation', 'Var', (141, 157))	('H3K9me2', 'Var', (82, 89))	('H2A.Z', 'Var', (162, 167))	('H3K9', 'Protein', (123, 127))	('K27', 'Gene', '342574', (96, 99))	('K27', 'Gene', (96, 99))	('CIS', 'Phenotype', 'HP:0030075', (0, 3))
62197	20823885	Epigenetic patterns similar to that of CIS cells were observed in human gonocytes present within sex cords in foetal testes but correspond to migrating primordial germ cell in mice.	('CIS', 'Phenotype', 'HP:0030075', (39, 42))	('human', 'Species', '9606', (66, 71))	('migrating', 'CPA', (142, 151))	('Epigenetic patterns', 'Var', (0, 19))	('mice', 'Species', '10090', (176, 180))
62198	20823885	Development of overt tumours involves epigenetic repression of the chromatin.	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('overt tumours', 'Disease', (15, 28))	('epigenetic repression', 'Var', (38, 59))	('chromatin', 'Protein', (67, 76))	('overt tumours', 'Disease', 'MESH:D009369', (15, 28))	('men', 'Species', '9606', (7, 10))
62210	20823885	Both histone marks are repressive and in the transition between erasure of H3K9me2 and establishment of H3K27me3 PGCs most probably display a transient period with possible hyper-transcription.	('H3K9me2', 'Var', (75, 82))	('K27', 'Gene', '342574', (106, 109))	('K27', 'Gene', (106, 109))	('men', 'Species', '9606', (96, 99))
62213	20823885	Immunohistochemical investigations have shown that CIS cells have arginine 3 of histone H2A and H4 dimethylated (H4/H2A R3me2), which are thought to repress - among others - the HOX genes, involved in somatic differentiation programs.	('CIS', 'Phenotype', 'HP:0030075', (51, 54))	('histone H2A', 'Protein', (80, 91))	('arginine 3', 'Var', (66, 76))	('arginine', 'Chemical', 'MESH:D001120', (66, 74))
62230	20823885	Immunohistochemical staining for the repressive chromatin modifications H3K9me2 and H3K27me3 revealed low levels of these modifications in CIS cells, whereas Sertoli cells in CIS-containing tubules showed high levels of both modifications (Figure 1C and D).	('CIS', 'Phenotype', 'HP:0030075', (139, 142))	('Sertoli cells', 'Phenotype', 'HP:0100619', (158, 171))	('H3K9me2', 'Var', (72, 79))	('CIS', 'Phenotype', 'HP:0030075', (175, 178))	('K27', 'Gene', '342574', (86, 89))	('K27', 'Gene', (86, 89))
62239	20823885	However, H3K4me2/3 was observed in a broad range of germ cells including elongating spermatids and in Sertoli cells (Supplementary Figure S1).	('men', 'Species', '9606', (123, 126))	('observed', 'Reg', (23, 31))	('Sertoli cells', 'Phenotype', 'HP:0100619', (102, 115))	('H3K4me2/3', 'Var', (9, 18))
62257	20823885	In this study, we performed a detailed analysis of epigenetic status of germ cell neoplasia and show that the precursor for the majority of germ cell cancers - carcinoma in situ - possesses low levels of repressive chromatin modifications (H3K9me2 and H3K27me3) concurrently with low DNA methylation and a range of activating chromatin modifications (H3K4me, H3K9ac, and H2A.	('low', 'NegReg', (280, 283))	('germ cell cancer', 'Phenotype', 'HP:0100728', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('neoplasia', 'Phenotype', 'HP:0002664', (82, 91))	('cancers - carcinoma', 'Disease', (150, 169))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('H2A', 'Var', (371, 374))	('carcinoma in situ', 'Disease', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('H3K4me', 'Var', (351, 357))	('DNA methylation', 'MPA', (284, 299))	('activating', 'PosReg', (315, 325))	('H3K9ac', 'Chemical', '-', (359, 365))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (160, 177))	('H3K9me2', 'Var', (240, 247))	('K27', 'Gene', '342574', (254, 257))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (72, 91))	('H3K9ac', 'Var', (359, 365))	('neoplasia', 'Disease', 'MESH:D009369', (82, 91))	('carcinoma in situ', 'Disease', 'MESH:D002278', (160, 177))	('neoplasia', 'Disease', (82, 91))	('repressive chromatin modifications', 'MPA', (204, 238))	('K27', 'Gene', (254, 257))	('cancers - carcinoma', 'Disease', 'MESH:D009369', (150, 169))
62258	20823885	Methylation of histone H3 at Lys4 is, however, known to be tightly associated with methylation of DNA.	('methylation', 'MPA', (83, 94))	('Methylation', 'MPA', (0, 11))	('associated', 'Reg', (67, 77))	('histone H3', 'Protein', (15, 25))	('Lys4', 'Var', (29, 33))	('Lys4', 'Chemical', '-', (29, 33))
62260	20823885	Such CpG regions are consequently methylated at Lys4 of histone H3, whereas the rest of the genome contains unmethylated H3K4.	('methylated', 'Var', (34, 44))	('histone H3', 'Protein', (56, 66))	('Lys4', 'Chemical', '-', (48, 52))
62263	20823885	In addition, as the PGC colonise the gonad in mice, a range of other epigenetic events occurs, which includes erasure of both H2A.Z and H3K9ac.	('H3K9ac', 'Var', (136, 142))	('erasure', 'NegReg', (110, 117))	('mice', 'Species', '10090', (46, 50))	('H3K9ac', 'Chemical', '-', (136, 142))	('H2A.Z', 'Protein', (126, 131))
62268	20823885	High levels of H4/H2A R3me2s have also been reported in human GW 19 gonocytes, matching the epigenetic profile of migrating PGCs in mice.	('human', 'Species', '9606', (56, 61))	('mice', 'Species', '10090', (132, 136))	('R3me2s', 'Var', (22, 28))	('H4/H2A', 'Protein', (15, 21))
62276	20823885	Seminomas show high levels of selected repressive modifications, exemplified by H3K9me2 and H3K27me3.	('H3K9me2', 'Var', (80, 87))	('Seminomas', 'Disease', (0, 9))	('K27', 'Gene', '342574', (94, 97))	('Seminomas', 'Disease', 'MESH:D018239', (0, 9))	('K27', 'Gene', (94, 97))
62425	19715611	Interestingly, in patients with bilateral disease and a family history of TGCT only 28% of tumours showed KIT mutations, suggesting that bilateral disease in the context of familial TGCT has a different pathogenesis from sporadic bilateral cases.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('bilateral disease', 'Disease', 'MESH:D006312', (32, 49))	('mutations', 'Var', (110, 119))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('bilateral disease', 'Disease', 'MESH:D006312', (137, 154))	('bilateral disease', 'Disease', (32, 49))	('tumours', 'Disease', (91, 98))	('bilateral disease', 'Disease', (137, 154))	('patients', 'Species', '9606', (18, 26))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
62431	19715611	Although most of the AZF deletions observed in infertile men are new (de novo) mutations, they have been inherited in some cases from (apparently fertile) fathers, and 0.4% of fertile men in the general population appear to carry an AZF deletion.	('AZF', 'Gene', (21, 24))	('deletions', 'Var', (25, 34))	('men', 'Species', '9606', (184, 187))	('infertile', 'Disease', 'MESH:D007247', (47, 56))	('men', 'Species', '9606', (57, 60))	('infertile', 'Disease', (47, 56))
62432	19715611	recently observed a particularly high percentage of 27.5% AZF (a-c) deletions in patients with low sperm counts as well as unilateral cryptorchism.	('deletions', 'Var', (68, 77))	('patients', 'Species', '9606', (81, 89))	('AZF (a-c', 'Gene', (58, 66))	('unilateral cryptorchism', 'Phenotype', 'HP:0012741', (123, 146))	('low sperm counts', 'Phenotype', 'HP:0000798', (95, 111))	('cryptorchism', 'Phenotype', 'HP:0000028', (134, 146))
62433	19715611	Taken together, these observations suggests that, at least from a theoretical point of view, constitutional AZF deletions might be one of the genetic contributors to the development of TDS and thereby of TGCT and other TDS manifestations.	('deletions', 'Var', (112, 121))	('TDS', 'Disease', (185, 188))	('men', 'Species', '9606', (177, 180))	('AZF', 'Gene', (108, 111))	('TGCT', 'Disease', (204, 208))
62435	19715611	However, more recently a novel Y-chromosome 1.6-MB deletion was reported, referred to as gr/gr, and is associated with spermatogenic failure.	('associated with', 'Reg', (103, 118))	('deletion', 'Var', (51, 59))	('spermatogenic failure', 'Disease', 'OMIM:108420', (119, 140))	('spermatogenic failure', 'Disease', (119, 140))
62437	19715611	Familial TGCT patients had a threefold increased risk of having these gr/gr deletions.	('deletions', 'Var', (76, 85))	('Familial TGCT', 'Disease', (0, 13))	('patients', 'Species', '9606', (14, 22))	('gr/gr', 'Gene', (70, 75))
62463	19715611	This suggests that in our Dutch population one or more low frequent mutations of an Xq27-linked gene contribute to TGCT development but not to cryptorchism.	('contribute', 'Reg', (101, 111))	('cryptorchism', 'Phenotype', 'HP:0000028', (143, 155))	('Xq27-linked', 'Gene', (84, 95))	('mutations', 'Var', (68, 77))	('TGCT', 'Disease', (115, 119))	('men', 'Species', '9606', (127, 130))
62479	19715611	A germ line mutation in the dead end gene (DND1) was found to cause this high tumour risk (and some testicular and spermatogenic abnormalities).	('DND1', 'Gene', '373863', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('cause', 'Reg', (62, 67))	('spermatogenic abnormalities', 'Phenotype', 'HP:0008669', (115, 142))	('mutation', 'Var', (12, 20))	('DND1', 'Gene', (43, 47))	('spermatogenic abnormalities', 'Disease', (115, 142))	('spermatogenic abnormalities', 'Disease', 'OMIM:108420', (115, 142))
62487	19715611	Should future studies identify clinically important TGCT-predisposing mutations, then testing for these mutations might be welcomed by a substantial subset of TGCT patients and families, as has been the case for many families with common hereditary tumour syndromes.	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('mutations', 'Var', (70, 79))	('TGCT-predisposing', 'Gene', (52, 69))	('hereditary tumour syndromes', 'Disease', 'MESH:D009386', (238, 265))	('hereditary tumour syndromes', 'Disease', (238, 265))	('patients', 'Species', '9606', (164, 172))
62532	33091877	Interestingly, lncRNA NONHSAT061240 (lnc-ZNF136) was highly enriched in two regulatory modes, the details for which were obtained using the UCSC and LNCipedia databases, including the sequence information, length, exon number, and position, among others (Supplementary Table 3).	('ZNF136', 'Gene', '7695', (41, 47))	('lncRNA', 'Var', (15, 21))	('ZNF136', 'Gene', (41, 47))
62554	33091877	Homozygous or compound heterozygous mutations, the majority of which are loss-of-function mutations, have been identified in patients with epidermolysis bullosa simplex with muscular dystrophy.	('muscular dystrophy', 'Phenotype', 'HP:0003560', (174, 192))	('muscular dystrophy', 'Disease', (174, 192))	('muscular dystrophy', 'Disease', 'MESH:D009136', (174, 192))	('epidermolysis bullosa simplex', 'Disease', (139, 168))	('loss-of-function', 'NegReg', (73, 89))	('compound heterozygous mutations', 'Var', (14, 45))	('Homozygous', 'Var', (0, 10))	('epidermolysis bullosa simplex', 'Disease', 'MESH:D016110', (139, 168))	('patients', 'Species', '9606', (125, 133))
62585	26303142	Whereas transient expression of RARalpha and RXRalpha enhanced 9-cis RA-treated StAR gene transcription, silencing of RXRalpha with siRNA, decreased StAR and steroid levels.	('steroid', 'Chemical', 'MESH:D013256', (158, 165))	('RA', 'Chemical', 'MESH:D014212', (69, 71))	('decreased', 'NegReg', (139, 148))	('transcription', 'MPA', (90, 103))	('RA', 'Chemical', 'MESH:D014212', (32, 34))	('silencing', 'Var', (105, 114))	('enhanced', 'PosReg', (54, 62))	('decreased StAR and steroid levels', 'Phenotype', 'HP:0008163', (139, 172))	('RXRalpha', 'Gene', (118, 126))
62590	26303142	The biological actions of retinoids are principally mediated by the activities of two families of nuclear receptors, the RARs and RXRs, each of which has three subtypes (alpha, beta and gamma) with additional isoforms resulting from alternative splicing.	('retinoids', 'Chemical', 'MESH:D012176', (26, 35))	('alternative splicing', 'Var', (233, 253))	('RXR', 'Gene', '6256', (130, 133))	('mediated', 'Reg', (52, 60))	('RXR', 'Gene', (130, 133))
62599	26303142	Noteworthy, phosphorylation of StAR, especially at Ser194, has been demonstrated to be an indispensable event to obtain the maximal cholesterol transferring activity of StAR for steroid biosynthesis.	('cholesterol transferring activity', 'MPA', (132, 165))	('steroid', 'Chemical', 'MESH:D013256', (178, 185))	('maximal', 'MPA', (124, 131))	('Ser194', 'Chemical', '-', (51, 57))	('Ser194', 'Var', (51, 57))	('cholesterol', 'Chemical', 'MESH:D002784', (132, 143))
62612	26303142	The -254/-1 bp StAR segment was used for generating mutations in the LXR-RXR/RAR heterodimeric motif 5'-TGACCCCTGCTTTCCC-3' (-200/-185 bp region in the mouse StAR promoter, Wt-LXR-RXR/RAR) using the Quikchange site directed mutagenesis kit (Stratagene, La Jolla, CA).	('mutations', 'Var', (52, 61))	('LXR', 'Gene', (69, 72))	('LXR', 'Gene', (176, 179))	('RXR', 'Gene', (73, 76))	('mouse', 'Species', '10090', (152, 157))	('RXR', 'Gene', (180, 183))	('LXR', 'Gene', '22259', (69, 72))	('men', 'Species', '9606', (23, 26))	('LXR', 'Gene', '22259', (176, 179))	('RXR', 'Gene', '6256', (73, 76))	('RXR', 'Gene', '6256', (180, 183))
62613	26303142	The sense strand of the oligonucleotide sequence used in mutating the LXR-RXR/RAR site was 5'-CCGTGAattCTGCTTgatCTATATG-3' (Mut-LXR-RXR/RAR; mutated bases in lowercase boldface letters) and the mutation was verified by EcoRI and Sau3A1.	('LXR', 'Gene', (128, 131))	('RXR', 'Gene', '6256', (74, 77))	('LXR', 'Gene', (70, 73))	('oligonucleotide', 'Chemical', 'MESH:D009841', (24, 39))	('RXR', 'Gene', (132, 135))	('mutated bases', 'Var', (141, 154))	('bases', 'Var', (149, 154))	('RXR', 'Gene', (74, 77))	('LXR', 'Gene', '22259', (128, 131))	('LXR', 'Gene', '22259', (70, 73))	('RXR', 'Gene', '6256', (132, 135))
62637	26303142	Briefly, following treatments, H295R and HaCaT cells were incubated with 1% formaldehyde for 10 min at 37  C to crosslink DNA and its associated proteins.	('crosslink', 'Var', (112, 121))	('men', 'Species', '9606', (24, 27))	('DNA', 'Gene', (122, 125))	('proteins', 'Protein', (145, 153))	('formaldehyde', 'Chemical', 'MESH:D005557', (76, 88))	('HaCaT', 'CellLine', 'CVCL:0038', (41, 46))
62655	26303142	2, KK-1 (A), H295R (B), A172 (C), and HaCaT (D) cells transfected with either pCMX-RARalpha (RARalpha) or pCMX-RXRalpha (RXRalpha) expression plasmid, within the context of the -254/-1 bp StAR-Luc containing wild type LXR-RXR/RAR (Wt-LXR-RXR/RAR), resulted in 2-3 fold increases in StAR promoter activity in response to 10 muM 9-cis RA, over the responses seen in mock-transfected (pCMX) cells.	('LXR', 'Gene', '22259', (218, 221))	('H295R', 'Var', (13, 18))	('RXR', 'Gene', '6256', (111, 114))	('RXR', 'Gene', (121, 124))	('RXR', 'Gene', (238, 241))	('RXR', 'Gene', '6256', (222, 225))	('RA', 'Chemical', 'MESH:D014212', (93, 95))	('RA', 'Chemical', 'MESH:D014212', (242, 244))	('StAR promoter activity', 'MPA', (282, 304))	('RA', 'Chemical', 'MESH:D014212', (226, 228))	('A172', 'Var', (24, 28))	('RA', 'Chemical', 'MESH:D014212', (83, 85))	('RXR', 'Gene', (111, 114))	('HaCaT', 'CellLine', 'CVCL:0038', (38, 43))	('RXR', 'Gene', (222, 225))	('LXR', 'Gene', (234, 237))	('KK-1', 'Var', (3, 7))	('muM', 'Gene', '56925', (323, 326))	('RXR', 'Gene', '6256', (121, 124))	('LXR', 'Gene', '22259', (234, 237))	('increases', 'PosReg', (269, 278))	('LXR', 'Gene', (218, 221))	('muM', 'Gene', (323, 326))	('RXR', 'Gene', '6256', (238, 241))	('RA', 'Chemical', 'MESH:D014212', (333, 335))
62656	26303142	Conversely, cells transfected with the -254/-1 bp StAR-Luc containing mutations in the LXR-RXR/RAR motif (Mut-LXR-RXR/RAR) decreased basal luciferase responses by 40-66% and coordinately repressed 9-cis RA-induced StAR reporter activity, demonstrating the importance of this putative element in retinoid mediated StAR gene transcription.	('mutations', 'Var', (70, 79))	('LXR', 'Gene', (87, 90))	('9-cis RA-induced StAR reporter activity', 'MPA', (197, 236))	('LXR', 'Gene', (110, 113))	('decreased', 'NegReg', (123, 132))	('RXR', 'Gene', '6256', (91, 94))	('RA', 'Chemical', 'MESH:D014212', (203, 205))	('repressed', 'NegReg', (187, 196))	('RXR', 'Gene', (114, 117))	('RA', 'Chemical', 'MESH:D014212', (118, 120))	('men', 'Species', '9606', (287, 290))	('LXR', 'Gene', '22259', (87, 90))	('LXR', 'Gene', '22259', (110, 113))	('RXR', 'Gene', (91, 94))	('retinoid', 'Chemical', 'MESH:D012176', (295, 303))	('RXR', 'Gene', '6256', (114, 117))	('RA', 'Chemical', 'MESH:D014212', (95, 97))	('basal', 'MPA', (133, 138))
62659	26303142	Depletion of RXRalpha attenuated basal and 9-cis RA-induced StAR and steroid levels between 43 and 68%.	('steroid', 'Chemical', 'MESH:D013256', (69, 76))	('RA', 'Chemical', 'MESH:D014212', (49, 51))	('Depletion', 'Var', (0, 9))	('attenuated', 'NegReg', (22, 32))
62662	26303142	4A show that a 32P-labeled oligonucleotide probe corresponding to the LXR-RXR/RAR region (a DR4-like sequence) in the mouse StAR promoter resulted in a major protein:DNA complex with H295R NE (lanes 1-7).	('protein', 'Protein', (158, 165))	('RXR', 'Gene', '6256', (74, 77))	('oligonucleotide', 'Chemical', 'MESH:D009841', (27, 42))	('LXR', 'Gene', (70, 73))	('32P', 'Chemical', 'MESH:C000615311', (15, 18))	('H295R NE', 'Var', (183, 191))	('mouse', 'Species', '10090', (118, 123))	('RXR', 'Gene', (74, 77))	('LXR', 'Gene', '22259', (70, 73))
62667	26303142	The LXR-RXR/RAR element was previously found to bind in vitro transcribed/translated RARalpha and RXRalpha proteins in EMSAs, as well as MA-10 NE, and protein:DNA binding was affected by its unlabeled and mutant sequences.	('RXR', 'Gene', '6256', (8, 11))	('bind', 'Interaction', (48, 52))	('RARalpha', 'Protein', (85, 93))	('RXR', 'Gene', (8, 11))	('RXR', 'Gene', '6256', (98, 101))	('binding', 'Interaction', (163, 170))	('LXR', 'Gene', '22259', (4, 7))	('mutant', 'Var', (205, 211))	('men', 'Species', '9606', (19, 22))	('RXR', 'Gene', (98, 101))	('LXR', 'Gene', (4, 7))
62673	26303142	Aberrant skin cholesterol synthesis, resulting in a global reduction in steroids, is associated with many skin disorders; thus, it was of interest to study cutaneous steroidogenesis.	('skin disorders', 'Disease', (106, 120))	('Aberrant', 'Var', (0, 8))	('skin disorders', 'Disease', 'MESH:D012871', (106, 120))	('Aberrant skin', 'Phenotype', 'HP:0011121', (0, 13))	('steroid', 'Chemical', 'MESH:D013256', (72, 79))	('skin disorders', 'Phenotype', 'HP:0000951', (106, 120))	('steroids', 'Chemical', 'MESH:D013256', (72, 80))	('steroids', 'MPA', (72, 80))	('reduction', 'NegReg', (59, 68))	('steroid', 'Chemical', 'MESH:D013256', (166, 173))	('cholesterol', 'Chemical', 'MESH:D002784', (14, 25))	('skin cholesterol synthesis', 'MPA', (9, 35))
62691	26303142	The magnitude of induction on the steroidogenic response mediated by retinoids and (Bu)2cAMP is similar to that achieved with a maximally stimulating dose of (Bu)2cAMP (1.0 mM).	('steroidogenic response', 'MPA', (34, 56))	('steroid', 'Chemical', 'MESH:D013256', (34, 41))	('retinoids', 'Chemical', 'MESH:D012176', (69, 78))	('(Bu)2cAMP', 'Chemical', '-', (158, 167))	('Bu)2cAMP', 'Var', (84, 92))	('(Bu)2cAMP', 'Chemical', '-', (83, 92))
62701	26303142	In contrast, substantial knockdown of endogenous RXRalpha protein resulted in ~50% decreases in StAR expression and steroid biosynthesis, suggesting other isoforms may play permissive roles in steroidogenesis.	('steroid', 'Chemical', 'MESH:D013256', (116, 123))	('decreases', 'NegReg', (83, 92))	('RXRalpha protein', 'Protein', (49, 65))	('StAR expression', 'MPA', (96, 111))	('endogenous', 'Var', (38, 48))	('steroid biosynthesis', 'MPA', (116, 136))	('steroid', 'Chemical', 'MESH:D013256', (193, 200))	('knockdown', 'Var', (25, 34))
62702	26303142	These results are reminiscent of previous findings that demonstrated that disruption of RARalpha, RARgamma, RXRalpha, and RXRbeta isoforms exhibits abnormalities in gonadal and adrenal steroidogenic functions.	('steroid', 'Chemical', 'MESH:D013256', (185, 192))	('disruption', 'Var', (74, 84))	('gonadal and', 'CPA', (165, 176))
62705	26303142	In the present study, the functional relevance of the LXR-RXR/RAR element was assessed by different approaches demonstrating that alteration/inhibition of RARalpha and RXRalpha markedly affected the steroidogenic response.	('LXR', 'Gene', '22259', (54, 57))	('men', 'Species', '9606', (69, 72))	('RARalpha', 'Gene', (155, 163))	('steroid', 'Chemical', 'MESH:D013256', (199, 206))	('alteration/inhibition', 'NegReg', (130, 151))	('steroidogenic response', 'MPA', (199, 221))	('RXR', 'Gene', '6256', (168, 171))	('LXR', 'Gene', (54, 57))	('RXR', 'Gene', '6256', (58, 61))	('RXR', 'Gene', (168, 171))	('affected', 'Reg', (186, 194))	('RXR', 'Gene', (58, 61))	('alteration/inhibition', 'Var', (130, 151))
62728	25814157	Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development (previously termed as an intersex condition) with dysgenic gonads.	('translocation', 'Var', (13, 26))	('dysgenic', 'Disease', (169, 177))	('SRY', 'Gene', '6736', (56, 59))	('men', 'Species', '9606', (114, 117))	('dysgenic gonads', 'Phenotype', 'HP:0000133', (169, 184))	('SRY', 'Gene', (56, 59))	('disorders of sex development', 'Disease', (90, 118))	('causes', 'Reg', (83, 89))	('dysgenic', 'Disease', 'None', (169, 177))	('Deletions', 'Var', (0, 9))
62730	25814157	Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('somatic cancers', 'Disease', (180, 195))	('rat', 'Species', '10116', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('Y chromosome genes', 'Gene', (85, 103))	('associated', 'Reg', (115, 125))	('loss', 'NegReg', (39, 43))	('ectopic', 'Var', (63, 70))	('somatic cancers', 'Disease', 'MESH:D009369', (180, 195))	('male-biased diseases', 'Disease', (139, 159))
62736	25814157	Men are prone to X-linked diseases caused by mutations on genes on their X chromosome while ectopic expression of the genes on their Y chromosome could have male-specific effects on normal development, physiology, and diseases.	('men', 'Species', '9606', (196, 199))	('X-linked diseases', 'Disease', 'MESH:D040181', (17, 34))	('mutations', 'Var', (45, 54))	('caused', 'Reg', (35, 41))	('X-linked diseases', 'Disease', (17, 34))	('prone', 'Reg', (8, 13))	('Men', 'Species', '9606', (0, 3))
62777	25814157	Abrogated TSPX expression in lung cancer is associated with accelerated cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Abrogated', 'Var', (0, 9))	('TSPX', 'Gene', '64061', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('expression', 'MPA', (15, 25))	('cancer', 'Disease', (34, 40))	('TSPX', 'Gene', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('rat', 'Species', '10116', (66, 69))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('cancer', 'Disease', (72, 78))
62834	25814157	Over-expression of RBMY caused tumorigenicity in mouse fibroblast 3T3 cells, and knock-down of RBMY in a liver cancer cell line HepG2 resulted in the reduction of transformation and anti-apoptotic efficiencies.	('anti-apoptotic efficiencies', 'CPA', (182, 209))	('knock-down', 'Var', (81, 91))	('3T3', 'CellLine', 'CVCL:0594', (66, 69))	('Over-expression', 'PosReg', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('RBMY', 'Gene', (19, 23))	('HepG2', 'CellLine', 'CVCL:0027', (128, 133))	('transformation', 'CPA', (163, 177))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RBMY', 'Gene', (95, 99))	('mouse', 'Species', '10090', (49, 54))	('liver cancer', 'Phenotype', 'HP:0002896', (105, 117))	('reduction', 'NegReg', (150, 159))	('liver cancer', 'Disease', 'MESH:D006528', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('liver cancer', 'Disease', (105, 117))
62836	25814157	While the mechanism is still unclear, these observations suggest that the ectopic expression of RBMY genes could contribute to HCC development.	('men', 'Species', '9606', (138, 141))	('contribute', 'Reg', (113, 123))	('RBMY genes', 'Gene', (96, 106))	('ectopic expression', 'Var', (74, 92))	('HCC', 'Disease', (127, 130))	('HCC', 'Phenotype', 'HP:0001402', (127, 130))
62837	25814157	On the contrary, multiple copies of BPY2, DAZ, and CDY1 genes are also mapped onto the microdeletion of AZFc region, and deletions of these AZF genes are associated with increased risks of seminoma.	('BPY2', 'Gene', '9083', (36, 40))	('BPY2', 'Gene', (36, 40))	('seminoma', 'Disease', 'MESH:D018239', (189, 197))	('AZF', 'Gene', (140, 143))	('DAZ', 'Gene', (42, 45))	('AZF', 'Gene', (104, 107))	('CDY1', 'Gene', (51, 55))	('AZF', 'Gene', '560', (140, 143))	('CDY1', 'Gene', '9085', (51, 55))	('seminoma', 'Disease', (189, 197))	('deletions', 'Var', (121, 130))	('AZF', 'Gene', '560', (104, 107))	('associated', 'Reg', (154, 164))	('DAZ', 'Gene', '1617', (42, 45))
62844	25814157	Recently, an epidemiologic study reported that loss of Y chromosome (LOY) in peripheral blood cells significantly associated with shorter cancer survival and higher risk of cancer incidence in men.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (173, 179))	('men', 'Species', '9606', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('loss', 'Var', (47, 51))	('shorter', 'NegReg', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
62846	25814157	found that LOY in peripheral blood associated with increased risk of both all-caused mortality and cancer mortality, particularly in nonhematological cancers.	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('LOY', 'Var', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
62849	25814157	Ectopic expression of one or a few of these Y chromosome genes, such as TSPY and RBMY, could exacerbate oncogenesis in the absence of proper counter-balance from the other MSY genes (Figure 4).	('TSPY', 'Gene', '7258', (72, 76))	('TSPY', 'Gene', (72, 76))	('Ectopic expression', 'Var', (0, 18))	('RBMY', 'Gene', (81, 85))	('exacerbate', 'PosReg', (93, 103))	('oncogenesis', 'CPA', (104, 115))
62863	21994786	In the case of Epstein-Barr virus (EBV), the switch between early and late viral genes is achieved mainly through the genetic and epigenetic regulation of alternative viral promoters.	('Epstein-Barr virus', 'Disease', (15, 33))	('epigenetic regulation', 'Var', (130, 151))	('EBV', 'Species', '10376', (35, 38))
62886	21994786	Mutation of these AU-rich sequences results in Rev-independent gag expression.	('gag', 'Gene', (63, 66))	('AU', 'Disease', 'MESH:C566303', (18, 20))	('Mutation', 'Var', (0, 8))	('results in', 'Reg', (36, 46))	('Rev', 'Gene', '155908', (47, 50))	('Rev', 'Gene', (47, 50))	('gag', 'Gene', '1491934', (63, 66))
62896	21994786	Nef enhances the clathrin-mediated endocytosis and degradation of CD4, the primary receptor for HIV entry.	('degradation', 'MPA', (51, 62))	('CD4', 'Gene', (66, 69))	('clathrin-mediated endocytosis', 'MPA', (17, 46))	('Nef', 'Var', (0, 3))	('CD4', 'Gene', '920', (66, 69))	('enhances', 'PosReg', (4, 12))
62912	21994786	As in HIV, expression of the highly condensed genetic information of HTLV-1 is achieved through ribosomal frameshifting (which generates a Gag-Pro-Pol polyprotein from the full-length transcript), polycistronic translation (which directs production of Tax and Rex from the same mRNA) and alternative splicing.	('Rex', 'Gene', (260, 263))	('pol', 'Gene', (151, 154))	('alternative splicing', 'Var', (288, 308))	('Pol', 'Gene', '100616496', (147, 150))	('pol', 'Gene', '100616496', (197, 200))	('HTLV-1', 'Gene', (69, 75))	('Pol', 'Gene', (147, 150))	('ribosomal frameshifting', 'Var', (96, 119))	('HTLV-1', 'Species', '11908', (69, 75))	('pol', 'Gene', '100616496', (151, 154))	('Rex', 'Gene', '1491937', (260, 263))	('pol', 'Gene', (197, 200))
62968	21994786	This process is mediated through binding of the cellular protein HuR to an as yet-unidentified element on FV RNA, with the presence of HuR on the RNA allowing engagement of the CRM1 pathway through recruitment of the HuR-CRM1 bridging proteins ANP32A and ANP32B.	('CRM1', 'Gene', (177, 181))	('ANP32A', 'Gene', '8125', (244, 250))	('CRM1', 'Gene', (221, 225))	('HuR', 'Gene', (65, 68))	('HuR', 'Gene', (217, 220))	('gag', 'Gene', '1491934', (161, 164))	('ANP32B', 'Gene', (255, 261))	('HuR', 'Gene', '1994', (217, 220))	('HuR', 'Gene', '1994', (65, 68))	('ANP32B', 'Gene', '10541', (255, 261))	('CRM1', 'Gene', '7514', (177, 181))	('HuR', 'Gene', (135, 138))	('presence', 'Var', (123, 131))	('binding', 'Interaction', (33, 40))	('ANP32A', 'Gene', (244, 250))	('recruitment', 'PosReg', (198, 209))	('CRM1', 'Gene', '7514', (221, 225))	('HuR', 'Gene', '1994', (135, 138))	('gag', 'Gene', (161, 164))
62971	21994786	The HERV-Ks are divided in type 1 and type 2 proviruses depending on the absence or presence of a 292 nt sequence at the boundary between the pol and env genes; the absence of this region in type 1 proviruses results in fusion of pol and env.	('HERV-K', 'Species', '45617', (4, 10))	('pol', 'Gene', '100616496', (142, 145))	('pol', 'Gene', (230, 233))	('results in', 'Reg', (209, 219))	('fusion', 'MPA', (220, 226))	('pol', 'Gene', (142, 145))	('absence', 'Var', (165, 172))	('env', 'Protein', (238, 241))	('pol', 'Gene', '100616496', (230, 233))
62974	21994786	Similar to Rev and Rex, Rec enhances stability and nuclear export of the unspliced and singly spliced mRNAs.	('Rex', 'Gene', (19, 22))	('nuclear export', 'MPA', (51, 65))	('Rev', 'Gene', '155908', (11, 14))	('Rex', 'Gene', '1491937', (19, 22))	('enhances', 'PosReg', (28, 36))	('stability', 'MPA', (37, 46))	('Rev', 'Gene', (11, 14))	('Rec', 'Var', (24, 27))
63292	22143885	Stat3 is the key downstream target of the LIF pathway, and dominant-negative Stat3 induces differentiation of ES cells in the presence of LIF.	('Stat3', 'Gene', '20848', (0, 5))	('dominant-negative', 'Var', (59, 76))	('induces', 'Reg', (83, 90))	('differentiation', 'CPA', (91, 106))	('Stat3', 'Gene', (77, 82))	('ES', 'Chemical', '-', (110, 112))	('Stat3', 'Gene', (0, 5))	('Stat3', 'Gene', '20848', (77, 82))
63293	22143885	Mouse ES cells can be maintained pluripotent in the absence of any cytokine signaling in medium that contains the fibroblast growth factor (FGF) receptor inhibitor SU5402, and the phospho-extracellular signal-regulated kinase (Erk) inhibitor PD184352 together with a pharmacological inhibitor of GSK3, CHIR99021.	('SU5402', 'Chemical', 'MESH:C105686', (164, 170))	('GSK3', 'Gene', (296, 300))	('PD184352', 'Var', (242, 250))	('PD184352', 'Chemical', 'MESH:C120227', (242, 250))	('phospho-extracellular signal-regulated kinase', 'Gene', (180, 225))	('ES', 'Chemical', '-', (6, 8))	('FGF', 'Gene', (140, 143))	('SU5402', 'Var', (164, 170))	('Mouse', 'Species', '10090', (0, 5))	('GSK3', 'Gene', '56637', (296, 300))	('pluripotent', 'MPA', (33, 44))	('phospho-extracellular signal-regulated kinase', 'Gene', '26413', (180, 225))	('FGF', 'Gene', '14173;2249;14175;14179', (140, 143))
63294	22143885	This finding highlights the fact that inhibition of the Ras-Mek-Erk pathway is pivotal for prevention of differentiation of mouse ES cells.	('ES', 'Chemical', '-', (130, 132))	('Mek', 'Gene', (60, 63))	('mouse', 'Species', '10090', (124, 129))	('inhibition', 'Var', (38, 48))	('Mek', 'Gene', '17242', (60, 63))
63302	22143885	We found that shRNA-mediated knockdown of the scaffolding protein Mp1 inhibits ES cell differentiation, whereas FGF4- or HrasV12-mediated proliferation is not affected.	('knockdown', 'Var', (29, 38))	('Hras', 'Gene', '15461', (121, 125))	('inhibits', 'NegReg', (70, 78))	('Mp1', 'Gene', (66, 69))	('ES', 'Chemical', '-', (79, 81))	('Hras', 'Gene', (121, 125))	('ES cell differentiation', 'CPA', (79, 102))
63312	22143885	Of the tested 12 putative hits, shFbxl12, shPtpn11, and shMp1 stood out as the shRNAs that showed an ES cell morphology after 3 wk of culture without LIF, which resembled the morphology of cells expressing pCAG-Nanog or cells that were grown in the presence of LIF (Fig.	('Ptpn11', 'Gene', '19247', (44, 50))	('pCAG', 'Chemical', '-', (206, 210))	('shMp1', 'Gene', (56, 61))	('Ptpn11', 'Gene', (44, 50))	('ES', 'Chemical', '-', (101, 103))	('shFbxl12', 'Var', (32, 40))
63314	22143885	Mp1 knockdown resulted in a phenotype that was comparable to ES cells overexpressing Nanog as indicated by the ES morphology, colony size, and positive staining for AP (Fig.	('knockdown', 'Var', (4, 13))	('Mp1', 'Gene', (0, 3))	('ES', 'Chemical', '-', (61, 63))	('ES', 'Chemical', '-', (111, 113))
63317	22143885	To rule out cell line-specific artifacts, we confirmed the inhibitory effect of Mp1 knockdown on differentiation in F1V6.5 and E14/Tg2a ES cell lines (Fig.	('knockdown', 'Var', (84, 93))	('Mp1', 'Gene', (80, 83))	('ES', 'Chemical', '-', (136, 138))
63318	22143885	To independently test whether Mp1 knockdown leads to a block in differentiation in the absence of LIF, we used Nanog-GFP reporter ES cells (Fig.	('knockdown', 'Var', (34, 43))	('ES', 'Chemical', '-', (130, 132))	('Mp1', 'Gene', (30, 33))	('differentiation', 'MPA', (64, 79))
63319	22143885	To test whether Mp1 knockdown prevents neuroectodermal differentiation, we cultured ES cells in serum-free medium (N2B27) containing LIF, without Bmp4, according to.	('knockdown', 'Var', (20, 29))	('Bmp4', 'Gene', '12159', (146, 150))	('Bmp4', 'Gene', (146, 150))	('ES', 'Chemical', '-', (84, 86))
63320	22143885	After a week, cells were replated, the cells with Mp1 knockdown stained positive for AP, and immunofluorescence staining showed expression of Oct3/4 (Fig.	('expression', 'Species', '29278', (128, 138))	('positive', 'Reg', (72, 80))	('Mp1', 'Gene', (50, 53))	('knockdown', 'Var', (54, 63))
63321	22143885	However, because ~50% of the ES cells loose their expression of Oct4, we cannot rule out that knockdown of Mp1 inhibits neuroectodermal differentiation and does not necessarily depend only on Mp1-mediated pluripotency regulation.	('knockdown', 'Var', (94, 103))	('expression', 'MPA', (50, 60))	('pluripotency', 'Disease', (205, 217))	('inhibits', 'NegReg', (111, 119))	('Oct4', 'Gene', '18999', (64, 68))	('pluripotency', 'Disease', 'None', (205, 217))	('expression', 'Species', '29278', (50, 60))	('ES', 'Chemical', '-', (29, 31))	('neuroectodermal differentiation', 'CPA', (120, 151))	('Mp1', 'Gene', (107, 110))	('loose', 'NegReg', (38, 43))	('Oct4', 'Gene', (64, 68))
63323	22143885	This showed that undifferentiated Nanog-GFP-positive ES cells had an enhanced proliferation rate upon knockdown of Mp1 compared with undifferentiated ES cells that were infected with a control shRNA (P < 0.001).	('Mp1', 'Gene', (115, 118))	('ES', 'Chemical', '-', (150, 152))	('enhanced', 'PosReg', (69, 77))	('knockdown', 'Var', (102, 111))	('proliferation rate', 'CPA', (78, 96))	('ES', 'Chemical', '-', (53, 55))
63324	22143885	These data show that Mp1 knockdown inhibits differentiation and leads to a proliferation advantage restricted to ES cells.	('ES', 'Chemical', '-', (113, 115))	('inhibits', 'NegReg', (35, 43))	('Mp1', 'Gene', (21, 24))	('proliferation advantage', 'CPA', (75, 98))	('differentiation', 'CPA', (44, 59))	('knockdown', 'Var', (25, 34))
63326	22143885	To analyze the role of activators of the FGF-Mek-Erk pathway in ES cells, we analyzed the function of different constitutive active isoforms of HRasV12, KRasV12, and BrafV600 in ES cells.	('KRasV12', 'Var', (153, 160))	('ES', 'Chemical', '-', (64, 66))	('Mek', 'Gene', '17242', (45, 48))	('ES', 'Chemical', '-', (178, 180))	('HRasV12', 'Var', (144, 151))	('FGF', 'Gene', (41, 44))	('BrafV600', 'Var', (166, 174))	('Mek', 'Gene', (45, 48))	('FGF', 'Gene', '14173;2249;14175;14179', (41, 44))
63328	22143885	HrasV12 overexpression strongly induced differentiation both in the presence of high LIF and at lower concentrations of LIF within 5 d. Upon knockdown of Mp1, HrasV12-induced differentiation was largely inhibited, especially in the presence of LIF.	('knockdown', 'Var', (141, 150))	('Hras', 'Gene', (159, 163))	('Hras', 'Gene', '15461', (0, 4))	('Mp1', 'Gene', (154, 157))	('Hras', 'Gene', (0, 4))	('Hras', 'Gene', '15461', (159, 163))	('inhibited', 'NegReg', (203, 212))	('expression', 'Species', '29278', (12, 22))
63330	22143885	Besides this expansion of ES cells, a lower amount of differentiation was observed compared with HrasV12, and this differentiation was inhibited by Mp1 knockdown at lower concentrations of LIF.	('ES', 'Chemical', '-', (26, 28))	('knockdown', 'Var', (152, 161))	('Hras', 'Gene', '15461', (97, 101))	('differentiation', 'CPA', (54, 69))	('Hras', 'Gene', (97, 101))	('inhibited', 'NegReg', (135, 144))
63332	22143885	This shows that overexpression of HrasV12 and BrafV600 lead primarily to differentiation which can be inhibited by Mp1 knockdown.	('Hras', 'Gene', '15461', (34, 38))	('differentiation', 'CPA', (73, 88))	('Hras', 'Gene', (34, 38))	('BrafV600', 'Var', (46, 54))	('expression', 'Species', '29278', (20, 30))
63334	22143885	To study whether Mp1 knockdown interferes with FGF4-dependent differentiation and proliferation, we used FGF4-deficient ES cells.	('ES', 'Chemical', '-', (120, 122))	('interferes', 'NegReg', (31, 41))	('Mp1', 'Gene', (17, 20))	('proliferation', 'CPA', (82, 95))	('knockdown', 'Var', (21, 30))
63337	22143885	For this, FGF4-/- ES cells with Mp1 knockdown (Fig.	('knockdown', 'Var', (36, 45))	('Mp1', 'Gene', (32, 35))	('ES', 'Chemical', '-', (18, 20))
63341	22143885	Alternatively, knockdown of Mp1 might stimulate the activation of the JAK-STAT3 pathway; however, we did not observe enhanced p-STAT3 levels (unpublished data).	('knockdown', 'Var', (15, 24))	('STAT3', 'Gene', '20848', (128, 133))	('STAT3', 'Gene', '20848', (74, 79))	('STAT3', 'Gene', (128, 133))	('STAT3', 'Gene', (74, 79))	('stimulate', 'PosReg', (38, 47))	('Mp1', 'Gene', (28, 31))
63343	22143885	To identify which genes are important for the maintenance of self-renewal in ES cells with Mp1 knockdown after induction with FGF4, we performed microarray analysis on day 3 after induction with FGF4 (Fig.	('knockdown', 'Var', (95, 104))	('ES', 'Chemical', '-', (77, 79))	('Mp1', 'Gene', (91, 94))
63344	22143885	We found that a panel of pluripotency determinators were regulated by FGF4 upon knockdown of Mp1, i.e., Esrrb, Zfp42, Tcl1, and Sox2.	('knockdown', 'Var', (80, 89))	('pluripotency determinators', 'Disease', (25, 51))	('Esrrb', 'Gene', (104, 109))	('Sox2', 'Gene', (128, 132))	('regulated', 'Reg', (57, 66))	('Esrrb', 'Gene', '26380', (104, 109))	('pluripotency determinators', 'Disease', 'MESH:D003643', (25, 51))	('FGF4', 'Gene', (70, 74))	('Sox2', 'Gene', '20674', (128, 132))	('Mp1', 'Gene', (93, 96))
63348	22143885	This showed that knockdown of Mp1 was able to generate a stronger resistance to LY294002-induced proliferation inhibition, which suggests that PI3K signaling levels are enhanced upon knockdown of Mp1 (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (80, 88))	('knockdown', 'Var', (183, 192))	('Mp1', 'Gene', (196, 199))	('PI3K signaling levels', 'MPA', (143, 164))	('knockdown', 'Var', (17, 26))	('resistance', 'MPA', (66, 76))	('enhanced', 'PosReg', (169, 177))
63351	22143885	Notably, phospho-Erk1,2 levels were markedly lower in cells with Mbd3 knockdown (unpublished data) as compared with the shGFP control, suggesting that the cells lack the ability to respond positively to the FGF4 signal through the lack of phopho-Erk1/2 activation.	('Erk1/2', 'Gene', (246, 252))	('lack', 'NegReg', (161, 165))	('Erk1', 'Gene', '26417', (17, 21))	('knockdown', 'Var', (70, 79))	('Mbd3', 'Gene', (65, 69))	('lower', 'NegReg', (45, 50))	('Erk1', 'Gene', (246, 250))	('Erk1/2', 'Gene', '26417;26413', (246, 252))	('Erk1', 'Gene', (17, 21))	('Mbd3', 'Gene', '17192', (65, 69))	('respond positively to the FGF4 signal', 'MPA', (181, 218))	('Erk1', 'Gene', '26417', (246, 250))
63352	22143885	In contrast, global phospho-Erk levels were only mildly affected by Mp1 knockdown, although reduced levels were observed in Lamp1-positive endosomes, as well as in cytoplasmic vesicles that lack Lamp1 expression (unpublished data).	('Mp1', 'Gene', (68, 71))	('Lamp1', 'Gene', (195, 200))	('Lamp1', 'Gene', '16783', (124, 129))	('expression', 'Species', '29278', (201, 211))	('Lamp1', 'Gene', (124, 129))	('knockdown', 'Var', (72, 81))	('Lamp1', 'Gene', '16783', (195, 200))
63353	22143885	These data show that Mp1 knockdown does only mildly affect phospho-Erk levels in ES cells, which argues that the differentiation inhibitory effect of knockdown of Mp1 is therefore not likely to be a result of total ablation of Erk signaling but rather a result of modulation of the Erk signaling network that leads to differentiation, possibly through endosomal signaling because Mp1 localizes to late endosomes in ES cells (unpublished data).	('Mp1', 'Gene', (163, 166))	('ES', 'Chemical', '-', (81, 83))	('knockdown', 'Var', (150, 159))	('ES', 'Chemical', '-', (415, 417))	('differentiation', 'CPA', (113, 128))	('knockdown', 'Var', (25, 34))	('affect', 'Reg', (52, 58))	('phospho-Erk', 'MPA', (59, 70))
63355	22143885	Mp1 knockdown directs FGF4 signaling toward self-renewal by transcriptional activation of the self-renewal regulators Esrrb, Zfp42, Tcl1, and SOX2 and simultaneously enhances PI3K signaling without changing the responsiveness to FGF4-mediated Erk2 phosphorylation.	('enhances', 'PosReg', (166, 174))	('SOX2', 'Gene', (142, 146))	('FGF4', 'Gene', (22, 26))	('Esrrb', 'Gene', (118, 123))	('PI3K signaling', 'MPA', (175, 189))	('knockdown', 'Var', (4, 13))	('Erk2', 'Gene', '26413', (243, 247))	('Erk2', 'Gene', (243, 247))	('Tcl1', 'Gene', (132, 136))	('SOX2', 'Gene', '20674', (142, 146))	('Mp1', 'Gene', (0, 3))	('Esrrb', 'Gene', '26380', (118, 123))	('Zfp42', 'Gene', (125, 130))	('activation', 'PosReg', (76, 86))
63356	22143885	Our data therefore implicate that the Mp1 knockdown rewires Ras-Mek-Erk signaling toward self-renewal without affecting the global Ras-Mek-Erk and PI3K signaling that contribute to the proliferative effect.	('Mek', 'Gene', (64, 67))	('rewires', 'Reg', (52, 59))	('Mek', 'Gene', '17242', (135, 138))	('Mp1', 'Gene', (38, 41))	('Mek', 'Gene', (135, 138))	('Mek', 'Gene', '17242', (64, 67))	('knockdown', 'Var', (42, 51))
63358	22143885	Because EC and Sem cells resemble ES cells, we reasoned that low levels of MP1 might resist differentiation cues and can thereby contribute to the progression of this tumor.	('differentiation cues', 'CPA', (92, 112))	('ES', 'Chemical', '-', (34, 36))	('contribute', 'Reg', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('resist', 'NegReg', (85, 91))	('low levels', 'Var', (61, 71))	('tumor', 'Disease', (167, 172))
63367	22143885	Although CC and YST showed low expression of Mp1 on the protein level (not depicted), some of the Ter samples (15%) that were analyzed (n = 124) expressed high levels of MP1 in differentiated tumor elements (Fig.	('tumor', 'Disease', (192, 197))	('Ter', 'Gene', '213236', (98, 101))	('expression', 'Species', '29278', (31, 41))	('MP1', 'Var', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Ter', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
63376	22143885	Together, our results show that knockdown of MP1 is able to inhibit differentiation of ES cells as well as GCTs.	('GCTs', 'CPA', (107, 111))	('inhibit', 'NegReg', (60, 67))	('knockdown', 'Var', (32, 41))	('MP1', 'Gene', (45, 48))	('ES', 'Chemical', '-', (87, 89))	('GCTs', 'Phenotype', 'HP:0100728', (107, 111))	('differentiation of ES cells', 'CPA', (68, 95))
63383	22143885	This indicates that knockdown of Capn10 gives a phenotype distinguishable from other hits such as shMp1 or shPtpn11, which gave prolonged pluripotency throughout the course of the experiment.	('pluripotency', 'Disease', (138, 150))	('Capn10', 'Gene', '23830', (33, 39))	('pluripotency', 'Disease', 'None', (138, 150))	('Capn10', 'Gene', (33, 39))	('knockdown', 'Var', (20, 29))	('Ptpn11', 'Gene', (109, 115))	('prolonged', 'PosReg', (128, 137))	('gave', 'Reg', (123, 127))	('Ptpn11', 'Gene', '19247', (109, 115))
63384	22143885	Among the candidate hits, we identified MP1 as a mediator of differentiation of ES cells, and knockdown of this gene prevents differentiation of ES cells.	('knockdown', 'Var', (94, 103))	('differentiation', 'CPA', (126, 141))	('MP1', 'Gene', (40, 43))	('ES', 'Chemical', '-', (80, 82))	('prevents', 'NegReg', (117, 125))	('ES', 'Chemical', '-', (145, 147))
63387	22143885	We observed that knockdown of Mp1 resulted in increased proliferation upon stimulation with FGF4, but without induction of differentiation, showing that knockdown of Mp1 results in uncoupling between proliferation and differentiation in ES cells.	('knockdown', 'Var', (153, 162))	('Mp1', 'Gene', (30, 33))	('results in', 'Reg', (170, 180))	('increased', 'PosReg', (46, 55))	('ES', 'Chemical', '-', (237, 239))	('proliferation', 'MPA', (56, 69))	('knockdown', 'Var', (17, 26))	('uncoupling', 'MPA', (181, 191))	('stimulation', 'Interaction', (75, 86))	('Mp1', 'Gene', (166, 169))	('FGF4', 'Gene', (92, 96))
63393	22143885	We show that Mp1 knockdown primarily affected HrasV12-induced differentiation, which suggests that HrasV12 specifically triggers a portion of Ras/Mapk signaling that leads to differentiation.	('affected', 'Reg', (37, 45))	('Hras', 'Gene', '15461', (99, 103))	('Mp1', 'Gene', (13, 16))	('Hras', 'Gene', (99, 103))	('leads to', 'Reg', (166, 174))	('Hras', 'Gene', '15461', (46, 50))	('triggers', 'Reg', (120, 128))	('Ras/Mapk signaling', 'MPA', (142, 160))	('knockdown', 'Var', (17, 26))	('Hras', 'Gene', (46, 50))
63398	22143885	Study of the intrinsic differences of different Ras isoforms has revealed that posttranslational modifications of their C termini has functional consequences, leading to palmitoylation (Hras, Nras, and Kras4A) or only farnesylation and geranylation (Kras 4B).	('Hras', 'Gene', (186, 190))	('leading to', 'Reg', (159, 169))	('Nras', 'Gene', (192, 196))	('modifications', 'Var', (97, 110))	('geranylation', 'MPA', (236, 248))	('Kras', 'Gene', (250, 254))	('Kras', 'Gene', '16653', (250, 254))	('Nras', 'Gene', '18176', (192, 196))	('Hras', 'Gene', '15461', (186, 190))	('Kras', 'Gene', (202, 206))	('Kras', 'Gene', '16653', (202, 206))	('farnesylation', 'MPA', (218, 231))	('palmitoylation', 'MPA', (170, 184))
63404	22143885	Because Mp1 is localized to the late endosomes, the loss of the small fraction of late endosomal activated Erk in ES cells might not be able to change the global levels of phospho-Erk, although we noticed that the intracellular localization of phospho-Erk was affected by Mp1 knockdown after FGF4 stimulation, resulting in reduced levels of phospho-Erk in Lamp1-positive endosomes and lipid rafts throughout the cell.	('knockdown', 'Var', (276, 285))	('affected', 'Reg', (260, 268))	('reduced', 'NegReg', (323, 330))	('Lamp1', 'Gene', (356, 361))	('levels of phospho-Erk in', 'MPA', (331, 355))	('lipid', 'Chemical', 'MESH:D008055', (385, 390))	('ES', 'Chemical', '-', (114, 116))	('Mp1', 'Gene', (272, 275))	('Lamp1', 'Gene', '16783', (356, 361))
63412	22143885	5 D), positive staining for AP, and the virtual absence of the epiblast marker FGF5 (not depicted) indicates that Mp1 knockdown does not result in an EpiSC maturation arrest.	('FGF', 'Gene', '14173;2249;14175;14179', (79, 82))	('knockdown', 'Var', (118, 127))	('FGF', 'Gene', (79, 82))	('Mp1', 'Gene', (114, 117))	('absence', 'NegReg', (48, 55))
63414	22143885	In this process, cells of the primitive streak undergo a Ras/MAPK governed epithelial to mesenchymal transition (EMT) and disruption of FGF8-, FGFR1-, or MAP4K4-mediated signaling results in inhibition of this EMT process and, therefore, mesoderm formation is inhibited.	('MAPK', 'Gene', (61, 65))	('epithelial to mesenchymal transition', 'CPA', (75, 111))	('inhibition', 'NegReg', (191, 201))	('MAPK', 'Gene', '5594;26413;26417', (61, 65))	('disruption', 'Var', (122, 132))	('inhibited', 'NegReg', (260, 269))	('FGFR1', 'Gene', (143, 148))	('EMT process', 'CPA', (210, 221))	('FGF8', 'Gene', '14179', (136, 140))	('FGFR1', 'Gene', '14182', (143, 148))	('MAP4K4', 'Gene', (154, 160))	('MAP4K4', 'Gene', '26921', (154, 160))	('FGF8', 'Gene', (136, 140))	('mesoderm formation', 'CPA', (238, 256))
63417	22143885	The phenotype observed with loss of Mp1 does partially overlap with loss of p14, the heterodimerizing partner of Mp1 (unpublished data).	('p14', 'Gene', '83409', (76, 79))	('loss', 'Var', (28, 32))	('p14', 'Gene', (76, 79))	('loss', 'Var', (68, 72))	('Mp1', 'Gene', (36, 39))
63418	22143885	In short-term assays, knockdown of p14 resulted in a maturation arrest similar to Mp1 knockdown; however, secondary lethal effects prevent a long-term effect in vitro and in vivo.	('p14', 'Gene', (35, 38))	('knockdown', 'Var', (22, 31))	('p14', 'Gene', '83409', (35, 38))	('maturation arrest', 'MPA', (53, 70))	('prevent', 'NegReg', (131, 138))
63422	22143885	We hypothesized that knockdown of Mp1 could direct low levels of FGF signaling toward self-renewal in the invasive GCT stages Sem and EC.	('FGF', 'Gene', '14173;2249;14175;14179', (65, 68))	('FGF', 'Gene', (65, 68))	('Mp1', 'Gene', (34, 37))	('self-renewal', 'CPA', (86, 98))	('knockdown', 'Var', (21, 30))
63423	22143885	We show that knockdown of Mp1 in NCC-IT cells results in inhibition of differentiation after treatment of the cells by SU-5402.	('SU-5402', 'Chemical', 'MESH:C105686', (119, 126))	('Mp1', 'Gene', (26, 29))	('inhibition', 'NegReg', (57, 67))	('differentiation', 'CPA', (71, 86))	('knockdown', 'Var', (13, 22))
63428	22143885	Our results show that knockdown of Mp1 can overrule the differentiation-inducing signal from FGF4/Ras signaling by activation of pluripotency regulators.	('activation', 'PosReg', (115, 125))	('knockdown', 'Var', (22, 31))	('pluripotency', 'Disease', (129, 141))	('Mp1', 'Gene', (35, 38))	('differentiation-inducing signal', 'MPA', (56, 87))	('pluripotency', 'Disease', 'None', (129, 141))
63462	22143885	Primers for amplification of the mouse -289 to +177 Nanog fragment were (with restriction sites for cloning purposes indicated in lowercase): Nanog -289 forward, 5'-CGCgtcgacTAAAGTGAAATGAGGTAAAGCC-3'; and Nanog +177 reverse 5'-CGCggatccGGAAAGATCATAGAAAGAAGAG-3'.	('mouse', 'Species', '10090', (33, 38))	('Nanog +177', 'Var', (205, 215))	('Nanog -289', 'Var', (142, 152))
63466	22143885	To analyze whether undifferentiated ES cells have a proliferation advantage upon knockdown of Mp1 versus the control hairpin shRnd1, Nanog-GFP reporter cells were treated in LDM for 4 d, as in the previous paragraph, pulsed with 10 microM BrdU for 1 h, and then FACS sorted.	('FACS', 'Gene', (262, 266))	('proliferation', 'CPA', (52, 65))	('FACS', 'Gene', '14081', (262, 266))	('knockdown', 'Var', (81, 90))	('Mp1', 'Gene', (94, 97))	('ES', 'Chemical', '-', (36, 38))	('BrdU', 'Chemical', 'MESH:D001973', (239, 243))
63475	22143885	Antibodies used were anti-V5 (R960-25; Invitrogen), anti-OCT3/4 (C10; Santa Cruz Biotechnology, Inc.), anti-nestin (611658; BD), anti-tubulin-III (Sigma-Aldrich), anti-phospho-ERK1/2 (Cell Signaling Technology), and anti-mouse CD107a (lysosomal associated membrane protein 1 [LAMP1]; BD).	('LAMP1', 'Gene', '16783', (276, 281))	('LAMP1', 'Gene', (276, 281))	('C10', 'Gene', (65, 68))	('C10', 'Gene', '20305', (65, 68))	('ERK1/2', 'Gene', (176, 182))	('anti-mouse', 'Var', (216, 226))	('lysosomal associated membrane protein 1', 'Gene', (235, 274))	('mouse', 'Species', '10090', (221, 226))	('lysosomal associated membrane protein 1', 'Gene', '16783', (235, 274))	('CD107a', 'Gene', (227, 233))	('anti-nestin', 'Var', (103, 114))	('ERK1/2', 'Gene', '26417;26413', (176, 182))	('CD107a', 'Gene', '16783', (227, 233))
63486	22143885	To measure the effect of FGF4 on phospho-Erk, E14T- and FGF4-deficient ES cells were grown overnight in serum-free medium (N2B27), including Bmp4 at 10 ng/ml, and treated with FGF4 at a concentration of 20 ng/ml.	('ES', 'Chemical', '-', (71, 73))	('E14T-', 'Var', (46, 51))	('Bmp4', 'Gene', '12159', (141, 145))	('FGF4-deficient', 'Gene', (56, 70))	('Bmp4', 'Gene', (141, 145))	('E14T', 'Mutation', 'p.E14T', (46, 50))
63519	31316051	When Smad4 was conditionally deleted in mouse Sertoli cells, the fertility of mutant mouse was impaired with smaller testis size and decreased sperm production at adult.	('smaller', 'NegReg', (109, 116))	('mouse', 'Species', '10090', (85, 90))	('deleted', 'Var', (29, 36))	('sperm production at adult', 'CPA', (143, 168))	('impaired', 'NegReg', (95, 103))	('Sertoli cell', 'Phenotype', 'HP:0100619', (46, 58))	('fertility', 'CPA', (65, 74))	('Smad4', 'Gene', (5, 10))	('mouse', 'Species', '10090', (40, 45))	('Smad4', 'Gene', '17128', (5, 10))	('testis size', 'CPA', (117, 128))	('smaller testis', 'Phenotype', 'HP:0008734', (109, 123))	('mutant', 'Var', (78, 84))	('Sertoli cells', 'Phenotype', 'HP:0100619', (46, 59))	('decreased', 'NegReg', (133, 142))
63529	31316051	knocked down BMP4 in human SCs, fibroblast growth factor-2 (FGF-2) and SCF production was also suppressed.	('fibroblast growth factor-2', 'Gene', (32, 58))	('suppressed', 'NegReg', (95, 105))	('BMP4', 'Gene', (13, 17))	('SCF', 'Gene', '4254', (71, 74))	('SCF', 'Gene', (71, 74))	('knocked down', 'Var', (0, 12))	('FGF-2', 'Gene', (60, 65))	('human', 'Species', '9606', (21, 26))	('fibroblast growth factor-2', 'Gene', '2247', (32, 58))
63539	31316051	If Smad3 and Smad4 are knocked down, TGF-beta3-induced JAM-B degradation will be inhibited in turn.	('knocked down', 'Var', (23, 35))	('Smad4', 'Gene', (13, 18))	('TGF-beta3-induced', 'Gene', (37, 54))	('Smad4', 'Gene', '17128', (13, 18))	('inhibited', 'NegReg', (81, 90))	('JAM-B', 'Gene', '67374', (55, 60))	('Smad3', 'Gene', (3, 8))	('Smad3', 'Gene', '17127', (3, 8))	('JAM-B', 'Gene', (55, 60))
63551	31316051	For example, in alpha1AMPK globally knocked out mouse, spermatozoa showed abnormal head, curved sheaths, and impaired mobility.	('impaired mobility', 'CPA', (109, 126))	('abnormal head', 'Phenotype', 'HP:0000234', (74, 87))	('mouse', 'Species', '10090', (48, 53))	('head', 'CPA', (83, 87))	('knocked out', 'Var', (36, 47))
63552	31316051	When alpha1AMPK is conditionally knocked out in mouse SCs, the mutant mice still showed an abnormal phenotype, including thin head spermatozoa, reduced expression of junctional proteins (beta-catenin, vimentin, occludin and ZO-1), and deregulation of energy homeostasis.	('reduced', 'NegReg', (144, 151))	('vimentin', 'Gene', '22352', (201, 209))	('deregulation', 'Reg', (235, 247))	('mutant', 'Var', (63, 69))	('mouse', 'Species', '10090', (48, 53))	('occludin', 'Protein', (211, 219))	('beta-catenin', 'Gene', (187, 199))	('vimentin', 'Gene', (201, 209))	('mice', 'Species', '10090', (70, 74))	('energy homeostasis', 'MPA', (251, 269))	('beta-catenin', 'Gene', '12387', (187, 199))	('expression', 'MPA', (152, 162))
63575	31316051	Recently, they clarified that miR-1285 can downregulate alpha2AMPK mRNA and protein level.	('miR-1285', 'Var', (30, 38))	('miR-1285', 'Chemical', '-', (30, 38))	('alpha2AMPK', 'Protein', (56, 66))	('downregulate', 'NegReg', (43, 55))
63592	31316051	Overexpression of TGF-beta3 in primary rat SCs can magnify above damage effect in vitro, with occludin, N-cadherin, and ZO-1 decline.	('ZO-1', 'CPA', (120, 124))	('decline', 'NegReg', (125, 132))	('rat', 'Species', '10116', (39, 42))	('TGF-beta3', 'Gene', (18, 27))	('Overexpression', 'Var', (0, 14))	('occludin', 'MPA', (94, 102))	('N-cadherin', 'Protein', (104, 114))
63593	31316051	In CdCl2-induced adult rat BTB damage, a specific p38 MAPK activity inhibitor SB202190 can blocked loss of ZO-1 and occludin, and thus abolish the damage of TGB-beta3 on the AJ and TJ barrier function.	('CdCl2', 'Chemical', 'MESH:D019256', (3, 8))	('SB202190', 'Var', (78, 86))	('ZO-1 and occludin', 'Gene', '292994;83497', (107, 124))	('rat', 'Species', '10116', (23, 26))	('blocked loss', 'NegReg', (91, 103))	('p38 MAPK', 'Gene', (50, 58))	('damage', 'MPA', (147, 153))	('abolish', 'NegReg', (135, 142))	('SB202190', 'Chemical', 'MESH:C090942', (78, 86))	('p38 MAPK', 'Gene', '26416', (50, 58))
63605	31316051	During CdCl2-induced BTB disruption, the JNK signaling pathway leads to alpha2-macroglobulin (alpha2-MG) expression, which is a protease inhibitor localized at the SCs-SCs and SCs-GCs interface.	('CdCl2', 'Chemical', 'MESH:D019256', (7, 12))	('alpha2-macroglobulin', 'Gene', '232345', (72, 92))	('alpha2-MG', 'Gene', (94, 103))	('alpha2-MG', 'Gene', '232345', (94, 103))	('leads to', 'Reg', (63, 71))	('disruption', 'Var', (25, 35))	('JNK signaling pathway', 'Pathway', (41, 62))	('alpha2-macroglobulin', 'Gene', (72, 92))	('expression', 'MPA', (105, 115))
63616	31316051	After pre-treatment of MEK1/2 inhibitor U0126, the number of pachytene spermatocytes and secondary spermatocytes declined.	('pachytene', 'Chemical', '-', (61, 70))	('U0126', 'Var', (40, 45))	('declined', 'NegReg', (113, 121))	('men', 'Species', '9606', (15, 18))	('MEK1/2', 'Gene', '26395;26396', (23, 29))	('U0126', 'Chemical', 'MESH:C113580', (40, 45))	('MEK1/2', 'Gene', (23, 29))
63632	31316051	Incubation of rat SCs with U0126 or PD98059 both blocked phosphorylated-ERK-induced transferrin secretion and LDH catalytic activity.	('catalytic activity', 'MPA', (114, 132))	('transferrin', 'Gene', (84, 95))	('U0126', 'Chemical', 'MESH:C113580', (27, 32))	('PD98059', 'Chemical', 'MESH:C093973', (36, 43))	('rat', 'Species', '10116', (14, 17))	('U0126', 'Var', (27, 32))	('LDH', 'CPA', (110, 113))	('blocked', 'NegReg', (49, 56))	('PD98059', 'Var', (36, 43))	('transferrin', 'Gene', '24825', (84, 95))
63634	31316051	Treating rat SCs cultures with FGF-2 could increase phosphorylated CREB level, while PD98059 incubation inhibited FGF-2 stimulation on phosphorylated CREB, LDH A, and transferrin uprising level.	('transferrin', 'Gene', (167, 178))	('PD98059', 'Var', (85, 92))	('transferrin', 'Gene', '24825', (167, 178))	('rat', 'Species', '10116', (9, 12))	('LDH A', 'Gene', (156, 161))	('LDH A', 'Gene', '24533', (156, 161))	('PD98059', 'Chemical', 'MESH:C093973', (85, 92))	('increase', 'PosReg', (43, 51))	('inhibited', 'NegReg', (104, 113))	('phosphorylated CREB level', 'MPA', (52, 77))	('FGF-2', 'Gene', (31, 36))
63645	31316051	However, number of pups per litter in SC-alpha1AMPK-cKO mice did decrease by 25%, accompanied with disturbed cell junction dynamics.	('disturbed', 'Reg', (99, 108))	('SC-alpha1AMPK-cKO', 'Var', (38, 55))	('cell junction dynamics', 'MPA', (109, 131))	('mice', 'Species', '10090', (56, 60))	('decrease', 'NegReg', (65, 73))
63653	31316051	When Smad4 was conditionally knocked out in mouse Sertoli cells and Leydig cells, 87.5% of the mutant mice exhibited Leydig cell adenomas at 56-62 weeks of age.	('mice', 'Species', '10090', (102, 106))	('exhibited', 'Reg', (107, 116))	('Leydig cell adenomas', 'Disease', 'MESH:D000236', (117, 137))	('Smad4', 'Gene', (5, 10))	('Leydig cell adenomas', 'Disease', (117, 137))	('mutant', 'Var', (95, 101))	('Smad4', 'Gene', '17128', (5, 10))	('Sertoli cells', 'Phenotype', 'HP:0100619', (50, 63))	('mouse', 'Species', '10090', (44, 49))	('Sertoli cell', 'Phenotype', 'HP:0100619', (50, 62))
63688	29416701	This is probably due Testicular Dysgenesis Syndrome (TDS), where altered Sertoli and Leydig cell function during testes development modifies the development of germ cells and leads to hypospadias, cryptorchidism, impaired spermatogenesis, decreased testosterone production, microlithiasis and testicular cancer.	('TDS', 'Disease', (53, 56))	('impaired spermatogenesis', 'CPA', (213, 237))	('cryptorchidism', 'Disease', 'MESH:D003456', (197, 211))	('hypospadias', 'Disease', 'MESH:D007021', (184, 195))	('Testicular Dysgenesis', 'Phenotype', 'HP:0008715', (21, 42))	('Testicular Dysgenesis Syndrome', 'Disease', 'MESH:D013733', (21, 51))	('decreased', 'NegReg', (239, 248))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('testosterone', 'Chemical', 'MESH:D013739', (249, 261))	('leads to', 'Reg', (175, 183))	('Testicular Dysgenesis Syndrome', 'Disease', (21, 51))	('cryptorchidism', 'Disease', (197, 211))	('microlithiasis and testicular cancer', 'Disease', 'MESH:C566478', (274, 310))	('men', 'Species', '9606', (152, 155))	('men', 'Species', '9606', (127, 130))	('testosterone production', 'MPA', (249, 272))	('modifies', 'Reg', (132, 140))	('cryptorchidism', 'Phenotype', 'HP:0000028', (197, 211))	('hypospadias', 'Phenotype', 'HP:0000047', (184, 195))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (213, 237))	('altered', 'Var', (65, 72))	('TDS', 'Disease', 'None', (53, 56))	('decreased testosterone', 'Phenotype', 'HP:0040171', (239, 261))	('hypospadias', 'Disease', (184, 195))	('development of germ cells', 'CPA', (145, 170))	('testicular cancer', 'Phenotype', 'HP:0010788', (293, 310))
63691	29416701	The risk of developing hormone-dependent cancers, such as the TGCTs, can be increased by small variations in estrogen levels during fetal development.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('men', 'Species', '9606', (145, 148))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('TGCTs', 'Disease', (62, 67))	('variations', 'Var', (95, 105))	('cancers', 'Disease', (41, 48))
63695	29416701	c-KIT/KITLG, POU5F1) with the development of this neoplasia, and the identification of aberrant epigenetic patterns in promoter regions of several genes, along with the expression of specific regulatory cluster (miRnas), have shed a better light in the comprehension of the development of this disease.	('c-KIT', 'Gene', (0, 5))	('aberrant epigenetic patterns', 'Var', (87, 115))	('c-KIT', 'Gene', '3815', (0, 5))	('neoplasia', 'Disease', (50, 59))	('POU5F1', 'Gene', '5460', (13, 19))	('neoplasia', 'Disease', 'MESH:D009369', (50, 59))	('neoplasia', 'Phenotype', 'HP:0002664', (50, 59))	('POU5F1', 'Gene', (13, 19))	('men', 'Species', '9606', (37, 40))	('men', 'Species', '9606', (281, 284))
63696	29416701	Cytogenetic and molecular abnormalities are associated with TGCTs, and include: aneuploidy; the gain and/or loss of some specific chromosomal regions such as the presence of iso-chromosome 12p and the amplification of 12p sequences, which exist in all germ cell tumors and take place early during the malignant transformation; the gain of chromosomal material in 1, 2p, 7, 8, 12, 14q, 15q, 17q, 21q, and X or the deletion of chromosomal material from 4, 5, 11q, 13q, and 18q2.	('deletion', 'Var', (413, 421))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('aneuploidy', 'Disease', (80, 90))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('gain', 'PosReg', (331, 335))	('molecular abnormalities', 'Disease', (16, 39))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('germ cell tumors', 'Phenotype', 'HP:0100728', (252, 268))	('molecular abnormalities', 'Disease', 'MESH:C567116', (16, 39))	('germ cell tumor', 'Phenotype', 'HP:0100728', (252, 267))
63698	29416701	In sporadic cases, the 1.6 Mb deletion in the AZF region of the Y chromosome represents the most common genetic alteration in patients with infertility and doubles the risk for developing TGCTs.	('infertility', 'Disease', (140, 151))	('deletion', 'Var', (30, 38))	('AZF', 'Gene', (46, 49))	('TGCTs', 'Disease', (188, 193))	('patients', 'Species', '9606', (126, 134))	('infertility', 'Disease', 'MESH:D007247', (140, 151))	('AZF', 'Gene', '560', (46, 49))	('infertility', 'Phenotype', 'HP:0000789', (140, 151))
63699	29416701	The strongest association for TGCTs susceptibility has resulted for single nucleotide polymorphisms (SNPs) at the 12q22 within the kit-ligand gene, which is correlated with a 2.5-fold increased risk of disease.	('TGCTs', 'Disease', (30, 35))	('single nucleotide polymorphisms', 'Var', (68, 99))	('kit-ligand', 'Gene', '4254', (131, 141))	('kit-ligand', 'Gene', (131, 141))
63703	29416701	Variations in KITLG sequence (rs3782179, rs4474514 and rs995030) responsible for the predisposition to develop TGCTs have been recently documented, and also have been correlated with the role for KITLG in pigmentation, and with the greater incidence of TGCTs in Caucasian than in African-Americans males.	('rs4474514', 'Var', (41, 50))	('men', 'Species', '9606', (140, 143))	('TGCTs', 'Disease', (111, 116))	('TGCTs', 'Disease', (253, 258))	('men', 'Species', '9606', (208, 211))	('correlated', 'Reg', (167, 177))	('rs3782179', 'Mutation', 'rs3782179', (30, 39))	('rs4474514', 'Mutation', 'rs4474514', (41, 50))	('KITLG', 'Gene', (14, 19))	('rs995030', 'Mutation', 'rs995030', (55, 63))	('rs995030', 'Var', (55, 63))	('rs3782179', 'Var', (30, 39))
63704	29416701	The KIT pathway has been suggested to be constitutively activated in human TGCTs as a result of gain of function mutations in the KIT oncogene and/or overexpression of KIT.	('TGCTs', 'Disease', (75, 80))	('overexpression', 'PosReg', (150, 164))	('human', 'Species', '9606', (69, 74))	('gain of function', 'PosReg', (96, 112))	('mutations', 'Var', (113, 122))	('KIT pathway', 'Pathway', (4, 15))	('KIT', 'Gene', (168, 171))	('KIT', 'Gene', (130, 133))	('activated', 'PosReg', (56, 65))
63709	29416701	Studies of single nucleotide polymorphisms in the gene regions of BAK1, DMRT1, TERTCLPTM1L, and KITLG demonstrated that these risk variants predispose to both bilateral and familial TGCTs.	('bilateral', 'Disease', (159, 168))	('predispose', 'Reg', (140, 150))	('single nucleotide polymorphisms', 'Var', (11, 42))	('DMRT1', 'Gene', (72, 77))	('BAK1', 'Gene', '578', (66, 70))	('CLPTM1L', 'Gene', '81037', (83, 90))	('variants', 'Var', (131, 139))	('DMRT1', 'Gene', '1761', (72, 77))	('CLPTM1L', 'Gene', (83, 90))	('BAK1', 'Gene', (66, 70))	('familial TGCTs', 'Disease', (173, 187))
63714	29416701	In addition, in PTEN a SNPs only (rs11202586) has shown association with the risk of developing TGCTs, regardless of histological subtype and hereditary factors.	('association', 'Reg', (56, 67))	('rs11202586', 'Mutation', 'rs11202586', (34, 44))	('PTEN', 'Gene', (16, 20))	('rs11202586', 'Var', (34, 44))	('PTEN', 'Gene', '5728', (16, 20))	('TGCTs', 'Disease', (96, 101))
63718	29416701	This is of considerable interest since point mutations are rare events in testicular germ cell tumors and P53 results no mutated in these tumors.	('point mutations', 'Var', (39, 54))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('germ cell tumors', 'Phenotype', 'HP:0100728', (85, 101))	('germ cell tumor', 'Phenotype', 'HP:0100728', (85, 100))	('P53', 'Gene', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('P53', 'Gene', '7157', (106, 109))	('tumors', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
63720	29416701	In addition, polymorphisms in cytochrome P450 Cyp-1A1 gene, encoding a hormone-metabolizing protein, have been identified and correlated with susceptibility to TGCTs development.	('men', 'Species', '9606', (173, 176))	('TGCTs', 'Disease', (160, 165))	('polymorphisms', 'Var', (13, 26))	('cytochrome P450 Cyp-1A1', 'Gene', (30, 53))	('correlated', 'Reg', (126, 136))	('cytochrome P450 Cyp-1A1', 'Gene', '1543', (30, 53))	('susceptibility', 'Reg', (142, 156))
63723	29416701	Changes in the length of these polymorphic trinucleotide repeats lead to AR altered transactivation, and it has been reported as strongly associated with the increased risk to develop seminoma, suggesting that AR increased transactivation may occur in the development of seminoma and/or in the progression of carcinoma in situ to seminoma.	('seminoma', 'Disease', (184, 192))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (309, 326))	('AR', 'Gene', '367', (73, 75))	('seminoma', 'Disease', 'MESH:D018239', (330, 338))	('carcinoma in situ to seminoma', 'Disease', 'MESH:D002278', (309, 338))	('seminoma', 'Disease', (271, 279))	('seminoma', 'Disease', (330, 338))	('associated', 'Reg', (138, 148))	('lead to', 'Reg', (65, 72))	('seminoma', 'Disease', 'MESH:D018239', (184, 192))	('Changes', 'Var', (0, 7))	('transactivation', 'MPA', (84, 99))	('carcinoma in situ to seminoma', 'Disease', (309, 338))	('men', 'Species', '9606', (263, 266))	('trinucleotide', 'Chemical', '-', (43, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('AR', 'Gene', '367', (210, 212))	('seminoma', 'Disease', 'MESH:D018239', (271, 279))
63724	29416701	It is postulated that the presence of these polymorphic sequences may be involved in increasing the risk of TGCTs, since these variants alter receptor function that leads to insensitivity of androgens, causing high concentrations of testosterone and estrogen in circulation.	('causing', 'Reg', (202, 209))	('variants', 'Var', (127, 135))	('TGCTs', 'Disease', (108, 113))	('receptor', 'Protein', (142, 150))	('alter', 'Reg', (136, 141))	('leads to', 'Reg', (165, 173))	('high concentrations of testosterone', 'Phenotype', 'HP:0030088', (210, 245))	('testosterone', 'Chemical', 'MESH:D013739', (233, 245))	('insensitivity of androgens', 'Phenotype', 'HP:0008226', (174, 200))	('high', 'PosReg', (210, 214))	('insensitivity of androgens', 'MPA', (174, 200))
63725	29416701	Moreover, specific SNPs (P390S, A279T, rs12014709) have been identified and associated with TGCTs development.	('P390S', 'Mutation', 'rs12014709', (25, 30))	('TGCTs', 'Disease', (92, 97))	('associated with', 'Reg', (76, 91))	('men', 'Species', '9606', (105, 108))	('A279T', 'Var', (32, 37))	('P390S', 'Var', (25, 30))	('A279T', 'Mutation', 'rs12014709', (32, 37))	('rs12014709', 'Var', (39, 49))	('rs12014709', 'Mutation', 'rs12014709', (39, 49))
63728	29416701	Located on chromosome region 9q24.3, DMRT1 is also involved in tumor development, with its genetic variants (rs755383 and rs7040024) having a strong relationship with susceptibility to develop TGCTs.	('tumor', 'Disease', (63, 68))	('relationship', 'Reg', (149, 161))	('DMRT1', 'Gene', '1761', (37, 42))	('TGCTs', 'Disease', (193, 198))	('men', 'Species', '9606', (76, 79))	('DMRT1', 'Gene', (37, 42))	('rs7040024', 'Mutation', 'rs7040024', (122, 131))	('involved', 'Reg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('rs7040024', 'Var', (122, 131))	('rs755383', 'Mutation', 'rs755383', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('rs755383', 'Var', (109, 117))	('susceptibility', 'Reg', (167, 181))
63730	29416701	In fact, epigenetic regulatory processes occur in both the mechanisms of initiating and protecting pluripotency of embryonic stem cells as well as in maintaining the identity of differentiated cell types.	('pluripotency of embryonic', 'Disease', (99, 124))	('pluripotency of embryonic', 'Disease', 'MESH:D009373', (99, 124))	('epigenetic', 'Var', (9, 19))	('maintaining', 'Reg', (150, 161))
63731	29416701	Deregulation of these processes may change chromosomal stability, stem cells properties, self-renewal and the potential to differentiate, leading to initiation and/or progression of cancer, including testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('testicular cancer', 'Phenotype', 'HP:0010788', (200, 217))	('testicular cancer', 'Disease', 'MESH:D013736', (200, 217))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('Deregulation', 'Var', (0, 12))	('self-renewal', 'CPA', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('stem cells properties', 'CPA', (66, 87))	('cancer', 'Disease', (211, 217))	('testicular cancer', 'Disease', (200, 217))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('chromosomal stability', 'CPA', (43, 64))	('change', 'Reg', (36, 42))	('leading to', 'Reg', (138, 148))
63732	29416701	In cancers, alterations in gene methylation in relation to tumor suppressor genes have been shown to be common and represent an important step in tumorigenesis.	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('alterations', 'Var', (12, 23))	('tumor', 'Disease', (146, 151))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('gene', 'MPA', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
63733	29416701	Aberrant hypermethylated CpG islands have been identified in about every tumors, including TGCTs.	('Aberrant hypermethylated', 'Var', (0, 24))	('TGCTs', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('identified', 'Reg', (47, 57))
63734	29416701	Interestingly, TGCTs uncommonly show tumor-related genes aberrant methylation.	('aberrant methylation', 'Var', (57, 77))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
63735	29416701	DNA hypomethylation of oncogenes leads to DNA overexpression that, in turn, may result in carcinogenesis.	('result in', 'Reg', (80, 89))	('overexpression', 'PosReg', (46, 60))	('hypomethylation', 'Var', (4, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('leads', 'Reg', (33, 38))	('DNA', 'MPA', (42, 45))	('carcinogenesis', 'Disease', (90, 104))
63741	29416701	Aberrant methylation of the regulatory genes promoter region silences their expression, representing a critical pathway in the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('men', 'Species', '9606', (134, 137))	('Aberrant methylation', 'Var', (0, 20))	('expression', 'MPA', (76, 86))	('silences', 'NegReg', (61, 69))	('cancer', 'Disease', (142, 148))
63742	29416701	Hypermethylation of CpG islands located in the tumor suppressor genes or tumor-related genes promoter regions is considered as a key mechanism for gene inactivation.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
63743	29416701	However, tumor suppressor genes or tumor-related genes aberrant de novo methylation is a rare event in TGCTs respect to testicular malignant lymphomas.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('malignant lymphomas', 'Disease', (131, 150))	('lymphomas', 'Phenotype', 'HP:0002665', (141, 150))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (9, 14))	('TGCTs', 'Disease', (103, 108))	('aberrant de novo methylation', 'Var', (55, 83))	('malignant lymphomas', 'Disease', 'MESH:D008223', (131, 150))
63756	29416701	However, both in seminomas and non-seminomas tumors, the LINE-1 DNA hypomethylation may be also due to epigenetic inactivation of PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs, predominantly expressed in the germ cell lineage and transcribed from genome regions containing transcribed transposable and other repetitive elements, and different Argonaute protein family members (PIWIL1, PIWIL2, PIWIL4).	('PIWI', 'Gene', (130, 134))	('PIWIL1', 'Gene', (396, 402))	('PIWI', 'Gene', '9271', (396, 400))	('PIWI', 'Gene', '9271', (404, 408))	('Argonaute protein', 'Protein', (362, 379))	('seminomas and non-seminomas tumors', 'Disease', 'MESH:D018239', (17, 51))	('PIWIL4', 'Gene', '143689', (412, 418))	('PIWI', 'Gene', '9271', (412, 416))	('hypomethylation', 'Var', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('PIWIL2', 'Gene', '55124', (404, 410))	('PIWI', 'Gene', (396, 400))	('PIWI', 'Gene', (404, 408))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PIWI', 'Gene', (412, 416))	('men', 'Species', '9606', (341, 344))	('PIWI', 'Gene', '9271', (130, 134))	('PIWIL4', 'Gene', (412, 418))	('PIWIL1', 'Gene', '9271', (396, 402))	('epigenetic inactivation', 'Var', (103, 126))	('due', 'Reg', (96, 99))	('PIWIL2', 'Gene', (404, 410))
63759	29416701	Detectable in germ cells, seminoma, embryonal carcinoma and carcinoma in situ, Nanog expression is not detectable in the adult testis or in differentiated somatic cells and its promoter resulted hypomethylated in spermatogonia and hypermethylated in sperm.	('seminoma', 'Disease', 'MESH:D018239', (26, 34))	('carcinoma in situ', 'Disease', 'MESH:D002278', (60, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('hypermethylated', 'Var', (231, 246))	('seminoma', 'Disease', (26, 34))	('carcinoma in situ', 'Disease', (60, 77))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (36, 55))	('embryonal carcinoma', 'Disease', (36, 55))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (60, 77))	('hypomethylated', 'Var', (195, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('Nanog', 'Gene', '79923', (79, 84))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (36, 55))	('Nanog', 'Gene', (79, 84))
63760	29416701	OCT3/4-SOX2 mediated expression of Nanog can be silenced by methylation of promoter CpG-sites.	('methylation', 'Var', (60, 71))	('Nanog', 'Gene', (35, 40))	('OCT3/4-SOX2', 'Gene', (0, 11))	('OCT3/4-SOX2', 'Gene', '6657;5460', (0, 11))	('expression', 'MPA', (21, 31))	('Nanog', 'Gene', '79923', (35, 40))	('silenced', 'NegReg', (48, 56))
63761	29416701	In humans, DNA methylation of distinct promoter elements (NRR) CpGs is able to epigenetically induce the silencing of Nanog, expression.	('methylation', 'Var', (15, 26))	('Nanog', 'Gene', '79923', (118, 123))	('men', 'Species', '9606', (51, 54))	('Nanog', 'Gene', (118, 123))	('induce', 'Reg', (94, 100))	('humans', 'Species', '9606', (3, 9))	('DNA', 'Var', (11, 14))	('silencing', 'MPA', (105, 114))
63763	29416701	Thus, in sperm and in adult testes NRR-hypermethylation could represent a tool by which NANOG expression could be epigenetically repress then controlling the pluripotency program and preventing germ cell malignancies.	('germ cell malignancies', 'Phenotype', 'HP:0100728', (194, 216))	('malignancies', 'Disease', (204, 216))	('NANOG', 'Gene', (88, 93))	('pluripotency', 'Disease', 'None', (158, 170))	('NANOG', 'Gene', '79923', (88, 93))	('preventing', 'NegReg', (183, 193))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('controlling', 'Reg', (142, 153))	('epigenetically', 'Var', (114, 128))	('pluripotency', 'Disease', (158, 170))
63765	29416701	Here, these changes in promoter methylation may inactivate PDE11A, SPRY4 and BAK1 and potentially activated KITLG and then the KIT pathway.	('SPRY4', 'Gene', (67, 72))	('KITLG', 'Pathway', (108, 113))	('activated', 'PosReg', (98, 107))	('SPRY4', 'Gene', '81848', (67, 72))	('BAK1', 'Gene', (77, 81))	('KIT pathway', 'Pathway', (127, 138))	('promoter methylation', 'MPA', (23, 43))	('PDE11A', 'Gene', (59, 65))	('PDE11A', 'Gene', '50940', (59, 65))	('inactivate', 'NegReg', (48, 58))	('changes', 'Var', (12, 19))	('BAK1', 'Gene', '578', (77, 81))
63769	29416701	Epigenetic modifications are also carried out in spermatogenesis by several members of the histone methyltranferases family (HMTs), which may mediate the dimethylation or trimethylation in histone 3 (H3) of lysine 9.	('carried', 'Reg', (34, 41))	('trimethylation', 'MPA', (171, 185))	('dimethylation', 'Var', (154, 167))	('lysine', 'Chemical', 'MESH:D008239', (207, 213))	('spermatogenesis', 'Disease', (49, 64))
63772	29416701	Interestingly, a p63 isoform (GTAp63), which is uniquely expressed in the testis of humans and great apes, is uniformly expressed in CIS cells, although a loss of expression, due to epigenetic regulation, has been observed in about 70-100% of all invasive tumour cells, leading to the hypothesis that in germ cells this protein may act as a tumour suppressor.	('p63', 'Gene', (17, 20))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('apes', 'Species', '4456', (101, 105))	('tumour', 'Disease', (256, 262))	('p63', 'Gene', '8626', (33, 36))	('humans', 'Species', '9606', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (341, 347))	('CIS', 'Phenotype', 'HP:0030075', (133, 136))	('p63', 'Gene', '8626', (17, 20))	('tumour', 'Disease', 'MESH:D009369', (341, 347))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('p63', 'Gene', (33, 36))	('epigenetic', 'Var', (182, 192))	('tumour', 'Disease', (341, 347))
63774	29416701	Furthermore, in carcinoma in situ low levels of repressive histone modifications at H3K9me2 and H3K27me3 along with high levels of H3K9 acetylation and H3K4 methylation exist.	('carcinoma in situ', 'Disease', 'MESH:D002278', (16, 33))	('carcinoma in situ', 'Disease', (16, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (16, 33))	('H3K27me3', 'Var', (96, 104))	('H3K4', 'Var', (152, 156))	('H3K9', 'Protein', (131, 135))	('H3K9me2', 'Protein', (84, 91))
63782	29416701	Frequently mutated in about half of all human cancers and functionally inactivated through non-genomic mechanisms in the remaining malignancies, the tumor suppressor p53 is not mutated in TGCTs, and is activated following exposure to chemotherapeutic agents, both events that have implications for the chemosensitivity of these tumors.	('malignancies', 'Disease', (131, 143))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumors', 'Disease', (328, 334))	('tumor', 'Disease', (328, 333))	('tumors', 'Disease', 'MESH:D009369', (328, 334))	('p53', 'Gene', '7157', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('activated', 'PosReg', (202, 211))	('inactivated', 'NegReg', (71, 82))	('human', 'Species', '9606', (40, 45))	('mutated', 'Var', (11, 18))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('p53', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (328, 334))	('tumor', 'Disease', (149, 154))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))
63783	29416701	Normal p53 activates two main distinct and mutually exclusive cellular programs, leading to apoptosis and to cell cycle arrest, respectively.	('activates', 'PosReg', (11, 20))	('apoptosis', 'CPA', (92, 101))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('p53', 'Gene', '7157', (7, 10))	('Normal', 'Var', (0, 6))	('leading', 'Reg', (81, 88))	('cell cycle arrest', 'CPA', (109, 126))	('p53', 'Gene', (7, 10))
63787	29416701	In TGCTs wild-type p53, whose silencing can completely abolish the sensitivity to cisplatin, decides between cell cycle arrest and apoptosis, leading to resistance and chemosensitivity, respectively.	('cell cycle', 'CPA', (109, 119))	('leading to', 'Reg', (142, 152))	('resistance', 'MPA', (153, 163))	('abolish', 'NegReg', (55, 62))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('p53', 'Gene', (19, 22))	('sensitivity to cisplatin', 'MPA', (67, 91))	('p53', 'Gene', '7157', (19, 22))	('chemosensitivity', 'MPA', (168, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('silencing', 'Var', (30, 39))
63791	29416701	Specific p53 modifications have been associated with the execution of apoptosis versus cell cycle arrest: the phosphorylation of p53 serine at position 46 by kinases DYRK2 and HIPK2 kinases, and the acetylation of two lysine residues K120 and K320 located in the DNA binding domain and in the tetramerization domain of p53, respectively, promote cell cycle arrest over apoptosis.	('serine', 'Chemical', 'MESH:D012694', (133, 139))	('p53', 'Gene', '7157', (9, 12))	('K320', 'Var', (243, 247))	('DYRK2', 'Gene', (166, 171))	('p53', 'Gene', (129, 132))	('HIPK2', 'Gene', '28996', (176, 181))	('p53', 'Gene', (319, 322))	('acetylation', 'MPA', (199, 210))	('K120', 'Var', (234, 238))	('lysine', 'Chemical', 'MESH:D008239', (218, 224))	('p53', 'Gene', (9, 12))	('phosphorylation', 'MPA', (110, 125))	('DYRK2', 'Gene', '8445', (166, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('cell cycle arrest', 'CPA', (346, 363))	('promote', 'PosReg', (338, 345))	('modifications', 'Var', (13, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (346, 363))	('p53', 'Gene', '7157', (129, 132))	('p53', 'Gene', '7157', (319, 322))	('HIPK2', 'Gene', (176, 181))
63810	29416701	Probably, in TGCTs the absence of p53 mutant deprives the respective cancer cells from several cancer promoting properties such as the ability to induce transcription from high affinity promoters (i.e.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('deprives', 'NegReg', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('absence', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (95, 101))	('transcription', 'MPA', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('induce', 'PosReg', (146, 152))	('cancer', 'Disease', (69, 75))
63812	29416701	The presence of p53 mutant has been proposed to enhance reprogramming of normal cells to pluripotent stem cells in the presence of Oct4 and Sox2.	('Sox2', 'Gene', (140, 144))	('reprogramming of normal cells', 'CPA', (56, 85))	('Oct4', 'Gene', '5460', (131, 135))	('p53', 'Gene', (16, 19))	('enhance', 'PosReg', (48, 55))	('Oct4', 'Gene', (131, 135))	('p53', 'Gene', '7157', (16, 19))	('Sox2', 'Gene', '6657', (140, 144))	('presence', 'Var', (4, 12))	('mutant', 'Var', (20, 26))
63813	29416701	Thus, in TGCTs, the absence of p53 mutations may be consistent with, or even imposed by, Oct4 (normally expressed in germ cell progenitors) (re)expression in order to support carcinogenesis by establishing the pro-survival embryonic network that is nowa typical feature of these tumors.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('Oct4', 'Gene', (89, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (175, 189))	('tumors', 'Disease', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('support', 'PosReg', (167, 174))	('carcinogenesis', 'Disease', (175, 189))	('Oct4', 'Gene', '5460', (89, 93))	('mutations', 'Var', (35, 44))
63816	29416701	Conversely, both mutations in p53 and loss of Oct4 expression lead to cisplatin resistance (Figure 1).	('Oct4', 'Gene', '5460', (46, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('loss', 'NegReg', (38, 42))	('p53', 'Gene', (30, 33))	('expression', 'MPA', (51, 61))	('lead to', 'Reg', (62, 69))	('cisplatin resistance', 'MPA', (70, 90))	('Oct4', 'Gene', (46, 50))	('p53', 'Gene', '7157', (30, 33))	('mutations', 'Var', (17, 26))
63832	29416701	DNA hypermethylation has been also strongly correlated with microsatellite instability and mutated BRAF V600E, two genetic anomalies often present in resistant tumors and linked to poor outcome.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('genetic anomalies', 'Disease', 'MESH:D030342', (115, 132))	('mutated', 'Var', (91, 98))	('BRAF', 'Gene', (99, 103))	('correlated', 'Reg', (44, 54))	('BRAF', 'Gene', '673', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('genetic anomalies', 'Disease', (115, 132))	('microsatellite instability', 'MPA', (60, 86))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
63833	29416701	Nevertheless, a different study have shown that no BRAF V600E mutations have been found in resistant TGCTs although other somatic mutations (PIK3CA, AKT1, KRAS, HRAS, FGFR3) have been identified in resistant TGCTs.	('HRAS', 'Gene', (161, 165))	('FGFR3', 'Gene', (167, 172))	('KRAS', 'Gene', (155, 159))	('HRAS', 'Gene', '3265', (161, 165))	('KRAS', 'Gene', '3845', (155, 159))	('V600E', 'Var', (56, 61))	('AKT1', 'Gene', '207', (149, 153))	('PIK3CA', 'Gene', (141, 147))	('BRAF', 'Gene', '673', (51, 55))	('AKT1', 'Gene', (149, 153))	('PIK3CA', 'Gene', '5290', (141, 147))	('FGFR3', 'Gene', '2261', (167, 172))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('BRAF', 'Gene', (51, 55))
63834	29416701	Interestingly, for the first time, FGFR3 is resulted as the most frequently mutated gene; however, the mutations occurring in FGFR3 have not been correlated to TGCTs cisplatin sensitivity or resistance.	('mutations', 'Var', (103, 112))	('correlated', 'Reg', (146, 156))	('FGFR3', 'Gene', (126, 131))	('FGFR3', 'Gene', '2261', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('FGFR3', 'Gene', (35, 40))	('FGFR3', 'Gene', '2261', (126, 131))
63835	29416701	On the contrary, all observed AKT1 and PIK3CA mutations resulted to be mutually exclusive and only present within cisplatin-resistant tumors.	('AKT1', 'Gene', '207', (30, 34))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('AKT1', 'Gene', (30, 34))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', '5290', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PIK3CA', 'Gene', (39, 45))
63839	29416701	OCT4 and microRNA-106b alter the cytoplasmic p21 expression since their high expression level is correlated with p21 low expression, offering in turn a greater sensitivity to cisplatin-based therapy in testicular cancers.	('microRNA-106b', 'Var', (9, 22))	('testicular cancers', 'Disease', 'MESH:D013736', (202, 220))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('p21', 'Gene', (45, 48))	('p21', 'Gene', '644914', (45, 48))	('sensitivity to cisplatin-based therapy', 'MPA', (160, 198))	('testicular cancers', 'Disease', (202, 220))	('testicular cancers', 'Phenotype', 'HP:0010788', (202, 220))	('testicular cancer', 'Phenotype', 'HP:0010788', (202, 219))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('greater', 'PosReg', (152, 159))	('expression level', 'MPA', (77, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('OCT4', 'Gene', '5460', (0, 4))	('p21', 'Gene', (113, 116))	('OCT4', 'Gene', (0, 4))	('p21', 'Gene', '644914', (113, 116))
63846	29416701	In fact, phospho-AKT levels (serine 473 or threonine 308) are greater in cisplatin-resistant cells than in normal cells, whereas there are no differences in total AKT protein levels between normal and cisplatin-resistant cells.	('AKT', 'Gene', (17, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('greater', 'PosReg', (62, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('AKT', 'Gene', (163, 166))	('threonine', 'Chemical', 'MESH:D013912', (43, 52))	('AKT', 'Gene', '207', (17, 20))	('serine', 'Chemical', 'MESH:D012694', (29, 35))	('cisplatin-resistant', 'Var', (73, 92))	('AKT', 'Gene', '207', (163, 166))
63854	29416701	As a result of PI3K activation, AKT phosphorylation takes place, ultimately leading to phosphorylation and activation of MDM2, and phosphorylation of p21, which thereby gets cytoplasmically translocated inducing cell cycle arrest and then protecting cancer cells from cisplatin-induced apoptosis.	('p21', 'Gene', '644914', (150, 153))	('AKT', 'Gene', '207', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cisplatin', 'Chemical', 'MESH:D002945', (268, 277))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('AKT', 'Gene', (32, 35))	('cell cycle arrest', 'CPA', (212, 229))	('activation', 'PosReg', (20, 30))	('p21', 'Gene', (150, 153))	('phosphorylation', 'MPA', (131, 146))	('phosphorylation', 'MPA', (87, 102))	('PI3K', 'Var', (15, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (212, 229))	('MDM2', 'Gene', '4193', (121, 125))	('activation', 'PosReg', (107, 117))	('MDM2', 'Gene', (121, 125))
63860	29416701	Its knockdown may negatively impact on cell growth by increasing genomic instability, thus triggering p53-dependent DNA damage response pathway and leading to cell cycle arrest and eventually to DNA repair or, alternatively, to cell death, depending on the damage intensity.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (159, 176))	('DNA damage response pathway', 'Pathway', (116, 143))	('triggering', 'Reg', (91, 101))	('increasing', 'PosReg', (54, 64))	('leading to', 'Reg', (148, 158))	('p53', 'Gene', '7157', (102, 105))	('cell cycle arrest', 'CPA', (159, 176))	('genomic instability', 'MPA', (65, 84))	('death', 'Disease', (233, 238))	('death', 'Disease', 'MESH:D003643', (233, 238))	('p53', 'Gene', (102, 105))	('knockdown', 'Var', (4, 13))	('impact', 'Reg', (29, 35))	('cell', 'CPA', (228, 232))
63864	29416701	Genetic and epigenetic events, along with environmental factors, play an important role in testicular cancer initiation and development.	('testicular cancer initiation', 'Disease', 'MESH:D013736', (91, 119))	('men', 'Species', '9606', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epigenetic events', 'Var', (12, 29))	('testicular cancer', 'Phenotype', 'HP:0010788', (91, 108))	('men', 'Species', '9606', (131, 134))	('Genetic', 'Var', (0, 7))	('development', 'CPA', (124, 135))	('testicular cancer initiation', 'Disease', (91, 119))
63908	28000896	cDNA was synthesized from 20 ng of total RNA and used to quantify miR-223-3p (ID 002295) and RNU48 (ID 001093).	('RNU48', 'Gene', '26801', (93, 98))	('miR-223', 'Gene', (66, 73))	('ID 001093', 'Var', (100, 109))	('ID 002295', 'Var', (78, 87))	('miR-223', 'Gene', '407008', (66, 73))	('RNU48', 'Gene', (93, 98))
63910	28000896	For miR-223 overexpression and inhibition, 2x105 cells were transfected with 30 nM of miRNA inhibitor (anti-miR-223, AM12301 or anti-miR negative control no.	('miR', 'Gene', '220972', (133, 136))	('miR', 'Gene', (133, 136))	('AM12301', 'Var', (117, 124))	('miR', 'Gene', (4, 7))	('miR-223', 'Gene', (4, 11))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('miR-223', 'Gene', (108, 115))	('miR', 'Gene', '220972', (4, 7))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('miR-223', 'Gene', '407008', (4, 11))	('miR-223', 'Gene', '407008', (108, 115))
63911	28000896	1, AM17010; Ambion) or 10 nM of miRNA mimic (pre-miR-223, PM12301 or pre-miR negative control no.	('miR', 'Gene', (32, 35))	('miR-223', 'Gene', (49, 56))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '220972', (32, 35))	('miR', 'Gene', '220972', (73, 76))	('miR-223', 'Gene', '407008', (49, 56))	('miR', 'Gene', (73, 76))	('AM17010', 'Var', (3, 10))	('PM12301', 'Var', (58, 65))
63922	28000896	70166; Sigma-Aldrich) in Tris-buffered saline/0.05% Tween-20, membranes were incubated with anti-FBXW7 (NBP1-59631; Novus Biologicals, Littleton, CO, USA; 1:1,000 dilution), anti-cleaved PARP (ab32064; Abcam, Cambridge, UK; 1:1,000 dilution) or anti-Myc-Tag (no.	('NBP1', 'Gene', (104, 108))	('Myc', 'Gene', (250, 253))	('Myc', 'Gene', '4609', (250, 253))	('PARP', 'Gene', '142', (187, 191))	('anti-cleaved', 'Var', (174, 186))	('PARP', 'Gene', (187, 191))	('NBP1', 'Gene', '4682', (104, 108))
63943	28000896	For the cPARP detection, silencing of miR-223-3p led to a significant increase of cPARP expression in both TCam-2 (1.6-fold, P=0.003) and 2102Ep (1.3-fold, P=0.007) cells, while overexpressing miR-223-3p resulted in a significant decrease of cPARP expression (TCam-2: 0.7-fold, P=0.016; 2102Ep: 0.8-fold, P=0.002) (Fig.	('silencing', 'Var', (25, 34))	('PARP', 'Gene', '142', (83, 87))	('miR-223', 'Gene', '407008', (38, 45))	('PARP', 'Gene', (243, 247))	('increase', 'PosReg', (70, 78))	('TCam', 'Chemical', '-', (107, 111))	('miR-223', 'Gene', '407008', (193, 200))	('PARP', 'Gene', '142', (9, 13))	('PARP', 'Gene', (83, 87))	('miR-223', 'Gene', (38, 45))	('decrease', 'NegReg', (230, 238))	('PARP', 'Gene', '142', (243, 247))	('TCam', 'Chemical', '-', (260, 264))	('miR-223', 'Gene', (193, 200))	('expression', 'MPA', (88, 98))	('PARP', 'Gene', (9, 13))
63948	28000896	The WST-1 assay also showed that silencing of miR-223-3p reduced cell growth at 72-h post-transfection in both TCam-2 (P=0.043) and 2102Ep (P=0.041) cells (Fig.	('TCam', 'Chemical', '-', (111, 115))	('miR-223', 'Gene', '407008', (46, 53))	('silencing', 'Var', (33, 42))	('cell growth at 72-h post-transfection', 'CPA', (65, 102))	('reduced', 'NegReg', (57, 64))	('miR-223', 'Gene', (46, 53))
63971	28000896	Furthermore, numerous cancer-associated mutations in FBXW7 have been found in many cancer types, and loss of FBXW7 function can lead to chromosomal instability and tumorigenesis.	('chromosomal instability', 'Phenotype', 'HP:0040012', (136, 159))	('tumor', 'Disease', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('numerous cancer', 'Disease', (13, 28))	('loss', 'Var', (101, 105))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('chromosomal', 'MPA', (136, 147))	('FBXW7', 'Gene', (53, 58))	('FBXW7', 'Gene', (109, 114))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lead to', 'Reg', (128, 135))	('numerous cancer', 'Disease', 'MESH:D009369', (13, 28))	('function', 'MPA', (115, 123))	('cancer', 'Disease', (83, 89))
64038	19440348	Though the mechanism that mediates these effects is not well understood, some investigators propose that EES not only interferes in the normal testis endocrine directly but also disrupts the hypothalamic-pituitary-testis axis, resulting in abnormal function of sertoli cells; this disruption impairs germ cell differentiation and the germ cells are subsequently transformed to develop into carcinoma in situ (CIS).	('carcinoma in situ', 'Disease', 'MESH:D002278', (390, 407))	('function', 'MPA', (249, 257))	('hypothalamic-pituitary-testis axis', 'Disease', 'MESH:D007029', (191, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('develop', 'PosReg', (377, 384))	('disrupts', 'NegReg', (178, 186))	('hypothalamic-pituitary-testis axis', 'Disease', (191, 225))	('disruption', 'Var', (281, 291))	('carcinoma in situ', 'Disease', (390, 407))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (390, 407))	('germ cell differentiation', 'CPA', (300, 325))	('impairs', 'NegReg', (292, 299))	('sertoli cells', 'Phenotype', 'HP:0100619', (261, 274))
64042	19440348	The "gr/gr" (carries a number of genes specifically involved in male germ cell development) deletion in the Y chromosome has been found to be associated with subfertility and TGCT.	('TGCT', 'Disease', (175, 179))	('men', 'Species', '9606', (86, 89))	('deletion', 'Var', (92, 100))	('associated', 'Reg', (142, 152))	('subfertility', 'Disease', (158, 170))
64043	19440348	found that the Ter mutation in the dead end gene (Dnd1) causes primordial germ cell (PGCs) loss and TGCTs, and loss of PGCs precedes development of embryonal carcinoma cells in 129-Ter/Ter mouse embryos.	('men', 'Species', '9606', (140, 143))	('mouse', 'Species', '10090', (189, 194))	('loss', 'Var', (111, 115))	('Dnd1', 'Gene', (50, 54))	('Dnd1', 'Gene', '213236', (50, 54))	('TGCTs', 'CPA', (100, 105))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (148, 167))	('embryonal carcinoma', 'Disease', (148, 167))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (148, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('loss', 'NegReg', (91, 95))
64044	19440348	Therefore, inactivation of Dnd1 expression is implicated as the causal event that drives PGCs to exit the germ line and transform to embryonal carcinoma cells and TGCTs in 129-Ter/Ter mice.	('embryonal carcinoma', 'Disease', (133, 152))	('inactivation', 'Var', (11, 23))	('drives', 'Reg', (82, 88))	('Dnd1', 'Gene', (27, 31))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (133, 152))	('Dnd1', 'Gene', '213236', (27, 31))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (133, 152))	('mice', 'Species', '10090', (184, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))
64048	19440348	Testicular cancer has a complex etiology; environmental factors and genetic mutations both contribute to the increased risk of developing testicular cancer.	('men', 'Species', '9606', (49, 52))	('testicular cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Testicular cancer', 'Disease', (0, 17))	('genetic mutations', 'Var', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('testicular cancer', 'Phenotype', 'HP:0010788', (138, 155))	('Testicular cancer', 'Disease', 'MESH:D013736', (0, 17))	('Testicular cancer', 'Phenotype', 'HP:0010788', (0, 17))	('testicular cancer', 'Disease', 'MESH:D013736', (138, 155))
64055	12966440	Nord et al has suggested that after chemotherapy, there is a higher annual increase of BMI in chemotherapy patients compared to controls.	('BMI', 'MPA', (87, 90))	('increase of BMI', 'Phenotype', 'HP:0031418', (75, 90))	('chemotherapy', 'Var', (94, 106))	('increase', 'PosReg', (75, 83))	('patients', 'Species', '9606', (107, 115))
64061	12966440	In support of this is the observation that patients treated with radiotherapy, who have an age at follow-up similar to controls, have a similar rate of increase of BMI to controls (Nord et al, Figure 1A).	('increase', 'PosReg', (152, 160))	('patients', 'Species', '9606', (43, 51))	('increase of BMI', 'Phenotype', 'HP:0031418', (152, 167))	('radiotherapy', 'Var', (65, 77))	('BMI', 'MPA', (164, 167))
64066	12966440	In total, 88% of patients with low testosterone have a BMI in the overweight range (>=25 kg m-2) compared to 58% of those with normal testosterone (Figure 2).	('testosterone', 'Chemical', 'MESH:D013739', (134, 146))	('testosterone', 'Chemical', 'MESH:D013739', (35, 47))	('low testosterone', 'Phenotype', 'HP:0040171', (31, 47))	('testosterone', 'Gene', (35, 47))	('patients', 'Species', '9606', (17, 25))	('overweight', 'Phenotype', 'HP:0025502', (66, 76))	('low', 'Var', (31, 34))	('BMI', 'MPA', (55, 58))
64071	33805941	A working model is developed that postulates that epigenetic features that drive testicular cancer malignancy also enable these tumors to be cured at a high rate with chemotherapy.	('testicular cancer malignancy', 'Disease', (81, 109))	('testicular cancer', 'Phenotype', 'HP:0010788', (81, 98))	('epigenetic features', 'Var', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('testicular cancer malignancy', 'Disease', 'MESH:D013736', (81, 109))
64072	33805941	Chemoresistance may occur by epigenetic uncoupling of malignancy and chemosensitivity, a scenario that may be amenable to epigenetic-based therapies.	('occur', 'Reg', (20, 25))	('men', 'Species', '9606', (111, 114))	('epigenetic uncoupling', 'Var', (29, 50))	('Chemoresistance', 'CPA', (0, 15))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('malignancy', 'Disease', (54, 64))
64075	33805941	In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy.	('past', 'Gene', (7, 11))	('epigenetics', 'Var', (62, 73))	('past', 'Gene', '10938', (7, 11))	('hypersensitivity', 'Disease', 'MESH:D004342', (147, 163))	('TGCT', 'Disease', (115, 119))	('hypersensitivity', 'Disease', (147, 163))
64098	33805941	In this mini-review, we summarize the main epigenetic features of testicular cancer, with a focus on DNA methylation, histone modifications, and miRNAs and their involvement in testicular carcinogenesis and response to chemotherapy.	('involvement', 'Reg', (162, 173))	('methylation', 'Var', (105, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('men', 'Species', '9606', (169, 172))	('carcinogenesis', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('modifications', 'Var', (126, 139))	('testicular cancer', 'Phenotype', 'HP:0010788', (66, 83))
64114	33805941	Genome-wide sequencing indicates secondary somatic gain/amplification of 12p in the majority of patients with gain in 12q, 8q, 22q, and deletion/loss of 11q, 18q, 18p, 9p, 4q, 10q, 5q, 16q, and 19q also occurring with much less frequency.	('deletion/loss', 'Var', (136, 149))	('gain/amplification', 'PosReg', (51, 69))	('12q', 'Var', (118, 121))	('gain', 'PosReg', (110, 114))	('18p', 'Var', (163, 166))	('patients', 'Species', '9606', (96, 104))
64117	33805941	Specific somatic mutations or amplifications in tumor DNA have been identified in a few genes, but only KIT, KRAS, and NRAS have been implicated repeatedly in different studies, mostly in seminomas.	('amplifications', 'Var', (30, 44))	('KIT', 'Gene', (104, 107))	('tumor', 'Disease', (48, 53))	('implicated', 'Reg', (134, 144))	('NRAS', 'Gene', (119, 123))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))	('NRAS', 'Gene', '4893', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('KIT', 'Gene', '3815', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('seminomas', 'Disease', 'MESH:D018239', (188, 197))	('seminomas', 'Disease', (188, 197))
64120	33805941	Other rare inherited germline inactivating PDE11A variants are most likely associated with TGCTs of young adults.	('PDE11A', 'Gene', (43, 49))	('TGCTs', 'Disease', (91, 96))	('variants', 'Var', (50, 58))	('associated', 'Reg', (75, 85))	('PDE11A', 'Gene', '50940', (43, 49))
64123	33805941	Interestingly, some studies have explored the potential association of TGCTs with inherited single nucleotide polymorphisms of the androgen receptor (AR), the estrogen receptors (ER) and genes involved in either synthesis or degradation of gonadal hormones.	('androgen receptor', 'Gene', (131, 148))	('AR', 'Gene', '367', (150, 152))	('TGCTs', 'Disease', (71, 76))	('association', 'Interaction', (56, 67))	('androgen receptor', 'Gene', '367', (131, 148))	('single nucleotide polymorphisms', 'Var', (92, 123))	('ER', 'Gene', '2069', (179, 181))
64124	33805941	It is important to remember that potential epigenetic disruptions may not necessarily target PGCs/gonocytes directly but may alter the epigenetic state of the somatic cells of the testis, Leydig and Sertoli cells which produce growth factors and hormones necessary to maintain the proper micro-environment during spermatogenesis.	('Sertoli cells', 'Phenotype', 'HP:0100619', (199, 212))	('men', 'Species', '9606', (301, 304))	('epigenetic disruptions', 'Var', (43, 65))	('epigenetic state', 'MPA', (135, 151))	('alter', 'Reg', (125, 130))
64125	33805941	Thus, from an epigenetic-centric view, epigenetic perturbations that arrest PGC/gonocyte differentiation leading to tumorigenic prone states are dominant events downstream of the many risk factors outlined in this section including environmental exposures, inheritable genetic factors and developmental reproductive disorders predicted to alter the microenvironment of the developing germ cell (Figure 1).	('men', 'Species', '9606', (296, 299))	('arrest PGC', 'Disease', (69, 79))	('epigenetic', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('arrest PGC', 'Disease', 'MESH:D006323', (69, 79))	('men', 'Species', '9606', (361, 364))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('men', 'Species', '9606', (239, 242))	('tumor', 'Disease', (116, 121))	('reproductive disorders', 'Phenotype', 'HP:0000078', (303, 325))
64128	33805941	This at least suggests that an epigenetic mediated tumorigenic state or states may be the true driver of TGCTs.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('epigenetic mediated', 'Var', (31, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
64133	33805941	Perhaps the most convincing mechanism for TGCT resistance due to acquired mutation is mutation of p53 or p53 compromised by increased MDM2 copy number.	('mutation', 'Var', (74, 82))	('MDM2', 'Gene', '4193', (134, 138))	('MDM2', 'Gene', (134, 138))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('p53', 'Gene', (98, 101))	('mutation', 'Var', (86, 94))	('TGCT resistance', 'MPA', (42, 57))	('p53', 'Gene', '7157', (98, 101))
64136	33805941	While genetic alterations in the p53 pathway do occur in cisplatin resistant cell models and in patients, the percentage is low and does not appear to explain the majority of cisplatin resistant disease.	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('patients', 'Species', '9606', (96, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('genetic alterations', 'Var', (6, 25))
64141	33805941	Again, the argument has been that alterations mostly in the levels of DNA repair and DNA damage response (DDR) pathway components and not common genetic mutations result in either more efficient DNA repair or increased tolerance to DNA damage in cisplatin refractory TGCT cells.	('DNA repair', 'MPA', (195, 205))	('men', 'Species', '9606', (15, 18))	('tolerance to DNA damage', 'MPA', (219, 242))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('increased', 'PosReg', (209, 218))	('alterations', 'Var', (34, 45))	('more', 'PosReg', (180, 184))
64147	33805941	Distinct epigenetic states have also been associated with subtype identity and cisplatin resistance in TGCTs.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('associated', 'Reg', (42, 52))	('epigenetic states', 'Var', (9, 26))	('cisplatin resistance', 'MPA', (79, 99))	('TGCTs', 'Disease', (103, 108))
64153	33805941	Experimentally induced differentiation of (embryonal carcinoma (EC) cells by retinoic acid or depletion of OCT4 also results in cisplatin resistance, further suggesting a tight link between pluripotency and chemosensitivity of TGCTs.	('OCT4', 'Gene', '5460', (107, 111))	('OCT4', 'Gene', (107, 111))	('retinoic acid', 'Chemical', 'MESH:D014212', (77, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cisplatin resistance', 'MPA', (128, 148))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (43, 62))	('results in', 'Reg', (117, 127))	('depletion', 'Var', (94, 103))	('men', 'Species', '9606', (6, 9))
64155	33805941	There have also been studies demonstrating epigenetic mediated conversion of seminoma to nonseminoma in a seminoma cell line xenograft.	('nonseminoma', 'Disease', 'None', (89, 100))	('seminoma', 'Disease', (92, 100))	('seminoma', 'Disease', (77, 85))	('conversion', 'Reg', (63, 73))	('seminoma', 'Disease', (106, 114))	('epigenetic mediated', 'Var', (43, 62))	('seminoma', 'Disease', 'MESH:D018239', (92, 100))	('seminoma', 'Disease', 'MESH:D018239', (77, 85))	('nonseminoma', 'Disease', (89, 100))	('seminoma', 'Disease', 'MESH:D018239', (106, 114))
64160	33805941	DNA methylation is the most studied epigenetic mark in TGCTs and there is relatively strong evidence that DNA methylation is differentially distributed among the histologically distinct subtypes of TGCTs and among cisplatin sensitive and resistant tumors.	('TGCTs', 'Disease', (198, 203))	('distributed', 'Reg', (140, 151))	('DNA', 'Gene', (106, 109))	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('methylation', 'Var', (110, 121))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
64167	33805941	Methylome studies in TGCTs have shown that GCNIS, seminomas and nonseminomas are consistently demethylated in repetitive LINE1 elements and at imprinted genes and the XIST locus.	('XIST', 'Gene', '7503', (167, 171))	('XIST', 'Gene', (167, 171))	('seminomas and nonseminomas', 'Disease', 'MESH:D018239', (50, 76))	('GCNIS', 'Disease', (43, 48))	('demethylated', 'Var', (94, 106))	('men', 'Species', '9606', (130, 133))
64168	33805941	GCNIS and seminomas are also demethylated at ALU elements while ALU elements are partially methylated in nonseminoma.	('seminomas', 'Disease', (10, 19))	('ALU', 'Chemical', '-', (45, 48))	('nonseminoma', 'Disease', 'None', (105, 116))	('men', 'Species', '9606', (52, 55))	('seminomas', 'Disease', 'MESH:D018239', (10, 19))	('men', 'Species', '9606', (71, 74))	('nonseminoma', 'Disease', (105, 116))	('ALU', 'Chemical', '-', (64, 67))	('GCNIS', 'Disease', (0, 5))	('demethylated', 'Var', (29, 41))
64170	33805941	This includes evidence that methylation of such genes as CRIPTO, HOXA9 MGMT, RASSFIA, SCGB3A1, CALCA, MMP9, CSFR1, and PTPRC is associated with distinct TGCT subtypes or poor prognosis.	('CALCA', 'Gene', (95, 100))	('PTPRC', 'Gene', (119, 124))	('HOXA9', 'Gene', '3205', (65, 70))	('SCGB3A1', 'Gene', '92304', (86, 93))	('CALCA', 'Gene', '796', (95, 100))	('MMP9', 'Gene', '4318', (102, 106))	('CSFR1', 'Gene', (108, 113))	('HOXA9', 'Gene', (65, 70))	('CRIPTO', 'Gene', (57, 63))	('PTPRC', 'Gene', '5788', (119, 124))	('MGMT', 'Gene', '4255', (71, 75))	('methylation', 'Var', (28, 39))	('associated', 'Reg', (128, 138))	('MGMT', 'Gene', (71, 75))	('TGCT', 'Disease', (153, 157))	('MMP9', 'Gene', (102, 106))	('CRIPTO', 'Gene', '6998', (57, 63))	('SCGB3A1', 'Gene', (86, 93))
64171	33805941	There is evidence to suggest that hypermethylation of TGCTs especially EC and other nonseminoma subtypes may be associated with cisplatin resistance.	('hypermethylation', 'Var', (34, 50))	('nonseminoma subtypes', 'Disease', 'MESH:C535673', (84, 104))	('nonseminoma subtypes', 'Disease', (84, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cisplatin resistance', 'MPA', (128, 148))	('TGCTs', 'Protein', (54, 59))	('associated', 'Reg', (112, 122))
64173	33805941	Additionally, cisplatin treatment has been shown to be associated with increased DNA methylation in vivo.	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('DNA methylation', 'MPA', (81, 96))	('cisplatin', 'Var', (14, 23))	('men', 'Species', '9606', (29, 32))	('increased', 'PosReg', (71, 80))
64178	33805941	In the epigenetic centric view, the unique epigenetic states of TGCTs may not only be responsible for tumorigenicity and chemosensitivity but may also be exploitable as therapeutic targets.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('epigenetic', 'Var', (43, 53))	('responsible', 'Reg', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('TGCTs', 'Gene', (64, 69))
64179	33805941	We and others have shown that EC cells are hypersensitive to the DNA methyltransferase inhibitors decitabine, azacytidine, guadecitabine, and MLo1302 in vitro and in vivo compared to somatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('MLo1302', 'Var', (142, 149))	('azacytidine', 'Chemical', 'MESH:D001374', (110, 121))	('guadecitabine', 'Chemical', 'MESH:C580831', (123, 136))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('decitabine', 'Chemical', 'MESH:D000077209', (98, 108))	('tumors', 'Disease', (191, 197))	('decitabine', 'Chemical', 'MESH:D000077209', (126, 136))	('MLo1302', 'Chemical', '-', (142, 149))
64190	33805941	Apart from HDAC inhibitors, EC and seminoma cells are also sensitive to the bromodomain inhibitor JQ1 and inhibitors of LSD1, a H3K4 demethylase.	('seminoma', 'Disease', 'MESH:D018239', (35, 43))	('seminoma', 'Disease', (35, 43))	('inhibitors', 'Var', (106, 116))	('LSD1', 'Gene', (120, 124))	('LSD1', 'Gene', '23028', (120, 124))
64192	33805941	We showed by RNA-seq and gene set enrichment analysis that a panel of isogenic cisplatin resistant EC lines have a dramatic enrichment in genes normally repressed by H3K27me3 and the polycomb repressive complex which correlated with a substantial decrease in global H3K27me3 and decreased expression of EZH2 and BMI1.	('men', 'Species', '9606', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('EZH2', 'Gene', '2146', (303, 307))	('decrease', 'NegReg', (247, 255))	('BMI1', 'Gene', '648', (312, 316))	('decreased', 'NegReg', (279, 288))	('BMI1', 'Gene', (312, 316))	('EZH2', 'Gene', (303, 307))	('men', 'Species', '9606', (40, 43))	('expression', 'MPA', (289, 299))	('global', 'MPA', (259, 265))	('H3K27me3', 'Var', (166, 174))
64193	33805941	Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSKJ4 resulted in increased cisplatin sensitivity to resistant cells, suggesting that the polycomb pathway is involved in the regulation of cisplatin sensitivity of TGCT cells.	('EZH2', 'Gene', (54, 58))	('methylation', 'Var', (33, 44))	('cisplatin sensitivity', 'MPA', (236, 257))	('conferred', 'Reg', (76, 85))	('cisplatin resistance', 'MPA', (86, 106))	('repression', 'NegReg', (13, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (348, 357))	('GSK126', 'Chemical', 'MESH:C577920', (69, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('EZH2', 'Gene', '2146', (54, 58))	('increased', 'PosReg', (226, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('GSKJ4', 'Chemical', 'MESH:C000593030', (208, 213))	('H3K27', 'Protein', (27, 32))
64194	33805941	As stated above, follow up analysis of these cisplatin resistant models suggest the same polycomb target genes are coordinately regulated by both H3K27 methylation and DNA methylation.	('H3K27', 'Protein', (146, 151))	('regulated', 'Reg', (128, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('DNA methylation', 'Var', (168, 183))	('methylation', 'Var', (152, 163))
64195	33805941	In summary, studies on epigenetic targeting of TGCTs suggest that tumorigenicity in this pluripotent, germ cell context may be especially vulnerable to epigenetic alterations compared to somatic cancers.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('epigenetic', 'Var', (152, 162))	('tumor', 'Disease', (66, 71))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('TGCTs', 'Gene', (47, 52))	('cancers', 'Disease', (195, 202))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
64206	33805941	The most common pathway is apoptotic death due to the increased chemosensitivity directly attributed to the epigenetic state.	('epigenetic', 'Var', (108, 118))	('death', 'Disease', (37, 42))	('chemosensitivity', 'MPA', (64, 80))	('increased', 'PosReg', (54, 63))	('death', 'Disease', 'MESH:D003643', (37, 42))
64221	33805941	In this review we have tried to make the case that epigenetics are exceptionally key drivers of TGCT biology compared to other more common somatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('epigenetics', 'Var', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))
64242	24639669	Recently, an association of polymorphic variants in genes encoding for ESR1, ESR2, and LH receptors with TGCC risk and metastasis has been demonstrated.	('LH', 'Chemical', 'MESH:D007986', (87, 89))	('association', 'Interaction', (13, 24))	('rat', 'Species', '10116', (146, 149))	('polymorphic variants', 'Var', (28, 48))	('ESR2', 'Gene', (77, 81))	('metastasis', 'CPA', (119, 129))	('ESR1', 'Gene', (71, 75))	('TGCC', 'Disease', (105, 109))
64271	24639669	Esr1 KO (alphaERKO) animals have reduced fertility because of abnormal fluid reabsorption in the efferent ductules, whereas in Esr2 KO (betaERKO) animals, spermatogenesis, steroidogenesis, and fertility were initially found unaffected.	('fluid reabsorption in the efferent ductules', 'MPA', (71, 114))	('steroid', 'Chemical', 'MESH:D013256', (172, 179))	('abnormal fluid', 'Phenotype', 'HP:0011032', (62, 76))	('Esr2 KO', 'Var', (127, 134))	('Esr1', 'Gene', (0, 4))	('fertility', 'CPA', (41, 50))	('reduced fertility', 'Phenotype', 'HP:0000144', (33, 50))	('reduced', 'NegReg', (33, 40))	('fluid reabsorption', 'Phenotype', 'HP:0005579', (71, 89))	('Esr1', 'Gene', '13982', (0, 4))
64282	24639669	In fact, c-fos up-regulation and ERK1/2 activation by estradiol or by selective agonists for ESR1 (PPT) or GPER (G-1) were overcome by the presence of the pure ESR1 antagonist ICI 182780, or by GPER gene silencing.	('ERK1/2', 'Enzyme', (33, 39))	('up-regulation', 'PosReg', (15, 28))	('PPT', 'Gene', (99, 102))	('gene silencing', 'Var', (199, 213))	('ICI', 'Chemical', '-', (176, 179))	('activation', 'PosReg', (40, 50))	('c-fos', 'Gene', '2353', (9, 14))	('estradiol', 'Chemical', 'MESH:D004958', (54, 63))	('c-fos', 'Gene', (9, 14))	('PPT', 'Gene', '6863', (99, 102))
64288	24639669	Particularly, in RS, estrogen through a functional cross-talk between GPER and ESR1 is able to activate EGFR/ERK pathway involved in the transcriptional modulation of genes controlling apoptosis and differentiation such as cyclin B1 and bax.	('RS', 'Phenotype', 'HP:0032560', (17, 19))	('cyclin B1', 'Gene', '891', (223, 232))	('cyclin B1', 'Gene', (223, 232))	('ESR1', 'Gene', (79, 83))	('EGFR/ERK pathway', 'Pathway', (104, 120))	('activate', 'PosReg', (95, 103))	('bax', 'Gene', (237, 240))	('cross-talk', 'Var', (51, 61))
64296	24639669	In addition, another interesting aspect is that genomic and rapid pathway can work independently but cooperate to reach the same goal as evidenced in Sertoli cells where E2-genomic action on cyclin D1 induces proliferation while E2 rapid action through GPER activates anti-apoptotic signals.	('proliferation', 'CPA', (209, 222))	('E2-genomic', 'Var', (170, 180))	('E2', 'Chemical', 'MESH:D004958', (170, 172))	('E2', 'Chemical', 'MESH:D004958', (229, 231))	('cyclin', 'Gene', (191, 197))	('Sertoli cell', 'Phenotype', 'HP:0100619', (150, 162))	('Sertoli cells', 'Phenotype', 'HP:0100619', (150, 163))	('induces', 'PosReg', (201, 208))	('rat', 'Species', '10116', (106, 109))	('anti-apoptotic signals', 'MPA', (268, 290))	('rat', 'Species', '10116', (216, 219))	('activates', 'PosReg', (258, 267))
64299	24639669	Recently, it has been reported that polymorphisms in ESR1, ESR2, and luteinizing-hormone-releasing hormone (LHRH) genes were linked to TGCC risk and metastasis occurrence.	('luteinizing-hormone-releasing hormone', 'Gene', (69, 106))	('LHRH', 'Gene', '2796', (108, 112))	('linked', 'Reg', (125, 131))	('LHRH', 'Gene', (108, 112))	('polymorphisms', 'Var', (36, 49))	('luteinizing-hormone-releasing hormone', 'Gene', '2796', (69, 106))	('metastasis occurrence', 'CPA', (149, 170))	('ESR2', 'Gene', (59, 63))	('TGCC', 'Disease', (135, 139))	('ESR1', 'Gene', (53, 57))
64300	24639669	In particular, two ESR2 and LHRH genetic variants were related to TGCC-reduced risk, while one polymorphism in ESR1 or LHCGR (LH/choriogonadotropin receptor) gene was associated with an increased risk for TGCC.	('variants', 'Var', (41, 49))	('ESR2', 'Gene', (19, 23))	('LHRH', 'Gene', (28, 32))	('LHCGR', 'Gene', (119, 124))	('ESR1', 'Gene', (111, 115))	('LH/choriogonadotropin receptor', 'Gene', (126, 156))	('TGCC', 'Disease', (205, 209))	('LHCGR', 'Gene', '3973', (119, 124))	('associated', 'Reg', (167, 177))	('TGCC-reduced', 'Disease', (66, 78))	('LHRH', 'Gene', '2796', (28, 32))	('LH/choriogonadotropin receptor', 'Gene', '3973', (126, 156))
64304	24639669	Thus, polymorphisms in genes encoding ESR2 and LHRH may influence the sensitivity of these cells to estradiol- and LH-mediated effects and influence TGCC development.	('LH', 'Chemical', 'MESH:D007986', (115, 117))	('influence', 'Reg', (139, 148))	('ESR2', 'Gene', (38, 42))	('TGCC development', 'CPA', (149, 165))	('polymorphisms', 'Var', (6, 19))	('estradiol', 'Chemical', 'MESH:D004958', (100, 109))	('sensitivity', 'MPA', (70, 81))	('LHRH', 'Gene', '2796', (47, 51))	('LH', 'Chemical', 'MESH:D007986', (47, 49))	('influence', 'Reg', (56, 65))	('LHRH', 'Gene', (47, 51))	('men', 'Species', '9606', (161, 164))
64307	24639669	Noteworthy, a polymorphism in ESR1 identified by Brokken and coworkers is associated with higher levels of LH in healthy control subjects, indicating that levels of gonadotropins influence the progression of CIS to either SE or NSE.	('ESR1', 'Gene', (30, 34))	('CIS', 'Phenotype', 'HP:0030075', (208, 211))	('polymorphism', 'Var', (14, 26))	('influence', 'Reg', (179, 188))	('levels', 'MPA', (97, 103))	('SE', 'Disease', 'None', (222, 224))	('SE', 'Disease', 'None', (229, 231))	('higher', 'PosReg', (90, 96))	('LH', 'Chemical', 'MESH:D007986', (107, 109))
64320	24639669	It has been reported in some models that GPER and ERs (ESR1/ESR2) or truncated splice variant of ERs could either cooperate or cross-talk.	('rat', 'Species', '10116', (119, 122))	('truncated splice variant', 'Var', (69, 93))	('cross-talk', 'Reg', (127, 137))	('ER', 'Gene', '2099', (97, 99))	('ER', 'Gene', '2099', (50, 52))	('ER', 'Gene', '2099', (43, 45))
64322	24639669	In addition, using RNAi silencing and G15, a selective GPER antagonist, the involvement of GPER in xenoestrogen-, bisphenol A-, and E2 coupled to bovine serum albumin (E2-BSA)-induced JKT-1 cell proliferation was definitively demonstrated.	('men', 'Species', '9606', (83, 86))	('bisphenol A', 'Chemical', 'MESH:C006780', (114, 125))	('E2', 'Chemical', 'MESH:D004958', (168, 170))	('JKT-1', 'CellLine', 'CVCL:T011', (184, 189))	('JKT-1 cell proliferation', 'CPA', (184, 208))	('rat', 'Species', '10116', (233, 236))	('E2', 'Chemical', 'MESH:D004958', (132, 134))	('bovine', 'Species', '9913', (146, 152))	('rat', 'Species', '10116', (202, 205))	('involvement', 'Reg', (76, 87))	('silencing', 'Var', (24, 33))
64331	24639669	Recently, in JKT-1 cells, Chevalier and coworkers showed that treatment with G-1, BPA, and very low doses (nanomolar) of E2-BSA, determined an increase in seminoma cell growth through a non-genomic GPER-dependent mechanism involving PKA and MAPK pathways.	('JKT-1', 'CellLine', 'CVCL:T011', (13, 18))	('BPA', 'Chemical', 'MESH:C006780', (82, 85))	('seminoma', 'Disease', 'MESH:D018239', (155, 163))	('men', 'Species', '9606', (67, 70))	('E2', 'Chemical', 'MESH:D004958', (121, 123))	('MAPK', 'Gene', (241, 245))	('E2-BSA', 'Var', (121, 127))	('seminoma', 'Disease', (155, 163))	('increase', 'PosReg', (143, 151))	('MAPK', 'Gene', '5595;5594;26413;50689;5595;50689', (241, 245))
64332	24639669	Opposite effects were produced by E2 that at physiological concentrations, binding intracellular ESR2 through a classical genomic mechanism, suppressed in vitro JKT-1 cell proliferation.	('JKT-1 cell proliferation', 'CPA', (161, 185))	('E2', 'Chemical', 'MESH:D004958', (34, 36))	('binding', 'Var', (75, 82))	('suppressed', 'NegReg', (141, 151))	('rat', 'Species', '10116', (179, 182))	('rat', 'Species', '10116', (66, 69))	('JKT-1', 'CellLine', 'CVCL:T011', (161, 166))	('ESR2', 'Gene', (97, 101))
64334	24639669	The presence of G15 instead abrogated E2-BSA and BPA-mediated effects on seminoma cell growth, confirming that estrogens and xenoestrogens through classical ERs and GPER can activate distinct genomic and non-genomic pathways depending on their relative affinity for the receptors and on cofactor expression within the cells.	('activate', 'PosReg', (174, 182))	('E2', 'Chemical', 'MESH:D004958', (38, 40))	('seminoma', 'Disease', 'MESH:D018239', (73, 81))	('BPA', 'Chemical', 'MESH:C006780', (49, 52))	('ER', 'Gene', '2099', (167, 169))	('abrogated', 'NegReg', (28, 37))	('presence', 'Var', (4, 12))	('seminoma', 'Disease', (73, 81))	('ER', 'Gene', '2099', (157, 159))
64347	24639669	We also have shown that ERs antagonists such as hydroxytamoxifen (OHT) and ICI182780 are able to reduce proliferation of a rat Leydig tumor cell line.	('rat', 'Species', '10116', (111, 114))	('ICI182780', 'Var', (75, 84))	('ICI182780', 'Chemical', 'MESH:D000077267', (75, 84))	('ER', 'Gene', '2099', (24, 26))	('Leydig tumor', 'Disease', (127, 139))	('proliferation', 'CPA', (104, 117))	('Leydig tumor', 'Phenotype', 'HP:0100618', (127, 139))	('rat', 'Species', '10116', (123, 126))	('reduce', 'NegReg', (97, 103))	('OHT', 'Chemical', 'MESH:D013629', (66, 69))	('hydroxytamoxifen', 'Chemical', 'MESH:C475919', (48, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Leydig tumor', 'Disease', 'MESH:D007984', (127, 139))
64355	24639669	These effects were dependent on GPER activation since silencing of the gene, using a specific siRNA, prevented cytochrome c release, Bax increase, Bcl-2 decrease, PARP-1 activation, and decrease in cell proliferation.	('Bcl-2', 'Gene', '596', (147, 152))	('cytochrome c', 'Gene', (111, 123))	('activation', 'PosReg', (170, 180))	('PARP-1', 'Gene', (163, 169))	('silencing', 'Var', (54, 63))	('Bax', 'Gene', (133, 136))	('PARP-1', 'Gene', '142', (163, 169))	('decrease', 'NegReg', (186, 194))	('increase', 'PosReg', (137, 145))	('cytochrome c', 'Gene', '54205', (111, 123))	('prevented', 'NegReg', (101, 110))	('rat', 'Species', '10116', (210, 213))	('cell proliferation', 'CPA', (198, 216))	('Bax', 'Gene', '581', (133, 136))	('Bcl-2', 'Gene', (147, 152))	('decrease', 'NegReg', (153, 161))
64361	24639669	On the other hand, chemotherapeutic agents currently used for the treatment of testicular cancers, such as Cisplatin, despite their potent anti-neoplastic action, have several side effects including nephrotoxicity, peripheral neuropathy, and azoospermia.	('testicular cancers', 'Disease', 'MESH:D013736', (79, 97))	('peripheral neuropathy', 'Disease', (215, 236))	('azoospermia', 'Phenotype', 'HP:0000027', (242, 253))	('Cisplatin', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('azoospermia', 'Disease', 'MESH:D053713', (242, 253))	('testicular cancers', 'Disease', (79, 97))	('men', 'Species', '9606', (71, 74))	('testicular cancers', 'Phenotype', 'HP:0010788', (79, 97))	('testicular cancer', 'Phenotype', 'HP:0010788', (79, 96))	('nephrotoxicity', 'Disease', (199, 213))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('nephrotoxicity', 'Disease', 'MESH:D007674', (199, 213))	('azoospermia', 'Disease', (242, 253))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (215, 236))	('Cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (215, 236))
64515	27184033	The tumor node metastasis (TNM) classification was pT1pNxpMx according to the Union for International Cancer Control (UICC) staging system, seventh edition.	('tumor', 'Disease', (4, 9))	('Cancer', 'Disease', (102, 108))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pT1pNxpMx', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
64606	26171934	Of major interest is that inhibition of the interaction between PD1 and PD-L1 can enhance T-cell responses in vitro and mediates clinical antitumour activity.	('tumour', 'Disease', (142, 148))	('PD1', 'Gene', (64, 67))	('inhibition', 'Var', (26, 36))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('enhance T-cell responses', 'Phenotype', 'HP:0005419', (82, 106))	('T-cell responses in vitro', 'CPA', (90, 115))	('interaction', 'Interaction', (44, 55))	('PD-L1', 'Gene', (72, 77))	('enhance', 'PosReg', (82, 89))
64624	26171934	A 5% cut-off value was applied for PD-L1 positivity as it has been proposed in non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('positivity', 'Var', (41, 51))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('non-small cell lung cancer', 'Disease', (79, 105))	('PD-L1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
64647	25460450	Chemotherapy may cause secondary cancer especially in long term.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cause', 'Reg', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Chemotherapy', 'Var', (0, 12))
64676	25460450	Cisplatin as an alkylating agent and etoposide as a Topoisomerase-II inhibitor have been shown to be the cause of secondary cancers.	('cause', 'Reg', (105, 110))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('etoposide', 'Chemical', 'MESH:D005047', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Cisplatin', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
64746	23267350	Considering all patients, HPV semen infection was significantly higher in patients at T12 respect to T0 (34.9% vs. 9.7%).	('HPV semen infection', 'Disease', 'MESH:D030361', (26, 45))	('patients', 'Species', '9606', (74, 82))	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (16, 24))	('HPV semen infection', 'Disease', (26, 45))	('T12', 'Var', (86, 89))
64784	27034882	Of all RSS patients, 38.5% have hypomethylation of chromosome 11p15.5, and 10% have maternal uniparental disomy for chromosome 7.	('RSS', 'Gene', '140821', (7, 10))	('maternal uniparental disomy', 'Disease', (84, 111))	('RSS', 'Gene', (7, 10))	('hypomethylation', 'Var', (32, 47))	('patients', 'Species', '9606', (11, 19))	('maternal uniparental disomy', 'Disease', 'MESH:D024182', (84, 111))
64805	27034882	The two reported causes of RSS are hypomethylation of chromosome 11p15.5 and maternal uniparental disomy for chromosome 7.	('maternal uniparental disomy', 'Disease', 'MESH:D024182', (77, 104))	('RSS', 'Gene', '140821', (27, 30))	('maternal uniparental disomy', 'Disease', (77, 104))	('hypomethylation', 'Var', (35, 50))	('RSS', 'Gene', (27, 30))
64811	27034882	A meta-analysis of 21 studies associated undescended testes with a 4.8 overall relative risk of testicular germ cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('undescended testes', 'Phenotype', 'HP:0000028', (41, 59))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('undescended', 'Var', (41, 52))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('germ cell tumors', 'Phenotype', 'HP:0100728', (107, 123))	('germ cell tumor', 'Phenotype', 'HP:0100728', (107, 122))
64814	27034882	Second, hypomethylation of chromosome 11p15.5, which occurs in 38.5% of RSS cases and leads to hypomethylation of the IGF2/H19 imprinting control region (ICR), may be a risk factor for seminoma.	('hypomethylation', 'MPA', (95, 110))	('IGF2', 'Gene', '3481', (118, 122))	('seminoma', 'Disease', 'MESH:D018239', (185, 193))	('risk factor', 'Reg', (169, 180))	('RSS', 'Gene', '140821', (72, 75))	('hypomethylation', 'Var', (8, 23))	('seminoma', 'Disease', (185, 193))	('IGF2', 'Gene', (118, 122))	('H19', 'Gene', '283120', (123, 126))	('H19', 'Gene', (123, 126))	('RSS', 'Gene', (72, 75))
64816	27034882	In their study, 9 of 10 testicular seminomas had hypomethylated IGF2/H19 ICRs (<=33% methylated).	('testicular seminomas', 'Phenotype', 'HP:0100617', (24, 44))	('testicular seminoma', 'Disease', (24, 43))	('seminomas', 'Disease', 'MESH:D018239', (35, 44))	('seminomas', 'Disease', (35, 44))	('IGF2', 'Gene', '3481', (64, 68))	('testicular seminoma', 'Disease', 'MESH:D018239', (24, 43))	('IGF2', 'Gene', (64, 68))	('H19 ICR', 'Gene', '105259599', (69, 76))	('testicular seminoma', 'Phenotype', 'HP:0100617', (24, 43))	('H19 ICR', 'Gene', (69, 76))	('hypomethylated', 'Var', (49, 63))
64817	27034882	Thus, hypomethylated chromosome 11p15.5 may cause RSS and testicular germ cell tumors through an epigenetic mechanism.	('cause', 'Reg', (44, 49))	('RSS', 'Gene', (50, 53))	('germ cell tumors', 'Phenotype', 'HP:0100728', (69, 85))	('tumors', 'Disease', (79, 85))	('RSS', 'Gene', '140821', (50, 53))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('germ cell tumor', 'Phenotype', 'HP:0100728', (69, 84))	('hypomethylated', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
64820	27034882	RSS fits in the TDS model because of genetic aberration (hypomethylation of chromosome 11p15.5 and maternal uniparental disomy for chromosome 7) and genitourinary anomalies (e.g., cryptorchidism, hypospadias, small testes, and penis), which implies that men with RSS are likely to develop testicular cancer.	('genitourinary anomalies', 'Disease', (149, 172))	('develop', 'PosReg', (281, 288))	('testicular cancer', 'Disease', 'MESH:D013736', (289, 306))	('genitourinary anomalies', 'Phenotype', 'HP:0000119', (149, 172))	('hypospadias', 'Phenotype', 'HP:0000047', (196, 207))	('small testes', 'Phenotype', 'HP:0008734', (209, 221))	('cryptorchidism', 'Disease', (180, 194))	('hypospadias', 'Disease', (196, 207))	('hypomethylation', 'Var', (57, 72))	('testicular cancer', 'Disease', (289, 306))	('small testes', 'Disease', (209, 221))	('hypospadias', 'Disease', 'MESH:D007021', (196, 207))	('testicular cancer', 'Phenotype', 'HP:0010788', (289, 306))	('genitourinary anomalies', 'Disease', 'MESH:D014564', (149, 172))	('men', 'Species', '9606', (254, 257))	('maternal uniparental disomy', 'Disease', 'MESH:D024182', (99, 126))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('RSS fits', 'Disease', (0, 8))	('RSS fits', 'Disease', 'MESH:C535683', (0, 8))	('maternal uniparental disomy', 'Disease', (99, 126))	('cryptorchidism', 'Phenotype', 'HP:0000028', (180, 194))	('RSS', 'Gene', (263, 266))	('RSS', 'Gene', (0, 3))	('RSS', 'Gene', '140821', (263, 266))	('RSS', 'Gene', '140821', (0, 3))
65117	30226466	used a genome-wide association study to seek out DNA variations that are more common in people with fibroids.	('people', 'Species', '9606', (88, 94))	('fibroids', 'Disease', (100, 108))	('variations', 'Var', (53, 63))
65120	30226466	Variation in a set of genes known to control development of the female reproductive organs was also identified in women with fibroids.	('fibroids', 'Disease', (125, 133))	('women', 'Species', '9606', (114, 119))	('Variation', 'Var', (0, 9))	('identified', 'Reg', (100, 110))
65131	30226466	Most ULs show somatic site-specific mutations at exons 1 and 2 of the mediator complex subunit 12 (MED12) gene.	('MED12', 'Gene', (99, 104))	('mediator complex subunit 12', 'Gene', '9968', (70, 97))	('mediator complex subunit 12', 'Gene', (70, 97))	('mutations', 'Var', (36, 45))
65132	30226466	These observations together with further scrutiny of driver mutations, chromosomal aberrations, gene expression, and clinicopathological characteristics have led to identification of at least three mutually exclusive UL subtypes; MED12 mutant, Fumarate Hydratase (FH) deficient, as well as High Mobility Group AT-Hook 2 (HMGA2) overexpressing lesions.	('HMGA2', 'Gene', '8091', (321, 326))	('MED12', 'Gene', (230, 235))	('High Mobility Group AT-Hook 2', 'Gene', '8091', (290, 319))	('overexpressing', 'PosReg', (328, 342))	('HMGA2', 'Gene', (321, 326))	('FH', 'Gene', '2271', (264, 266))	('deficient', 'NegReg', (268, 277))	('mutant', 'Var', (236, 242))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (71, 94))	('Fumarate Hydratase', 'Gene', (244, 262))	('Fumarate Hydratase', 'Gene', '2271', (244, 262))	('High Mobility Group AT-Hook 2', 'Gene', (290, 319))
65136	30226466	Our analysis of the X chromosome identifies a risk allele near MED12 that drives UL tumorigenesis towards somatic MED12 mutations.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('MED12', 'Gene', (63, 68))	('tumor', 'Disease', (84, 89))	('mutations', 'Var', (120, 129))	('MED12', 'Gene', (114, 119))
65140	30226466	In NFBC, the SNP identified in the stage two meta-analysis, rs117245733 at 13q14.11, was replicated (p=0.034; linear mixed model; OR = 1.50; 95% CI 1.03 - 2.19).	('rs117245733', 'Mutation', 'rs117245733', (60, 71))	('rs117245733', 'Var', (60, 71))	('NFBC', 'Disease', (3, 7))
65145	30226466	Indeed, the 221 mutation positive patients were found to have a significantly higher GRS (Wilcoxon rank-sum p=7.9 x 10-4; adjusted p=0.0032; two-sided; W = 1.6 x 104).	('higher', 'PosReg', (78, 84))	('mutation', 'Var', (16, 24))	('patients', 'Species', '9606', (34, 42))	('GRS', 'CPA', (85, 88))
65150	30226466	Strikingly, the risk allele (rs5937008) did significantly increase the number of MED12-mutation-positive tumors (p=0.0087; negative binomial model rate ratio 1.23; 95% CI 1.05 - 1.44).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('increase', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('rs5937008', 'Var', (29, 38))	('MED12-mutation-positive', 'Gene', (81, 104))	('rs5937008', 'Mutation', 'rs5937008', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
65155	30226466	No significant association was observed between the risk allele and MED12 expression (rs5936989; Appendix 1:figure 11).	('expression', 'MPA', (74, 84))	('rs5936989', 'Mutation', 'rs5936989', (86, 95))	('rs5936989;', 'Var', (86, 96))	('MED12', 'Gene', (68, 73))
65156	30226466	Our analysis of the 57 GRS SNPs revealed altogether 17,030 (9,466 in tumors and 7564 in matched myometrium) cis methylation quantitative trait loci (cis-meQTL) with nominal p<0.05.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('cis methylation', 'Var', (108, 123))
65160	30226466	One of the risk alleles at TERT (rs2736100) was significantly associated with shorter telomere length (p=0.01; Kruskal-Wallis) (Appendix 1:figure 12).	('rs2736100', 'Mutation', 'rs2736100', (33, 42))	('shorter telomere length', 'Phenotype', 'HP:0031413', (78, 101))	('telomere length', 'CPA', (86, 101))	('TERT', 'Gene', (27, 31))	('TERT', 'Gene', '7015', (27, 31))	('rs2736100', 'Var', (33, 42))	('shorter', 'NegReg', (78, 85))
65162	30226466	The other two LD-independent SNPs at TERT, rs72709458 and rs2853676, or the SNPs at TERC (rs10936600) and OBFC1 (rs1265164) did not show association to telomere length (p=0.24, p=0.57, p=0.07 and p=0.48, respectively; Kruskal-Wallis).	('TERC', 'Gene', (84, 88))	('telomere', 'MPA', (152, 160))	('OBFC1', 'Gene', '79991', (106, 111))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('rs2853676', 'Mutation', 'rs2853676', (58, 67))	('rs1265164', 'Mutation', 'rs1265164', (113, 122))	('OBFC1', 'Gene', (106, 111))	('rs72709458', 'Var', (43, 53))	('TERC', 'Gene', '7012', (84, 88))	('rs2853676', 'Var', (58, 67))	('rs1265164', 'Var', (113, 122))	('rs10936600', 'Mutation', 'rs10936600', (90, 100))	('rs72709458', 'Mutation', 'rs72709458', (43, 53))	('rs10936600', 'Var', (90, 100))
65163	30226466	The combined effect of TERT (rs72709458, rs2736100, rs2853676), TERC (rs10936600) and OBFC1 (rs1265164) had a negative trend with telomere length (p=0.055; linear model 95% CI -408.5 - 4.7 per one risk allele; see Appendix 1:figure 13).	('OBFC1', 'Gene', (86, 91))	('TERT', 'Gene', (23, 27))	('TERC', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (23, 27))	('rs2736100', 'Var', (41, 50))	('rs1265164', 'Var', (93, 102))	('OBFC1', 'Gene', '79991', (86, 91))	('rs72709458', 'Var', (29, 39))	('TERC', 'Gene', '7012', (64, 68))	('rs1265164', 'Mutation', 'rs1265164', (93, 102))	('rs2736100', 'Mutation', 'rs2736100', (41, 50))	('negative', 'NegReg', (110, 118))	('rs72709458', 'Mutation', 'rs72709458', (29, 39))	('rs2853676', 'Var', (52, 61))	('rs10936600', 'Mutation', 'rs10936600', (70, 80))	('telomere length', 'MPA', (130, 145))	('rs2853676', 'Mutation', 'rs2853676', (52, 61))
65166	30226466	highlight OBFC1 (at 10q24.33) as a candidate gene and, while the SNP that they reported does not replicate in UKBB, the OBFC1 region is identified in our discovery stage (rs1265164; Table 1).	('OBFC1', 'Gene', '79991', (120, 125))	('rs1265164', 'Mutation', 'rs1265164', (171, 180))	('OBFC1', 'Gene', '79991', (10, 15))	('OBFC1', 'Gene', (120, 125))	('OBFC1', 'Gene', (10, 15))	('rs1265164', 'Var', (171, 180))
65170	30226466	The top association at 6q25.2 (rs58415480) resides within intron 107 of Spectrin Repeat Containing Nuclear Envelope Protein 1 (SYNE1), 130 kb downstream of ESR1, the latter being the only gene that resides completely within the topologically associating domain (TAD; Appendix 1:figure 1).	('rs58415480', 'Mutation', 'rs58415480', (31, 41))	('ESR1', 'Gene', '2099', (156, 160))	('SYNE1', 'Gene', (127, 132))	('SYNE1', 'Gene', '23345', (127, 132))	('TAD', 'Disease', (262, 265))	('ESR1', 'Gene', (156, 160))	('TAD', 'Disease', 'None', (262, 265))	('rs58415480', 'Var', (31, 41))
65175	30226466	The strongest association at 11p13 (rs10835889) is 40 kb downstream of the closest gene WT1, at a region with enhancer activity (Appendix 1:figure 1).	('WT1', 'Gene', (88, 91))	('rs10835889', 'Mutation', 'rs10835889', (36, 46))	('WT1', 'Gene', '7490', (88, 91))	('rs10835889', 'Var', (36, 46))
65177	30226466	The lead SNP at 1p36.12 (rs2235529) resides at the second intron of WNT4.	('rs2235529', 'Mutation', 'rs2235529', (25, 34))	('rs2235529', 'Var', (25, 34))	('WNT4', 'Gene', (68, 72))	('WNT4', 'Gene', '54361', (68, 72))
65179	30226466	WNT4 is known to be overexpressed in uterine leiomyomas with MED12 mutations, and knock-down of MED12 in UL cells reduces WNT4 expression.	('knock-down', 'Var', (82, 92))	('MED12', 'Gene', (61, 66))	('expression', 'MPA', (127, 137))	('leiomyomas', 'Disease', (45, 55))	('reduces', 'NegReg', (114, 121))	('mutations', 'Var', (67, 76))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (37, 55))	('MED12', 'Gene', (96, 101))	('leiomyomas', 'Disease', 'MESH:D007889', (45, 55))	('WNT4', 'Gene', (122, 126))	('WNT4', 'Gene', (0, 4))	('WNT4', 'Gene', '54361', (0, 4))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (37, 54))	('WNT4', 'Gene', '54361', (122, 126))	('overexpressed', 'PosReg', (20, 33))
65182	30226466	Of note, recent GWAS on gestational duration suggested that binding of the estrogen receptor at WNT4 is altered by rs3820282 (r2 = 0.92 with our lead SNP).	('WNT4', 'Gene', '54361', (96, 100))	('rs3820282', 'Var', (115, 124))	('altered', 'Reg', (104, 111))	('rs3820282', 'Mutation', 'rs3820282', (115, 124))	('WNT4', 'Gene', (96, 100))	('estrogen receptor', 'Gene', '2099', (75, 92))	('binding', 'Interaction', (60, 67))	('estrogen receptor', 'Gene', (75, 92))
65188	30226466	Mutations in SALL1 and a deletion at the GWAS signal have been associated with Townes-Brocks syndrome, a condition associated with kidney malformations.	('Townes-Brocks syndrome', 'Disease', 'MESH:C536974', (79, 101))	('SALL1', 'Gene', '6299', (13, 18))	('kidney malformations', 'Phenotype', 'HP:0012210', (131, 151))	('associated', 'Reg', (63, 73))	('deletion', 'Var', (25, 33))	('Townes-Brocks syndrome', 'Disease', (79, 101))	('Mutations', 'Var', (0, 9))	('kidney malformations', 'Disease', 'MESH:D000014', (131, 151))	('kidney malformations', 'Disease', (131, 151))	('SALL1', 'Gene', (13, 18))
65190	30226466	The lead SNP at 11q (rs141379009) resides in the 22nd intron of ATM, and the SNP at 17 p in the 3'-untranslated region of TP53.	('TP53', 'Gene', (122, 126))	('rs141379009', 'Var', (21, 32))	('ATM', 'Gene', (64, 67))	('ATM', 'Gene', '472', (64, 67))	('TP53', 'Gene', '7157', (122, 126))	('rs141379009', 'Mutation', 'rs141379009', (21, 32))
65195	30226466	The neoplasia predisposing effect of the risk alleles at the TERT locus (rs72709458; rs2736100; rs2853676) has been overwhelmingly documented (Appendix 1:table 11).	('neoplasia', 'Disease', 'MESH:D009369', (4, 13))	('neoplasia', 'Phenotype', 'HP:0002664', (4, 13))	('TERT', 'Gene', (61, 65))	('TERT', 'Gene', '7015', (61, 65))	('rs2736100', 'Mutation', 'rs2736100', (85, 94))	('rs2853676', 'Var', (96, 105))	('rs72709458; rs2736100; rs2853676', 'Var', (73, 105))	('neoplasia', 'Disease', (4, 13))	('rs72709458', 'Mutation', 'rs72709458', (73, 83))	('rs2853676', 'Mutation', 'rs2853676', (96, 105))
65196	30226466	Previous studies have reported contradicting observations on the effect of rs2736100 on telomere length.	('rs2736100', 'Var', (75, 84))	('telomere length', 'MPA', (88, 103))	('rs2736100', 'Mutation', 'rs2736100', (75, 84))
65197	30226466	In our patient cohort, the risk allele at TERT (rs2736100) is significantly associated with shorter telomere length (Appendix 1:figure 12), whereas the combined effect of SNPs at TERT, TERC and OBFC1 did not reach statistical significance.	('shorter telomere length', 'Phenotype', 'HP:0031413', (92, 115))	('OBFC1', 'Gene', (194, 199))	('patient', 'Species', '9606', (7, 14))	('rs2736100', 'Var', (48, 57))	('TERT', 'Gene', (179, 183))	('telomere length', 'MPA', (100, 115))	('TERT', 'Gene', '7015', (179, 183))	('TERC', 'Gene', (185, 189))	('TERT', 'Gene', (42, 46))	('OBFC1', 'Gene', '79991', (194, 199))	('rs2736100', 'Mutation', 'rs2736100', (48, 57))	('TERT', 'Gene', '7015', (42, 46))	('shorter', 'NegReg', (92, 99))	('TERC', 'Gene', '7012', (185, 189))
65198	30226466	GRS associated merely with a susceptibility to the most common UL subtype, MED12 mutation positive tumors.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('MED12', 'Gene', (75, 80))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutation positive', 'Var', (81, 98))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
65200	30226466	An outstanding susceptibility locus was identified 250 kb upstream of MED12: our in-house patient cohort - together with a mutation-screening of their 1481 tumors - revealed that the risk allele could facilitate selection of somatic MED12 mutations.	('mutations', 'Var', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('MED12', 'Gene', (233, 238))	('facilitate', 'PosReg', (201, 211))	('patient', 'Species', '9606', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
65207	30226466	Further sample QC excluded excess kinship (field 22021; 408,797 samples passed), sex-chromosome aneuploidy (field 22019; 408,241) and inconsistent gender (fields 31 and 22001, and one male with self-reported ULs; 408,081).	('excluded', 'NegReg', (18, 26))	('fields 31', 'Var', (155, 164))	('field 22019; 408,241', 'Var', (108, 128))	('sex-chromosome aneuploidy', 'Disease', 'MESH:D000782', (81, 106))	('sex-chromosome aneuploidy', 'Disease', (81, 106))
65209	30226466	Sample QC excluded excess kinship (field 22021), sex-chromosome aneuploidy (field 22019) and inconsistent gender (fields 31 and 22001).	('sex-chromosome aneuploidy', 'Disease', (49, 74))	('field 22019', 'Var', (76, 87))	('sex-chromosome aneuploidy', 'Disease', 'MESH:D000782', (49, 74))
65212	30226466	MED12 mutations were screened by Sanger sequencing the MED12 exons 1 and 2 and their flanking sequences (60 bp) from all uterine leiomyoma and matching normal myometrium samples.	('MED12', 'Gene', (55, 60))	('MED12', 'Gene', (0, 5))	('leiomyoma', 'Disease', (129, 138))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (121, 138))	('leiomyoma', 'Disease', 'MESH:D007889', (129, 138))	('mutations', 'Var', (6, 15))
65222	30226466	Clonally related tumors had identical changes in driver genes and shared at least a subset of somatic copy-number changes and/or copy neutral loss of heterozygosity (see Mehine et al.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('loss of', 'NegReg', (142, 149))	('copy neutral', 'Var', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('copy-number changes', 'Var', (102, 121))
65239	30226466	LocusZoom (http://locuszoom.org/) plots include the ENCODE tracks for DNase I hypersensitive sites for hTERT-HM (ENCFF001SPI, ENCFF001UXF) and uterus (ENCFF689EGI).	('hTERT-HM', 'CellLine', 'CVCL:S888', (103, 111))	('ENCFF001SPI', 'Var', (113, 124))	('ENCFF689EGI', 'Var', (151, 162))	('hypersensitive', 'Disease', 'MESH:D004342', (78, 92))	('ENCFF001UXF', 'Var', (126, 137))	('hypersensitive', 'Disease', (78, 92))
65241	30226466	Additional uterus-specific ChIP-seq data for CTCF (ENCFF282BOE, ENCFF634DDY) and POLR2A (ENCFF822OTY, ENCFF164YIY) were also included.	('ENCFF164YIY', 'CellLine', 'CVCL:8099', (102, 113))	('ENCFF164YIY', 'Var', (102, 113))	('POLR2A', 'Gene', '5430', (81, 87))	('CTCF', 'Gene', (45, 49))	('ENCFF822OTY', 'Var', (89, 100))	('CTCF', 'Gene', '10664', (45, 49))	('POLR2A', 'Gene', (81, 87))	('ENCFF634DDY', 'Var', (64, 75))	('ENCFF282BOE', 'Var', (51, 62))
65245	30226466	The authors conclude that their reported observations indicate a genetic predisposition to uterine fibroids, a heritable component to MED12 somatic mutations in uterine fibroids, and an explanation for the increased prevalence of genitourinary disease in women of African origin.	('mutations', 'Var', (148, 157))	('uterine fibroid', 'Phenotype', 'HP:0000131', (91, 106))	('genitourinary disease', 'Phenotype', 'HP:0000119', (230, 251))	('MED12', 'Gene', (134, 139))	('uterine fibroids', 'Phenotype', 'HP:0000131', (91, 107))	('uterine fibroid', 'Phenotype', 'HP:0000131', (161, 176))	('genitourinary disease', 'Disease', 'MESH:D014564', (230, 251))	('women', 'Species', '9606', (255, 260))	('genitourinary disease', 'Disease', (230, 251))	('uterine fibroids', 'Phenotype', 'HP:0000131', (161, 177))	('uterine fibroids', 'Disease', (91, 107))
65246	30226466	Essential revisions: 1) Conclusions are not sufficiently justified by the findings: This is a very interesting study that leverages several powerful resources to evaluate the relationship between GWAS variants and risk for uterine leiomyoma.	('GWAS', 'Gene', (196, 200))	('leiomyoma', 'Disease', (231, 240))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (223, 240))	('variants', 'Var', (201, 209))	('leiomyoma', 'Disease', 'MESH:D007889', (231, 240))
65247	30226466	They did find strong associations between their polygenic risk score and uterine leiomyoma outcome and some promising findings from their secondary functional evaluates via tissue gene expression, DNA methylation, and telomere length analyses.	('polygenic', 'Var', (48, 57))	('leiomyoma', 'Disease', (81, 90))	('leiomyoma', 'Disease', 'MESH:D007889', (81, 90))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (73, 90))
65259	30226466	Given the high frequency of MED12 mutations in leiomyomas the heritability to MED12 mutations is possibly one of the strongest points of the manuscript, however no real validation has been demonstrated in the study.	('leiomyomas', 'Disease', 'MESH:D007889', (47, 57))	('MED12', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))	('leiomyomas', 'Disease', (47, 57))
65260	30226466	What was the effect size in patients with both MED12 mutated positive and negative leiomyoma?	('leiomyoma', 'Disease', (83, 92))	('MED12', 'Gene', (47, 52))	('leiomyoma', 'Disease', 'MESH:D007889', (83, 92))	('mutated positive', 'Var', (53, 69))	('patients', 'Species', '9606', (28, 36))
65261	30226466	A strong association between the risk allele rs5937008 and the MED12 status is described and the authors argue that the risk allele could facilitate selection of somatic MED12 mutations, possibly through increased expression.	('MED12', 'Gene', (170, 175))	('mutations', 'Var', (176, 185))	('rs5937008', 'Mutation', 'rs5937008', (45, 54))	('facilitate', 'PosReg', (138, 148))	('rs5937008', 'Var', (45, 54))
65264	30226466	Although I understand that not all associations can be experimentally proven, a functional evaluation of this phenomenon and how would the rs5937008 drive MED12 mutations would greatly improve the manuscript and provide strong evidence of the rs5937008 allele and UL development.	('rs5937008', 'Mutation', 'rs5937008', (243, 252))	('rs5937008', 'Gene', (139, 148))	('manuscript', 'MPA', (197, 207))	('improve', 'PosReg', (185, 192))	('mutations', 'Var', (161, 170))	('MED12', 'Gene', (155, 160))	('UL development', 'CPA', (264, 278))	('rs5937008', 'Mutation', 'rs5937008', (139, 148))	('rs5937008', 'Var', (243, 252))
65266	30226466	TERT SNPs rs72709458; rs2736100; rs2853676 are known to be related to many different neoplasias.	('rs2736100; rs2853676', 'Var', (22, 42))	('rs72709458', 'Var', (10, 20))	('rs2853676', 'Var', (33, 42))	('neoplasias', 'Disease', 'MESH:D009369', (85, 95))	('rs2853676', 'Mutation', 'rs2853676', (33, 42))	('rs2736100', 'Mutation', 'rs2736100', (22, 31))	('neoplasias', 'Disease', (85, 95))	('rs72709458', 'Mutation', 'rs72709458', (10, 20))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('related', 'Reg', (59, 66))	('neoplasia', 'Phenotype', 'HP:0002664', (85, 94))	('neoplasias', 'Phenotype', 'HP:0002664', (85, 95))
65268	30226466	In the same fashion that for rs5937008, it would be of great interest to confirm a functional effect by which rs58415480 regulates ESR1 expression or the repercussion of the lead SNP at 2p on GREB1 mediated regulation of ESR1.	('ESR1', 'Gene', (131, 135))	('rs58415480', 'Mutation', 'rs58415480', (110, 120))	('expression', 'MPA', (136, 146))	('ESR1', 'Gene', '2099', (221, 225))	('ESR1', 'Gene', '2099', (131, 135))	('GREB1', 'Gene', (192, 197))	('ESR1', 'Gene', (221, 225))	('GREB1', 'Gene', '9687', (192, 197))	('regulates', 'Reg', (121, 130))	('rs5937008', 'Var', (29, 38))	('rs5937008', 'Mutation', 'rs5937008', (29, 38))	('rs58415480', 'Var', (110, 120))
65275	30226466	WNT4 (and WNT/beta-catenin signaling pathway) plays a significant role in the myomagenesis of MED12 mutated leiomyomas.	('beta-catenin', 'Gene', (14, 26))	('mutated', 'Var', (100, 107))	('leiomyomas', 'Disease', 'MESH:D007889', (108, 118))	('leiomyomas', 'Disease', (108, 118))	('beta-catenin', 'Gene', '1499', (14, 26))	('myomagenesis', 'CPA', (78, 90))	('WNT4', 'Gene', (0, 4))	('WNT4', 'Gene', '54361', (0, 4))	('MED12', 'Gene', (94, 99))
65280	30226466	Other subtype-specific associations were not evaluated due to the GRS association merely to patients with MED12 mutated lesions.	('mutated lesions', 'Var', (112, 127))	('MED12', 'Gene', (106, 111))	('patients', 'Species', '9606', (92, 100))
65281	30226466	We made no a priori hypothesis regarding these specific SNPs and MED12 mutated tumors.	('mutated', 'Var', (71, 78))	('MED12', 'Gene', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
65283	30226466	the effect of rs2736100 on telomere length).	('telomere length', 'MPA', (27, 42))	('effect', 'Reg', (4, 10))	('rs2736100', 'Mutation', 'rs2736100', (14, 23))	('rs2736100', 'Var', (14, 23))
65285	26843623	Epigenetic loss of PIWI proteins expression was previously demonstrated in testicular germ cell tumors (TGCTs), implying their involvement in TGCT development.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PIWI', 'Gene', '9271', (19, 23))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('germ cell tumors', 'Phenotype', 'HP:0100728', (86, 102))	('germ cell tumor', 'Phenotype', 'HP:0100728', (86, 101))	('involvement', 'Reg', (127, 138))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('PIWI', 'Gene', (19, 23))	('Epigenetic loss', 'Var', (0, 15))
65293	26843623	One of the key players in spermatogenesis is PIWI pathway responsible for epigenetic silencing of retrotransposons.	('epigenetic silencing', 'Var', (74, 94))	('PIWI', 'Gene', '9271', (45, 49))	('PIWI', 'Gene', (45, 49))
65295	26843623	demonstrated CpG island (CGI) hypermethylation and a concomitant decrease in expression level of PIWI pathway genes in TGCTs compared to the testes of healthy individuals, suggesting a role of PIWI in TGCT tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('PIWI', 'Gene', '9271', (97, 101))	('PIWI', 'Gene', '9271', (193, 197))	('tumor', 'Disease', (206, 211))	('PIWI', 'Gene', (97, 101))	('TGCTs', 'Disease', (119, 124))	('PIWI', 'Gene', (193, 197))	('expression level', 'MPA', (77, 93))	('decrease', 'NegReg', (65, 73))	('hypermethylation', 'Var', (30, 46))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
65329	26843623	One of the major roles of PIWI proteins in spermatogenesis is maintenance of genomic stability through epigenetic silencing of retrotransposons.	('retrotransposons', 'Protein', (127, 143))	('epigenetic silencing', 'Var', (103, 123))	('PIWI', 'Gene', '9271', (26, 30))	('genomic stability', 'CPA', (77, 94))	('PIWI', 'Gene', (26, 30))
65330	26843623	It is known that deregulation of retrotransposon expression may lead to neoplastic transformations in various types of cancers.	('lead to', 'Reg', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('retrotransposon', 'Protein', (33, 48))	('neoplastic transformations', 'CPA', (72, 98))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('deregulation', 'Var', (17, 29))
65332	26843623	Indeed, methylation level of LINE-1 correlates with expression of PIWI genes: promoters of these retrotransposons are hypermethylated in premalignant testis tissues adjacent to nonseminomas unlike those adjacent to seminomas (Figure 3).	('seminomas', 'Disease', 'MESH:D018239', (180, 189))	('seminomas', 'Disease', (180, 189))	('PIWI', 'Gene', (66, 70))	('nonseminomas', 'Disease', 'None', (177, 189))	('seminomas', 'Disease', 'MESH:D018239', (215, 224))	('seminomas', 'Disease', (215, 224))	('hypermethylated', 'Var', (118, 133))	('PIWI', 'Gene', '9271', (66, 70))	('nonseminomas', 'Disease', (177, 189))
65342	26843623	In the second experiment, we wanted to assess how promoter DNA methylation influences expression of PIWIL1 and PIWIL2 in their natural genomic DNA context.	('PIWIL2', 'Gene', '55124', (111, 117))	('PIWIL1', 'Gene', '9271', (100, 106))	('expression', 'MPA', (86, 96))	('PIWIL2', 'Gene', (111, 117))	('methylation', 'Var', (63, 74))	('influences', 'Reg', (75, 85))	('PIWIL1', 'Gene', (100, 106))
65346	26843623	As expected, in A549 cells promoter demethylation led to an increase in H3K4me3 (histone methylation mark of active transcription, Figure 6B) and upregulated PIWIL1 and PIWIL2 expression (Figure 6C).	('H3K4me3', 'Protein', (72, 79))	('promoter demethylation', 'Var', (27, 49))	('PIWIL2', 'Gene', '55124', (169, 175))	('increase', 'PosReg', (60, 68))	('PIWIL1', 'Gene', (158, 164))	('expression', 'MPA', (176, 186))	('PIWIL2', 'Gene', (169, 175))	('upregulated', 'PosReg', (146, 157))	('PIWIL1', 'Gene', '9271', (158, 164))	('A549', 'CellLine', 'CVCL:0023', (16, 20))
65348	26843623	Drug-induced demethylation did not produce any changes in transcription for both PIWIL1 and PIWIL2 (Figure 6C).	('transcription', 'MPA', (58, 71))	('PIWIL1', 'Gene', (81, 87))	('PIWIL2', 'Gene', '55124', (92, 98))	('demethylation', 'Var', (13, 26))	('PIWIL1', 'Gene', '9271', (81, 87))	('PIWIL2', 'Gene', (92, 98))
65350	26843623	Overall, these seemingly conflicting findings in in vitro experiments imply a more complex link between CGI methylation in the promoter regions and PIWIL1/2 transcription and, possibly, interplay with other expression regulatory systems.	('transcription', 'MPA', (157, 170))	('PIWIL1/2', 'Gene', '9271;55124', (148, 156))	('PIWIL1/2', 'Gene', (148, 156))	('methylation', 'Var', (108, 119))
65372	26843623	TGCT testicular germ cell tumor ChIP chromatin immunoprecipitation H3K4me3 histone 3 lysine 4 trimethylation.	('H3K4me3', 'Var', (67, 74))	('lysine 4', 'Chemical', '-', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('germ cell tumor', 'Phenotype', 'HP:0100728', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
65428	23519268	Experimental animal models suggest a causative role for an abnormal testicular position on the disruption of spermatogenesis however the link between cryptorchidism and TGCT is less clear.	('cryptorchidism', 'Phenotype', 'HP:0000028', (150, 164))	('abnormal', 'Var', (59, 67))	('abnormal testicular', 'Phenotype', 'HP:0000035', (59, 78))	('disruption', 'MPA', (95, 105))	('spermatogenesis', 'CPA', (109, 124))	('men', 'Species', '9606', (6, 9))
65436	23519268	Indeed, the causative role of an abnormal testis position in infertility has been demonstrated in several animal experimental models.	('abnormal testis', 'Phenotype', 'HP:0000035', (33, 48))	('infertility', 'Phenotype', 'HP:0000789', (61, 72))	('infertility', 'Disease', 'MESH:D007247', (61, 72))	('abnormal', 'Var', (33, 41))	('men', 'Species', '9606', (119, 122))	('infertility', 'Disease', (61, 72))
65450	23519268	Analysis of mutant gubernaculum development and the comparisons of gene expression in mutant and wild-type tissues performed in our laboratory, indicated that the NOTCH and WNT/beta-catenin cell signaling pathways might mediate the INSL3 effects at the cellular level (Kaftanovskaya et al.,).	('mutant', 'Var', (86, 92))	('mutant', 'Var', (12, 18))	('beta-catenin', 'Gene', (177, 189))	('men', 'Species', '9606', (39, 42))	('beta-catenin', 'Gene', '1499', (177, 189))
65455	23519268	A non-functional hypothalamo-pituitary-gonadal (HPG) axis results in hypogonadotrophic hypogonadism.	('hypogonadotrophic hypogonadism', 'Phenotype', 'HP:0000044', (69, 99))	('hypothalamo-pituitary-gonadal', 'Disease', (17, 46))	('hypothalamo-pituitary-gonadal', 'Disease', 'OMIM:615926', (17, 46))	('hypogonadotrophic hypogonadism', 'Disease', 'MESH:D007006', (69, 99))	('results in', 'Reg', (58, 68))	('hypogonadotrophic hypogonadism', 'Disease', (69, 99))	('hypogonadism', 'Phenotype', 'HP:0000135', (87, 99))	('non-functional', 'Var', (2, 16))
65456	23519268	The homozygous mutant mice for gonadotropin-releasing hormone (GNRH, hpg), GNRH-receptor (Gnrhr), and the LH receptor knockout mouse (LuRKO) devoid of LH stimulation, all have impaired inguinoscrotal testicular descent (Klonisch et al.,; Pask et al.,; Feng et al.,).	('gonadotropin-releasing hormone', 'Gene', '14714', (31, 61))	('mouse', 'Species', '10090', (127, 132))	('Gnrhr', 'Gene', (90, 95))	('gonadotropin-releasing hormone', 'Gene', (31, 61))	('GNRH-receptor', 'Gene', (75, 88))	('GNRH', 'Gene', '14714', (75, 79))	('GNRH', 'Gene', (75, 79))	('impaired inguinoscrotal testicular', 'Disease', (176, 210))	('mutant', 'Var', (15, 21))	('GNRH', 'Gene', '14714', (63, 67))	('impaired inguinoscrotal testicular', 'Disease', 'MESH:D013733', (176, 210))	('GNRH', 'Gene', (63, 67))	('mice', 'Species', '10090', (22, 26))	('Gnrhr', 'Gene', '14715', (90, 95))	('GNRH-receptor', 'Gene', '14715', (75, 88))
65460	23519268	The link between inguinoscrotal cryptorchidism detected in the transgenic mouse and in some cases human mutants for several transcriptional factors, such as homeobox genes HOXA10 or HOXA11; Wilms tumor 1 (WT1); ARID domain-containing protein 5B (ARID5B), and androgen signaling in gubernaculum development still need to be determined (Klonisch et al.,; Kaftanovskaya et al.,).	('Wilms tumor', 'Disease', (190, 201))	('HOXA11', 'Gene', (182, 188))	('HOXA10', 'Gene', '3206', (172, 178))	('inguinoscrotal cryptorchidism', 'Disease', (17, 46))	('men', 'Species', '9606', (301, 304))	('inguinoscrotal cryptorchidism', 'Disease', 'MESH:D003456', (17, 46))	('cryptorchidism', 'Phenotype', 'HP:0000028', (32, 46))	('HOXA11', 'Gene', '3207', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('ARID5B', 'Gene', '84159', (246, 252))	('mutants', 'Var', (104, 111))	('Wilms tumor', 'Disease', 'MESH:D009396', (190, 201))	('mouse', 'Species', '10090', (74, 79))	('WT1', 'Gene', (205, 208))	('ARID5B', 'Gene', (246, 252))	('Wilms tumor', 'Phenotype', 'HP:0002667', (190, 201))	('ARID domain-containing protein 5B', 'Gene', (211, 244))	('HOXA10', 'Gene', (172, 178))	('WT1', 'Gene', '7490', (205, 208))	('ARID domain-containing protein 5B', 'Gene', '84159', (211, 244))	('human', 'Species', '9606', (98, 103))
65489	23519268	Significantly, mice with mutations in Kitl genes require a specific genetic background to develop testicular cancer.	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Kitl', 'Gene', '17311', (38, 42))	('testicular cancer', 'Phenotype', 'HP:0010788', (98, 115))	('testicular cancer', 'Disease', 'MESH:D013736', (98, 115))	('testicular cancer', 'Disease', (98, 115))	('mice', 'Species', '10090', (15, 19))	('Kitl', 'Gene', (38, 42))
65490	23519268	Mice harboring a mutation of the Steel locus, which deletes Kitl, bred on a 129 background have a higher incidence of testicular cancer than wild-type controls.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('testicular cancer', 'Phenotype', 'HP:0010788', (118, 135))	('testicular cancer', 'Disease', 'MESH:D013736', (118, 135))	('mutation', 'Var', (17, 25))	('Kitl', 'Gene', (60, 64))	('deletes', 'Var', (52, 59))	('testicular cancer', 'Disease', (118, 135))	('Mice', 'Species', '10090', (0, 4))	('Kitl', 'Gene', '17311', (60, 64))
65494	23519268	DMRT1 is expressed in the male gonad during Sertoli cell maturation and the deletion of this gene is associated with gonadoblastoma (Kanetsky et al.,).	('gonadoblastoma', 'Phenotype', 'HP:0000150', (117, 131))	('deletion', 'Var', (76, 84))	('DMRT1', 'Gene', '1761', (0, 5))	('Sertoli cell', 'Phenotype', 'HP:0100619', (44, 56))	('gonadoblastoma', 'Disease', (117, 131))	('associated', 'Reg', (101, 111))	('DMRT1', 'Gene', (0, 5))	('gonadoblastoma', 'Disease', 'MESH:D018238', (117, 131))
65496	23519268	Among these, the alleles of AR gene with short GGN repeats were linked to an increased risk of metastatic disease (Vastermark et al.,).	('short GGN repeats', 'Var', (41, 58))	('metastatic disease', 'Disease', (95, 113))	('AR', 'Gene', '367', (28, 30))	('linked', 'Reg', (64, 70))
65497	23519268	The role of somatic mutations in p53, PTEN, and other classical tumor suppressor genes in TGCT remains contradictory, however TGCT response to cisplatin-based chemotherapy indicates cancer cell sensitivity to p53 activation (Gutekunst et al.,).	('PTEN', 'Gene', '5728', (38, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('activation', 'PosReg', (213, 223))	('p53', 'Gene', (33, 36))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (20, 29))	('PTEN', 'Gene', (38, 42))
65498	23519268	In some studies, a downstream target of p53, DAPK-1 was hypermethylated in seminomas compared to normal testes and was found to be clinically useful for testicular germ cell tumor stage diagnosis (Christoph et al.,).	('tumor', 'Disease', (174, 179))	('DAPK-1', 'Gene', '1612', (45, 51))	('hypermethylated', 'Var', (56, 71))	('germ cell tumor', 'Phenotype', 'HP:0100728', (164, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('DAPK-1', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('seminomas', 'Disease', 'MESH:D018239', (75, 84))	('seminomas', 'Disease', (75, 84))
65507	23519268	A mouse model expressing a full-length human GDNF transgene specifically in spermatogonia, began to develop tumors from 1 year of age (Meng et al.,).	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('develop', 'PosReg', (100, 107))	('human', 'Species', '9606', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('mouse', 'Species', '10090', (2, 7))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('transgene', 'Var', (50, 59))	('GDNF', 'Gene', (45, 49))
65508	23519268	These tumors expressed the transgene, were derived from early germ cells, were alkaline phosphatase positive, and most closely resembled classical human seminomas.	('human', 'Species', '9606', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('seminomas', 'Disease', 'MESH:D018239', (153, 162))	('seminomas', 'Disease', (153, 162))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('transgene', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('alkaline phosphatase positive', 'Phenotype', 'HP:0003155', (79, 108))
65523	23519268	The analysis highlighted a single nucleotide polymorphism in TGFBR3 mildly associated with all four symptoms of TDS.	('TDS', 'Disease', (112, 115))	('TGFBR3', 'Gene', '7049', (61, 67))	('single nucleotide polymorphism', 'Var', (27, 57))	('TGFBR3', 'Gene', (61, 67))	('associated', 'Reg', (75, 85))
65525	23519268	A member of the TGFbeta superfamily, BMP7 was found to contain genomic variants in some patients with TDS symptoms, most notably those with cryptorchidism and testicular cancer.	('TDS symptoms', 'Disease', (102, 114))	('cryptorchidism', 'Phenotype', 'HP:0000028', (140, 154))	('BMP7', 'Gene', '655', (37, 41))	('patients', 'Species', '9606', (88, 96))	('contain', 'Reg', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cryptorchidism and testicular cancer', 'Disease', 'MESH:D013736', (140, 176))	('BMP7', 'Gene', (37, 41))	('genomic variants', 'Var', (63, 79))	('testicular cancer', 'Phenotype', 'HP:0010788', (159, 176))
65526	23519268	Likewise, mutations in the KITLG locus were mostly closely linked to an increased risk of testicular cancer and were not connected to any other TDS symptoms.	('testicular cancer', 'Phenotype', 'HP:0010788', (90, 107))	('testicular cancer', 'Disease', 'MESH:D013736', (90, 107))	('testicular cancer', 'Disease', (90, 107))	('KITLG', 'Gene', '4254', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('linked to', 'Reg', (59, 68))	('mutations', 'Var', (10, 19))	('KITLG', 'Gene', (27, 32))
65527	23519268	Mutations in this gene have previously been associated with infertility as well as germ cell tumors (Galan et al.,).	('associated', 'Reg', (44, 54))	('infertility', 'Phenotype', 'HP:0000789', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('germ cell tumors', 'Phenotype', 'HP:0100728', (83, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('infertility', 'Disease', 'MESH:D007247', (60, 71))	('germ cell tumor', 'Phenotype', 'HP:0100728', (83, 98))	('tumors', 'Disease', (93, 99))	('infertility', 'Disease', (60, 71))
65528	23519268	It should be pointed out however, that currently no mouse mutations in the genes encoding members of BMP/TGFbeta signaling are known to cause isolated cryptorchidism.	('mutations', 'Var', (58, 67))	('cause', 'Reg', (136, 141))	('isolated cryptorchidism', 'Disease', (142, 165))	('mouse', 'Species', '10090', (52, 57))	('cryptorchidism', 'Phenotype', 'HP:0000028', (151, 165))	('BMP', 'Gene', '655;9573', (101, 104))	('BMP', 'Gene', (101, 104))
65541	23519268	In p53-/- and lpr/lpr double mutant mice, apoptosis is further delayed compared to the cryptorchid control group, showing that Fas is responsible for the later stage germ cell loss (Yin et al.,).	('lpr', 'Gene', '14102', (14, 17))	('lpr', 'Gene', '14102', (18, 21))	('lpr', 'Gene', (14, 17))	('double mutant', 'Var', (22, 35))	('lpr', 'Gene', (18, 21))	('Fas', 'Chemical', 'MESH:C038178', (127, 130))	('apoptosis', 'CPA', (42, 51))	('delayed', 'NegReg', (63, 70))	('mice', 'Species', '10090', (36, 40))	('p53-/- and lpr', 'Gene', '22060', (3, 17))	('cryptorchid control', 'Phenotype', 'HP:0000028', (87, 106))
65560	23519268	The amplification of genes in this genomic region including NANOG, DPPA3, GDF3 may provide a selective proliferation advantage and subsequent reactivation of a stem-like phenotype (Houldsworth et al.,).	('NANOG', 'Gene', '79923', (60, 65))	('GDF3', 'Gene', '9573', (74, 78))	('GDF3', 'Gene', (74, 78))	('NANOG', 'Gene', (60, 65))	('DPPA3', 'Gene', (67, 72))	('DPPA3', 'Gene', '359787', (67, 72))	('reactivation', 'CPA', (142, 154))	('amplification', 'Var', (4, 17))
65564	23519268	In a study by Cortes et al., one invasive TGCT and six CISs were found in testicular biopsies of 182 cryptorchid patients with intra-abdominal testes, abnormal genitalia, and/or abnormal karyotype, but no cases were found in any of the 1281 cryptorchid patients without these additional characteristics.	('abnormal genitalia', 'Phenotype', 'HP:0000078', (151, 169))	('patients', 'Species', '9606', (113, 121))	('patients', 'Species', '9606', (253, 261))	('abnormal genitalia', 'Disease', 'MESH:C564563', (151, 169))	('intra-abdominal testes', 'Disease', (127, 149))	('abnormal genitalia', 'Disease', (151, 169))	('intra-abdominal testes', 'Disease', 'MESH:D013736', (127, 149))	('abnormal', 'Var', (178, 186))
65572	23519268	KITLG secreted by Sertoli cells and also found to be mutated in some seminomas, facilitates the differentiation of spermatogonial cells (Pellegrini et al.,).	('seminomas', 'Disease', 'MESH:D018239', (69, 78))	('differentiation', 'CPA', (96, 111))	('seminomas', 'Disease', (69, 78))	('Sertoli cell', 'Phenotype', 'HP:0100619', (18, 30))	('facilitates', 'PosReg', (80, 91))	('KITLG', 'Gene', '4254', (0, 5))	('mutated', 'Var', (53, 60))	('Sertoli cells', 'Phenotype', 'HP:0100619', (18, 31))	('KITLG', 'Gene', (0, 5))
65576	23519268	Taken in conjunction with the finding that GDNF overexpression in mice leads to the formation of seminomas in advanced age, it is conceivable to suggest that changes in somatic cells in the testis can lead to the deregulation of the SSC somatic niche (Clark,; Kristensen et al.,).	('seminomas', 'Disease', 'MESH:D018239', (97, 106))	('seminomas', 'Disease', (97, 106))	('changes', 'Var', (158, 165))	('mice', 'Species', '10090', (66, 70))	('deregulation', 'MPA', (213, 225))	('SSC somatic niche', 'CPA', (233, 250))	('lead to', 'Reg', (201, 208))
65579	23519268	Accumulation of additional mutations or chromosome rearrangements, including amplification of chromosome 12p, might provide a selective growth advantage for SSC or differentiating germ cells.	('chromosome 12p', 'Gene', (94, 108))	('men', 'Species', '9606', (60, 63))	('growth advantage', 'CPA', (136, 152))	('amplification', 'Var', (77, 90))
65586	23519268	The aberrant testicular environment also has a detrimental effect on Sertoli and Leydig cells that may lead to an inability to support the stem cell population.	('Sertoli', 'CPA', (69, 76))	('inability', 'NegReg', (114, 123))	('men', 'Species', '9606', (31, 34))	('men', 'Species', '9606', (52, 55))	('detrimental', 'NegReg', (47, 58))	('aberrant', 'Var', (4, 12))	('aberrant testicular', 'Phenotype', 'HP:0000035', (4, 23))
65657	18657195	The first study found no association of single nucleotide polymorphisms of XPD, ERCC1, XRCC3 and OGG1 with risk of TGCT or either histologic type.	('association', 'Interaction', (25, 36))	('XPD', 'Disease', (75, 78))	('XPD', 'Disease', 'MESH:C562591', (75, 78))	('ERCC1', 'Gene', (80, 85))	('XRCC3', 'Gene', (87, 92))	('TGCT', 'Disease', (115, 119))	('single nucleotide polymorphisms', 'Var', (40, 71))	('OGG1', 'Gene', (97, 101))
65661	18657195	Notable evidence includes cryptorchidism, low birth weight and low birth order being predominantly associated with an increased risk of seminoma, while participation in specific sporting activities and long gestational duration appear more protective against seminoma relative to nonseminoma.	('seminoma', 'Disease', (259, 267))	('seminoma', 'Disease', (283, 291))	('low birth weight', 'Phenotype', 'HP:0001518', (42, 58))	('low birth order', 'Var', (63, 78))	('nonseminoma', 'Disease', 'None', (280, 291))	('low birth order', 'Phenotype', 'HP:0001518', (63, 78))	('seminoma', 'Disease', (136, 144))	('cryptorchidism', 'Disease', (26, 40))	('seminoma', 'Disease', 'MESH:D018239', (259, 267))	('nonseminoma', 'Disease', (280, 291))	('seminoma', 'Disease', 'MESH:D018239', (283, 291))	('low birth weight', 'Var', (42, 58))	('seminoma', 'Disease', 'MESH:D018239', (136, 144))	('associated', 'Reg', (99, 109))	('cryptorchidism', 'Phenotype', 'HP:0000028', (26, 40))
65684	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
65686	30072739	Somatic mutations in oncogenes and tumor suppressors represent the most classic biomarkers as they are the main direct drivers of cancer progression .	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (35, 40))	('oncogenes', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Somatic mutations', 'Var', (0, 17))
65689	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
65699	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))
65713	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
65718	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('snoRNA', 'Gene', (19, 25))	('C/D', 'Var', (15, 18))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
65728	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('300.13 +- 4.21', 'Var', (112, 126))
65810	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('expression', 'MPA', (19, 29))	('snoRNA', 'Gene', '85390', (72, 78))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
65811	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('sarcoma', 'Disease', (153, 160))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('SNORD145', 'Var', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('snoRNA', 'Gene', (62, 68))	('survival times', 'CPA', (99, 113))	('shorter', 'NegReg', (91, 98))	('sdRNAs', 'MPA', (35, 41))	('snoRNA', 'Gene', '85390', (62, 68))	('kidney clear cell carcinoma', 'Disease', (117, 144))
65812	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
65830	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
65841	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))
65868	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
65870	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('GSE33858', 'Var', (52, 60))	('EBI', 'Gene', '6907', (150, 153))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
65896	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('snoRNA', 'Gene', (197, 203))	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', '85390', (197, 203))
65897	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
65900	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
65906	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
65918	28604728	Across the 44 independent TGCT risk loci (19 new and 25 previously reported), we confirmed a significant enrichment of enhancer/promoter associated histone marks, including H3K4me1, H3K4me3 and H3K9ac, using available ChIP-Seq data from the TGCT cell line NTERA2 (P<5.0x10-3) (Supplementary Table 1).	('NTERA2', 'CellLine', 'CVCL:0034', (256, 262))	('H3K4me1', 'Var', (173, 180))	('men', 'Species', '9606', (111, 114))	('TGCT', 'Phenotype', 'HP:0010788', (26, 30))	('P<5', 'Gene', '10130', (264, 267))	('H3K4me3', 'Var', (182, 189))	('enhancer/promoter', 'PosReg', (119, 136))	('men', 'Species', '9606', (283, 286))	('P<5', 'Gene', (264, 267))	('H3K9ac', 'Var', (194, 200))	('TGCT', 'Phenotype', 'HP:0010788', (241, 245))
65926	28604728	Notably the new TGCT risk locus at 8p23.1 features a looping chromatin interaction from risk SNP rs17153755 to the promoter of GATA4, which is supported by an overlapping predicted strong enhancer region and a nominal eQTL effect (TCGA data, P=3.1 x 10-2) (Fig.	('looping', 'Reg', (53, 60))	('TGCT', 'Phenotype', 'HP:0010788', (16, 20))	('rs17153755', 'Var', (97, 107))	('rs17153755', 'Mutation', 'rs17153755', (97, 107))	('enhancer', 'PosReg', (188, 196))	('GATA4', 'Gene', '2626', (127, 132))	('TGCT', 'Disease', (16, 20))	('GATA4', 'Gene', (127, 132))
65927	28604728	The rs17153755 risk allele was associated with down-regulation of GATA4 expression, consistent with the hypothesised role of GATA4 as a tumor suppressor gene.	('rs17153755', 'Mutation', 'rs17153755', (4, 14))	('GATA4', 'Gene', '2626', (66, 71))	('GATA4', 'Gene', '2626', (125, 130))	('GATA4', 'Gene', (66, 71))	('GATA4', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('expression', 'MPA', (72, 82))	('down-regulation', 'NegReg', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('rs17153755', 'Var', (4, 14))
65928	28604728	In addition the risk locus at 16q24.2 only contains a single gene ZFPM1 (alias FOG, Friend of GATA1), which encodes an essential regulator of GATA1, in which we noted a predicted damaging missense polymorphism (rs3751673, NP_722520.2:p.Arg22Gly).	('p.Arg22Gly', 'Var', (234, 244))	('rs3751673', 'Var', (211, 220))	('GATA1', 'Gene', (142, 147))	('rs3751673', 'Mutation', 'rs3751673', (211, 220))	('alias FOG', 'Disease', (73, 82))	('GATA1', 'Gene', (94, 99))	('ZFPM1', 'Gene', (66, 71))	('alias FOG', 'Disease', 'None', (73, 82))	('NP_722520.2:p.Arg22Gly', 'Mutation', 'rs3751673', (222, 244))	('ZFPM1', 'Gene', '161882', (66, 71))	('GATA1', 'Gene', '2623', (142, 147))	('GATA1', 'Gene', '2623', (94, 99))
65930	28604728	We also observed promoter variants at 8q13.3 and 9p24.3, providing support respectively for the role of PRDM14 and DMRT1 in TGCT oncogenesis, both of which encode important transcriptional regulators of germ cell specification and sex determination.	('PRDM14', 'Gene', '63978', (104, 110))	('TGCT', 'Gene', (124, 128))	('DMRT1', 'Gene', (115, 120))	('TGCT', 'Phenotype', 'HP:0010788', (124, 128))	('PRDM14', 'Gene', (104, 110))	('sex determination', 'Disease', (231, 248))	('sex determination', 'Disease', 'MESH:D003643', (231, 248))	('DMRT1', 'Gene', '1761', (115, 120))	('variants', 'Var', (26, 34))
65931	28604728	Of final note the new locus at 20q13.2 was characterized by a predicted disrupted POU5F1 binding motif, together with a looping Hi-C contact from risk SNP rs12481572 to the promoter of SALL4, a gene associated with the maintenance of pluripotency in embryonic stem cells.	('binding', 'Interaction', (89, 96))	('Hi-C', 'Chemical', '-', (128, 132))	('rs12481572', 'Var', (155, 165))	('pluripotency', 'Disease', 'None', (234, 246))	('SALL4', 'Gene', '57167', (185, 190))	('SALL4', 'Gene', (185, 190))	('POU5F1', 'Gene', '5460', (82, 88))	('disrupted', 'NegReg', (72, 81))	('POU5F1', 'Gene', (82, 88))	('rs12481572', 'Mutation', 'rs12481572', (155, 165))	('pluripotency', 'Disease', (234, 246))
65933	28604728	Notably at locus 17q22 we observed a promoter variant (rs302875) which displays a strong eQTL effect (GTEx data, P=4.9 x 10-7) on TEX14 (Testis-Expressed 14), which encodes an important regulator of kinetochore-microtubule assembly in testicular germ cells.	('TEX14', 'Gene', (130, 135))	('rs302875', 'Mutation', 'rs302875', (55, 63))	('TEX14', 'Gene', '56155', (130, 135))	('Testis-Expressed 14', 'Gene', '56155', (137, 156))	('Testis-Expressed 14', 'Gene', (137, 156))	('rs302875', 'Var', (55, 63))
65934	28604728	At new risk locus 15q25.2 we identified a nominal eQTL association (rs2304416, TCGA data, P=3.2 x 10-2) and accompanying chromatin looping interaction with mitotic spindle assembly related gene WDR73 (Fig.	('eQTL', 'Disease', (50, 54))	('WDR73', 'Gene', (194, 199))	('rs2304416', 'Mutation', 'rs2304416', (68, 77))	('rs2304416', 'Var', (68, 77))	('WDR73', 'Gene', '84942', (194, 199))
65935	28604728	WDR73 encodes a protein with a crucial role in the regulation of microtubule organization during interphase and biallelic mutations cause Galloway-Mowat Syndrome, a human syndrome of nephrosis and neuronal dysmigration.	('human', 'Species', '9606', (165, 170))	('WDR73', 'Gene', '84942', (0, 5))	('biallelic mutations', 'Var', (112, 131))	('nephrosis', 'Phenotype', 'HP:0000100', (183, 192))	('WDR73', 'Gene', (0, 5))	('Galloway-Mowat Syndrome', 'Disease', (138, 161))	('nephrosis and neuronal dysmigration', 'Disease', 'MESH:C537548', (183, 218))	('cause', 'Reg', (132, 137))
65937	28604728	Thirdly, the central role of KIT-MAPK signalling in TGCT oncogenesis was further supported at four loci, by Hi-C looping interactions (at 11q14.1, 15q22.31), eQTL effects (at 6p21.31) and promoter variants (at 6p21.31, 11q14.1, 15q22.31).	('at 6p21.31', 'Var', (207, 217))	('TGCT', 'Phenotype', 'HP:0010788', (52, 56))	('Hi-C', 'Chemical', '-', (108, 112))	('TGCT', 'Disease', (52, 56))
65938	28604728	Recent tumour sequencing studies have established that KIT is the major somatic driver gene for TGCT and a relationship between the previously identified risk SNP rs995030 (12q21) and KITLG expression has been demonstrated through allele-specific p53 binding by Zeron-Medina et al.	('rs995030', 'Mutation', 'rs995030', (163, 171))	('KITLG', 'Gene', (184, 189))	('binding', 'Interaction', (251, 258))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('rs995030', 'Var', (163, 171))	('TGCT', 'Phenotype', 'HP:0010788', (96, 100))	('TGCT', 'Disease', (96, 100))	('p53', 'Gene', '7157', (247, 250))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))	('KITLG', 'Gene', '4254', (184, 189))	('p53', 'Gene', (247, 250))
65939	28604728	Here we report a new locus at 15q22.31, containing a variant within the promoter of MAP2K1 (Fig.	('MAP2K1', 'Gene', (84, 90))	('variant', 'Var', (53, 60))	('MAP2K1', 'Gene', '5604', (84, 90))
65942	28604728	In addition, within the 11q14.1 risk locus, we identify a candidate promoter variant for GAB2, which encodes a docking protein for signal transduction to MAPK and PI3K pathways which interacts directly with KIT.	('GAB2', 'Gene', '9846', (89, 93))	('GAB2', 'Gene', (89, 93))	('variant', 'Var', (77, 84))
65943	28604728	Finally in our analysis we identify both a candidate promoter variant and a nominal eQTL effect for BAK1 (6p21.31)(TCGA data, P=1.9 x 10-2), which encodes a protein regulating apoptosis which binds with KIT.	('binds', 'Interaction', (192, 197))	('eQTL', 'MPA', (84, 88))	('BAK1', 'Gene', '578', (100, 104))	('BAK1', 'Gene', (100, 104))	('variant', 'Var', (62, 69))
65947	28604728	This analysis suggests a model of TGCT susceptibility based on transcriptional dysregulation, which is likely to contribute to the developmental arrest of primordial germ cells coupled with chromosomal instability through defective microtubule function and accompanied upregulation of KIT-MAPK signalling.	('upregulation', 'PosReg', (269, 281))	('men', 'Species', '9606', (138, 141))	('defective', 'NegReg', (222, 231))	('TGCT', 'Disease', (34, 38))	('developmental arrest', 'Phenotype', 'HP:0007281', (131, 151))	('microtubule function', 'MPA', (232, 252))	('dysregulation', 'Var', (79, 92))	('TGCT', 'Phenotype', 'HP:0010788', (34, 38))	('chromosomal', 'MPA', (190, 201))	('chromosomal instability', 'Phenotype', 'HP:0040012', (190, 213))
65978	28604728	3C was used to validate selected chromatin interactions detected by CHi-C (3p24.3, 4q24, 11q14.1, 15q22.31, 15q25.2, 16q12.1, and 16q23.1) (Supplementary Fig.	('15q25.2', 'Var', (108, 115))	('Hi-C', 'Chemical', '-', (69, 73))	('CHi-C', 'Var', (68, 73))	('chromatin interactions', 'MPA', (33, 55))	('16q12.1', 'Var', (117, 124))	('men', 'Species', '9606', (146, 149))	('4q24', 'Var', (83, 87))
65985	28604728	Regions were amplified using both P-E and P-C primer pairs in BAC and NTERA2 libraries using a QIAGEN Multiplex PCR Kit (QIAGEN, Hilden, Germany).	('P-C primer pairs', 'Var', (42, 58))	('NTERA2', 'CellLine', 'CVCL:0034', (70, 76))	('P-E', 'Var', (34, 37))
66001	28604728	To validate the specificity of these motifs for TGCT we conducted variant set enrichment analysis, using the same method as detailed above (based on Cowper-Sal lari et al), which confirmed enrichment for disruption of these 10 motifs in the 44 TGCT risk loci compared to the null distribution (Supplementary Table 10).	('TGCT', 'Disease', (244, 248))	('men', 'Species', '9606', (300, 303))	('men', 'Species', '9606', (84, 87))	('TGCT', 'Phenotype', 'HP:0010788', (244, 248))	('disruption', 'Var', (204, 214))	('TGCT', 'Phenotype', 'HP:0010788', (48, 52))	('men', 'Species', '9606', (195, 198))
66002	28604728	Risk loci were then annotated with six types of functional data: (i) presence of a Hi-C contact linking to a gene promoter, (ii) presence of an expression quantitative trait locus, (iii) presence of a ChIP-seq peak, (iv) presence of a disrupted transcription factor binding motif, (v) presence of a variant within a gene promoter boundary, with boundaries defined using the Ensembl regulatory build, (vi) presence of a non-synonymous coding change.	('Hi-C', 'Chemical', '-', (83, 87))	('variant', 'Var', (299, 306))	('presence', 'Reg', (285, 293))
66046	23362440	According to the 2009 TNM classification, stage I testicular cancer includes the following substages: stage IA, pT1N0M0S0; stage IB, pT2-T4N0M0S0; and stage IS, any pT/TxN0M0S1-S3.	('pT2-T4N0M0S0', 'Var', (133, 145))	('testicular cancer', 'Phenotype', 'HP:0010788', (50, 67))	('testicular cancer', 'Disease', 'MESH:D013736', (50, 67))	('pT1', 'Gene', '58492', (112, 115))	('testicular cancer', 'Disease', (50, 67))	('stage', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('pT1', 'Gene', (112, 115))
66239	21461280	Several other studies have shown that bilateral TM is associated with the pre-invasive stage of germ cell testicular cancer more so than unilateral.	('associated with', 'Reg', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pre-invasive', 'Disease', (74, 86))	('testicular cancer', 'Phenotype', 'HP:0010788', (106, 123))	('bilateral', 'Var', (38, 47))	('testicular cancer', 'Disease', 'MESH:D013736', (106, 123))	('TM', 'Phenotype', 'HP:0012215', (48, 50))	('testicular cancer', 'Disease', (106, 123))
66596	19223531	If significant exposure occurred in utero, PCBs may also affect the risk of the male reproductive congenital anomalies that are associated with TGCT.	('congenital anomalies', 'Disease', 'MESH:D000013', (98, 118))	('reproductive congenital anomalies', 'Phenotype', 'HP:0000078', (85, 118))	('affect', 'Reg', (57, 63))	('PCBs', 'Var', (43, 47))	('PCBs', 'Chemical', 'MESH:D011078', (43, 47))	('congenital anomalies', 'Disease', (98, 118))
66622	19223531	Three of the four Wolff Group 3 (phenobarbitol, CYP1A, and CYP2B inducers) PCBs were significantly inversely related to risk (PCB-153, PCB-180, PCB-183) while there was no relationship with PCB-99.	('PCB', 'Gene', '5091', (75, 78))	('phenobarbitol', 'Chemical', 'MESH:D010634', (33, 46))	('PCB', 'Gene', (75, 78))	('PCB', 'Gene', (135, 138))	('PCB', 'Gene', (190, 193))	('CYP2B', 'Gene', '1556', (59, 64))	('PCB', 'Gene', '5091', (190, 193))	('related', 'Reg', (109, 116))	('inversely', 'NegReg', (99, 108))	('PCB', 'Gene', '5091', (126, 129))	('PCB', 'Gene', (126, 129))	('PCB', 'Gene', '5091', (144, 147))	('PCB', 'Gene', (144, 147))	('CYP2B', 'Gene', (59, 64))	('PCBs', 'Chemical', 'MESH:D011078', (75, 79))	('PCB', 'Gene', '5091', (135, 138))	('CYP1A', 'Var', (48, 53))
66630	19223531	In conclusion, the current study suggests that PCBs are inversely associated with the risk of TGCT, particularly with nonseminoma.	('nonseminoma', 'Disease', (118, 129))	('PCBs', 'Var', (47, 51))	('nonseminoma', 'Disease', 'None', (118, 129))	('PCBs', 'Chemical', 'MESH:D011078', (47, 51))	('TGCT', 'Disease', (94, 98))
66652	16762081	Our findings suggest that TSPY expression increases cell proliferation in vitro and tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('increases', 'PosReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cell proliferation', 'CPA', (52, 70))	('rat', 'Species', '10116', (64, 67))	('tumor', 'Disease', (84, 89))	('expression', 'Var', (31, 41))	('TSPY', 'Gene', (26, 30))
66653	16762081	Microarray analysis demonstrates that numerous genes involved in the cell cycle and apoptosis are affected by TSPY expression in the HeLa cells.	('apoptosis', 'CPA', (84, 93))	('affected', 'Reg', (98, 106))	('TSPY', 'Gene', (110, 114))	('cell cycle', 'CPA', (69, 79))	('HeLa', 'CellLine', 'CVCL:0030', (133, 137))	('rat', 'Species', '10116', (27, 30))	('expression', 'Var', (115, 125))
66668	16762081	Deletion mapping for the gonadoblastoma locus on the Y chromosome (GBY) has localized this oncogenic locus in a critical region (~1-2 Mb) on the short arm of this chromosome that contains most of the functional copies of the TSPY gene.	('short arm', 'Phenotype', 'HP:0009824', (145, 154))	('gonadoblastoma', 'Phenotype', 'HP:0000150', (25, 39))	('TSPY', 'Gene', (225, 229))	('gonadoblastoma', 'Disease', (25, 39))	('gonadoblastoma', 'Disease', 'MESH:D018238', (25, 39))	('Deletion', 'Var', (0, 8))
66672	16762081	Our results suggest that ectopic expression of TSPY increases cell proliferation in vitro and tumorigenesis in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('increases', 'PosReg', (52, 61))	('rat', 'Species', '10116', (74, 77))	('cell proliferation', 'CPA', (62, 80))	('tumor', 'Disease', (94, 99))	('TSPY', 'Gene', (47, 51))	('ectopic expression', 'Var', (25, 43))
66684	16762081	EGFP expression in cultured cells was observed directly under a Zeiss Axiophot fluorescence microscope using an excitation filter HQ 480/40 and an emission filter HQ 510 LP (Chroma Technology Corp., Rockingham, VT).	('P', 'Chemical', 'MESH:D010758', (171, 172))	('Chroma Technology Corp', 'Disease', 'None', (174, 196))	('P', 'Chemical', 'MESH:D010758', (3, 4))	('VT', 'Disease', 'MESH:D017180', (211, 213))	('HQ 510 LP', 'Var', (163, 172))	('Chroma Technology Corp', 'Disease', (174, 196))
66733	16762081	Although we cannot rule out completely that co-expression of TSPY might enhance the TK-Hyg gene expression, these results, and those from cell proliferation analysis described below, suggested that over-expression of TSPY enhances the efficiency of cell growth under such selection.	('TSPY', 'Gene', (217, 221))	('enhance', 'PosReg', (72, 79))	('co-expression', 'Var', (44, 57))	('expression', 'MPA', (96, 106))	('TK-Hyg gene', 'Gene', (84, 95))	('enhances', 'PosReg', (222, 230))	('cell growth', 'CPA', (249, 260))	('rat', 'Species', '10116', (150, 153))	('over-expression', 'PosReg', (198, 213))
66737	16762081	These findings suggest that ectopic expression of TSPY potentiates cell proliferation in cultured cells.	('cell proliferation in cultured', 'CPA', (67, 97))	('TSPY', 'Gene', (50, 54))	('rat', 'Species', '10116', (79, 82))	('ectopic expression', 'Var', (28, 46))	('potentiates', 'PosReg', (55, 66))
66742	16762081	An accelerated tumor growth was observed in mice inoculated with HeLa Tet-off cells over-expressing TSPY (without doxycycline in their drinking water) compared to the group repressing TSPY (with doxycycline in their drinking water).	('rat', 'Species', '10116', (9, 12))	('over-expressing', 'Var', (84, 99))	('TSPY', 'Gene', (100, 104))	('doxycycline', 'Chemical', 'MESH:D004318', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Tet', 'Chemical', 'MESH:C010349', (70, 73))	('drinking water', 'Chemical', 'MESH:D060766', (216, 230))	('accelerated', 'PosReg', (3, 14))	('tumor', 'Disease', (15, 20))	('doxycycline', 'Chemical', 'MESH:D004318', (195, 206))	('HeLa', 'CellLine', 'CVCL:0030', (65, 69))	('mice', 'Species', '10090', (44, 48))	('drinking water', 'Chemical', 'MESH:D060766', (135, 149))
66744	16762081	These results suggested that ectopic expression of TSPY increased tumor growth in athymic nude mice.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TSPY', 'Gene', (51, 55))	('ectopic expression', 'Var', (29, 47))	('increased', 'PosReg', (56, 65))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('nude mice', 'Species', '10090', (90, 99))
66750	16762081	Our study, so far, showed that ectopic expression of TSPY in HeLa and NIH3T3 cells potentiated cell proliferation in vitro and tumor growth in nude mice.	('cell proliferation', 'CPA', (95, 113))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('NIH3T3', 'CellLine', 'CVCL:0594', (70, 76))	('HeLa', 'CellLine', 'CVCL:0030', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('nude mice', 'Species', '10090', (143, 152))	('TSPY', 'Gene', (53, 57))	('ectopic expression', 'Var', (31, 49))	('potentiated', 'PosReg', (83, 94))	('rat', 'Species', '10116', (107, 110))
66761	16762081	Our results showed that cells expressing TSPY progressed through the G1 and S phases (Figure 3F) at similar rates to those lacking TSPY expression (Figure 3E).	('progressed', 'PosReg', (46, 56))	('rat', 'Species', '10116', (108, 111))	('TSPY', 'Var', (41, 45))	('S', 'Chemical', 'MESH:D013455', (76, 77))	('S', 'Chemical', 'MESH:D013455', (132, 133))	('S phases', 'CPA', (76, 84))	('S', 'Chemical', 'MESH:D013455', (42, 43))
66784	16762081	In additional to CCND2, another genes, the transmembrane and tetratricopeptide repeats (TMTC1) from chromosome 12p was also up-regulated by the ectopic expression of TSPY in HeLa cells.	('CCND2', 'Gene', '894', (17, 22))	('up-regulated', 'PosReg', (124, 136))	('TMTC1', 'Gene', '83857', (88, 93))	('rat', 'Species', '10116', (64, 67))	('TSPY', 'Gene', (166, 170))	('ectopic expression', 'Var', (144, 162))	('HeLa', 'CellLine', 'CVCL:0030', (174, 178))	('CCND2', 'Gene', (17, 22))	('TMTC1', 'Gene', (88, 93))
66790	16762081	CUL1, IGFBP3, TIMP1, and SPARC were confirmed as down-regulated genes in cells expressing TSPY (Figure 6B); each of these also showed a slight change in fold expression compared to the microarray data.	('TIMP1', 'Gene', '7076', (14, 19))	('CUL1', 'Gene', '8454', (0, 4))	('IGFBP3', 'Gene', (6, 12))	('change', 'Reg', (143, 149))	('SPARC', 'Gene', '6678', (25, 30))	('down-regulated', 'NegReg', (49, 63))	('TSPY', 'Var', (90, 94))	('IGFBP3', 'Gene', '3486', (6, 12))	('fold expression', 'MPA', (153, 168))	('TIMP1', 'Gene', (14, 19))	('SPARC', 'Gene', (25, 30))	('CUL1', 'Gene', (0, 4))
66799	16762081	Deletion of the acidic domain in CDA1/TSPX eliminates its inhibitory effects on the G2/M progression in the cell cycle, suggesting the TSPY and TSPX might possess contrasting functions on cell cycle modulation.	('TSPX', 'Gene', '64061', (144, 148))	('TSPX', 'Gene', '64061', (38, 42))	('CDA1', 'Gene', '64061', (33, 37))	('inhibitory effects', 'MPA', (58, 76))	('TSPX', 'Gene', (38, 42))	('TSPX', 'Gene', (144, 148))	('CDA1', 'Gene', (33, 37))	('G2/M progression in the cell cycle', 'CPA', (84, 118))	('eliminates', 'NegReg', (43, 53))	('Deletion', 'Var', (0, 8))
66806	16762081	The present studies were designed to address the question on the effects of ectopic TSPY expression in cell proliferation and tumorigenesis in immunodeficient mice.	('ectopic', 'Var', (76, 83))	('rat', 'Species', '10116', (115, 118))	('immunodeficient', 'Disease', 'MESH:D007153', (143, 158))	('immunodeficient', 'Disease', (143, 158))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('TSPY', 'Gene', (84, 88))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', (126, 131))
66808	16762081	Significantly, NIH3T3 cells are non-tumorigenic, the development of small tumors in nude mice inoculated with TSPY expressing NIH3T3 cells suggests that TSPY could potentially play the role of an oncogene.	('small tumors', 'Disease', (68, 80))	('S', 'Chemical', 'MESH:D013455', (111, 112))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('small tumors', 'Disease', 'MESH:D058405', (68, 80))	('nude mice', 'Species', '10090', (84, 93))	('S', 'Chemical', 'MESH:D013455', (154, 155))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('NIH3T3', 'CellLine', 'CVCL:0594', (15, 21))	('NIH3T3', 'Var', (126, 132))	('tumor', 'Disease', (36, 41))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('NIH3T3', 'CellLine', 'CVCL:0594', (126, 132))
66814	16762081	The present studies have demonstrated that ectopic TSPY expression expedites cell cycle progression through shortening of the G2/M transition.	('TSPY', 'Gene', (51, 55))	('rat', 'Species', '10116', (32, 35))	('expedites', 'PosReg', (67, 76))	('ectopic', 'Var', (43, 50))	('G2/M transition', 'CPA', (126, 141))	('shortening', 'NegReg', (108, 118))	('cell cycle progression', 'CPA', (77, 99))	('expression', 'Var', (56, 66))
66902	25288876	A Review of Cancer Risk Prediction Models with Genetic Variants Cancer risk prediction models are important in identifying individuals at high risk of developing cancer, which could result in targeted screening and interventions to maximize the treatment benefit and minimize the burden of cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('Cancer', 'Disease', (64, 70))	('Cancer', 'Disease', 'MESH:D009369', (12, 18))	('Genetic Variants', 'Var', (47, 63))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (290, 296))	('men', 'Species', '9606', (250, 253))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('Cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Disease', (12, 18))
66903	25288876	The cancer-associated genetic variants identified in genome-wide or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('variants', 'Var', (30, 38))	('improve', 'PosReg', (167, 174))	('result in', 'Reg', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('men', 'Species', '9606', (268, 271))	('men', 'Species', '9606', (246, 249))	('carcinogenesis', 'Disease', 'MESH:D063646', (196, 210))	('patients', 'Species', '9606', (278, 286))	('cancer', 'Disease', (143, 149))	('carcinogenesis', 'Disease', (196, 210))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('enhance', 'PosReg', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))
66913	25288876	The cancer-associated genetic variants identified in GWAS or candidate gene association studies have been shown to collectively enhance cancer risk prediction, improve our understanding of carcinogenesis, and possibly result in the development of targeted treatments for patients.	('variants', 'Var', (30, 38))	('men', 'Species', '9606', (261, 264))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('result in', 'Reg', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('men', 'Species', '9606', (239, 242))	('cancer', 'Disease', (136, 142))	('carcinogenesis', 'Disease', (189, 203))	('enhance', 'PosReg', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('patients', 'Species', '9606', (271, 279))	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('improve', 'PosReg', (160, 167))
66914	25288876	For example, clinicians already use these kinds of guidelines in making decisions about assessments in order to identify carriers of BRCA1 and BRCA2 mutations, which indicate very high risks of breast and ovarian cancer.	('BRCA2', 'Gene', '675', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (149, 158))	('men', 'Species', '9606', (94, 97))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (194, 219))	('BRCA1', 'Gene', '672', (133, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('BRCA2', 'Gene', (143, 148))	('BRCA1', 'Gene', (133, 138))
66915	25288876	The number of rapidly discovered cancer-associated genetic variants continues to rise and is reflected by the increasing number of published articles looking closely at the performance of genetic variants in popular cancer risk prediction models.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('variants', 'Var', (59, 67))	('man', 'Species', '9606', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
66916	25288876	These studies have prompted an updated assessment of the associations between genetic variants and cancer risk.	('men', 'Species', '9606', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('variants', 'Var', (86, 94))	('cancer', 'Disease', (99, 105))	('associations', 'Interaction', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
66918	25288876	This paper examines in detail the performance of cancer risk prediction models with genetic variants by examining the relevant studies through PubMed, Medline, and Web of Science.	('man', 'Species', '9606', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('genetic variants', 'Var', (84, 100))
66919	25288876	This review article summarizes what has been learned regarding the contribution of genetic variants as an alternative or as a supplement to the components of risk prediction models for cancer including breast cancer, prostate cancer, testicular cancer, lung cancer, and bladder cancer, as well as cancers of the head and neck.	('testicular cancer', 'Disease', (234, 251))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('prostate cancer', 'Phenotype', 'HP:0012125', (217, 232))	('prostate cancer', 'Disease', (217, 232))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('testicular cancer', 'Phenotype', 'HP:0010788', (234, 251))	('cancer', 'Disease', (278, 284))	('cancers of the head and neck', 'Phenotype', 'HP:0012288', (297, 325))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('lung cancer', 'Disease', (253, 264))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bladder cancer', 'Disease', 'MESH:D001749', (270, 284))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('bladder cancer', 'Disease', (270, 284))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('bladder cancer', 'Phenotype', 'HP:0009725', (270, 284))	('cancer', 'Disease', (245, 251))	('lung cancer', 'Disease', 'MESH:D008175', (253, 264))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('testicular cancer', 'Disease', 'MESH:D013736', (234, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('cancer', 'Disease', (297, 303))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('cancers', 'Disease', (297, 304))	('breast cancer', 'Disease', (202, 215))	('men', 'Species', '9606', (132, 135))	('cancer', 'Disease', (209, 215))	('cancer', 'Disease', (226, 232))	('variants', 'Var', (91, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (217, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
66927	25288876	Approximately, 60% of women with an inherited mutation in BRCA1 or BRCA2 will develop breast cancer sometime during their lives, compared with about 12% of women in the general population.	('BRCA1', 'Gene', (58, 63))	('women', 'Species', '9606', (22, 27))	('women', 'Species', '9606', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BRCA2', 'Gene', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('BRCA2', 'Gene', '675', (67, 72))	('mutation', 'Var', (46, 54))	('develop', 'PosReg', (78, 85))	('BRCA1', 'Gene', '672', (58, 63))
66928	25288876	Women with inherited BRCA1 or BRCA2 gene mutations also have an increased risk of ovarian cancer.	('mutations', 'Var', (41, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', '672', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('BRCA1', 'Gene', (21, 26))	('ovarian cancer', 'Disease', (82, 96))	('BRCA2', 'Gene', (30, 35))	('BRCA2', 'Gene', '675', (30, 35))
66934	25288876	No significant evidence was found that polygenic risk score (PRS) using common variants could improve risk prediction for breast cancer over replicated SNP scores that had been robustly replicated across several independent sample sets.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('variants', 'Var', (79, 87))	('improve', 'PosReg', (94, 101))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))
66935	25288876	Some polymorphisms identified in GWAS were also associated with an increased risk of breast cancer for BRCA1 or BRCA2 mutation carriers.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('BRCA1', 'Gene', '672', (103, 108))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('associated with', 'Reg', (48, 63))	('BRCA1', 'Gene', (103, 108))	('BRCA2', 'Gene', (112, 117))	('mutation', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRCA2', 'Gene', '675', (112, 117))	('polymorphisms', 'Var', (5, 18))
66938	25288876	Three additional SNPs (ie, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12) were also evaluated in this study.	('rs6504950', 'Var', (54, 63))	('STXBP4', 'Gene', (67, 73))	('STXBP4', 'Gene', '252983', (67, 73))	('rs10941679', 'Mutation', 'rs10941679', (85, 95))	('COX11', 'Gene', '1353', (74, 79))	('NEK10', 'Gene', (47, 52))	('SLC4A7', 'Gene', (40, 46))	('NEK10', 'Gene', '152110', (47, 52))	('SLC4A7', 'Gene', '9497', (40, 46))	('rs4973768', 'Mutation', 'rs4973768', (27, 36))	('rs6504950', 'Mutation', 'rs6504950', (54, 63))	('COX11', 'Gene', (74, 79))	('rs4973768', 'Var', (27, 36))	('rs10941679', 'Var', (85, 95))
66940	25288876	Based on the joint genotype distribution of seven risk-associated SNPs in BRCA2 mutation carriers, the top 5% high-risk BRCA2 carriers were predicted to develop breast cancer by the age of 80 with a probability of 80-96%, whereas the bottom 5% low-risk BRCA2 carriers only have a risk of 42-50% of developing breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('BRCA2', 'Gene', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('breast cancer', 'Disease', (161, 174))	('breast cancer', 'Disease', 'MESH:D001943', (309, 322))	('BRCA2', 'Gene', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('develop', 'PosReg', (153, 160))	('BRCA2', 'Gene', (120, 125))	('breast cancer', 'Disease', (309, 322))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA2', 'Gene', '675', (253, 258))	('BRCA2', 'Gene', '675', (120, 125))	('mutation', 'Var', (80, 88))
66943	25288876	Although each low-penetrance variant confers only a small increase in the risk of breast cancer, a combination of single variants may act cumulatively to increase the risk.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('variant', 'Var', (29, 36))	('increase', 'PosReg', (154, 162))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
66945	25288876	In addition, they created a polygenic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using AUC.	('variants', 'Var', (62, 70))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('association', 'Interaction', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))
66959	25288876	Recently, more than 30 discovered SNPs have been associated with prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('associated', 'Reg', (49, 59))	('SNPs', 'Var', (34, 38))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
66960	25288876	SNPs identified and associated with prostate cancer in GWAS are common but confer only small increases in the risk.	('prostate cancer', 'Disease', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('SNPs', 'Var', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (36, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (36, 51))
66969	25288876	Other studies have combined genetic variants along with PSA to predict the risk of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('PSA', 'Gene', '354', (56, 59))	('PSA', 'Gene', (56, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('variants', 'Var', (36, 44))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
66970	25288876	specifically combined 33 genetic variants with PSA and evaluated the risk.	('variants', 'Var', (33, 41))	('PSA', 'Gene', '354', (47, 50))	('combined', 'Reg', (13, 21))	('PSA', 'Gene', (47, 50))
66971	25288876	The AUC was used to assess whether the GRS of 33 SNPs in addition to pre-diagnostic PSA improves prostate cancer prediction.	('improves', 'PosReg', (88, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('PSA', 'Gene', (84, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('GRS of 33 SNPs', 'Var', (39, 53))	('PSA', 'Gene', '354', (84, 87))	('prostate cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
66997	25288876	Previously published GWAS and candidate gene data have also been used to build a multiplicative model with risk variants and estimate the AUC as a measure of discrimination between testicular cancer cases and controls.	('testicular cancer', 'Disease', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('testicular cancer', 'Phenotype', 'HP:0010788', (181, 198))	('testicular cancer', 'Disease', 'MESH:D013736', (181, 198))	('variants', 'Var', (112, 120))	('AUC', 'MPA', (138, 141))
67028	25288876	Four independent SNPs were found to be associated with a risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SNPs', 'Var', (17, 21))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('associated', 'Reg', (39, 49))
67034	25288876	further evaluated a panel of 1,440 inflammatory gene variants in a two-phase analysis (discovery and replication), adding top GWAS lung cancer hits from white populations, and 28 SNPs from a published gene panel.	('top GWAS lung cancer hits', 'Disease', 'MESH:D008175', (122, 147))	('top GWAS lung cancer hits', 'Disease', (122, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('variants', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
67036	25288876	One inflammation SNP, rs950286, which is intergenic between IRF4 and EXOC2 genes, was successfully replicated with a concordant odds ratio of 1.46 (1.14-1.87) in discovery, 1.37 (1.05-1.77) in replication, and a combined odds ratio of 1.40 (1.17-1.68).	('EXOC2', 'Gene', '55770', (69, 74))	('rat', 'Species', '10116', (133, 136))	('rat', 'Species', '10116', (226, 229))	('inflammation SNP', 'Disease', (4, 20))	('rs950286', 'Var', (22, 30))	('IRF4', 'Gene', '3662', (60, 64))	('IRF4', 'Gene', (60, 64))	('rs950286', 'Mutation', 'rs950286', (22, 30))	('EXOC2', 'Gene', (69, 74))	('inflammation SNP', 'Disease', 'MESH:D007249', (4, 20))
67043	25288876	The model consisted of 678 white patients and 678 controls and included mutagen sensitivity and pack-years as well as six other risk factors, while achieving a 0.80 AUC, demonstrating good discrimination ability.	('mutagen sensitivity', 'Var', (72, 91))	('rat', 'Species', '10116', (177, 180))	('patients', 'Species', '9606', (33, 41))	('included', 'Reg', (63, 71))
67046	25288876	In a recent paper published in Cancer Research, Garcia-Closas and colleagues examined how genetic variants were recently identified in GWAS for bladder cancer interaction with smoking status to influence bladder cancer risk.	('influence', 'Reg', (194, 203))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('bladder cancer', 'Disease', (204, 218))	('Garcia-Closas', 'Disease', 'MESH:C536767', (48, 61))	('interaction', 'Interaction', (159, 170))	('Garcia-Closas', 'Disease', (48, 61))	('Cancer', 'Disease', (31, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (204, 218))	('bladder cancer', 'Phenotype', 'HP:0009725', (204, 218))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('variants', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
67060	25288876	Several studies have reported that SNPs of genes in multiple biological pathways are involved in the development of head and neck cancer.	('SNPs', 'Var', (35, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (116, 136))	('men', 'Species', '9606', (108, 111))	('involved', 'Reg', (85, 93))	('head and neck cancer', 'Disease', 'MESH:D006258', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
67061	25288876	performed a two-stage GWAS with a total of 8,605 cases and 11,405 controls and reported that five genetic variants had significant associations with risk of upper aerodigestive tract cancers including head and neck cancer in Europeans.	('variants', 'Var', (106, 114))	('associations', 'Interaction', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('head and neck cancer', 'Phenotype', 'HP:0012288', (201, 221))	('upper aerodigestive tract cancers', 'Disease', (157, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('head and neck cancer', 'Disease', 'MESH:D006258', (201, 221))	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (157, 190))
67074	25288876	Table 1 indicates that the cancer risk prediction models with genetic variants generally outperform the models without genetic variants in both discrimination and prediction of cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('outperform', 'NegReg', (89, 99))	('variants', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
67087	25288876	Due to the difference in effect sizes of associated SNPs, the power of genetic variants in prediction for different cancers is different as well.	('variants', 'Var', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
67092	25288876	For example, abnormalities of the P53 gene (which codes for the P53 protein) have been found in more than half of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('P53', 'Gene', (64, 67))	('P53', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('P53', 'Gene', '7157', (64, 67))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('P53', 'Gene', '7157', (34, 37))	('found', 'Reg', (87, 92))	('abnormalities', 'Var', (13, 26))
67093	25288876	Acquired mutations of this gene appear in a wide range of cancers, including lung, colorectal, and breast cancer.	('colorectal', 'Disease', (83, 93))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', (99, 112))	('mutations', 'Var', (9, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('lung', 'Disease', (77, 81))	('appear', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
67100	24639717	The expression of Toll-Like Receptors (TLRs) in testicular cancer: A case control study Background: It has been suggested that malfunction of immune system may causes testicular cancer.	('testicular cancer', 'Disease', (48, 65))	('malfunction of immune system', 'Phenotype', 'HP:0002721', (127, 155))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('malfunction', 'Var', (127, 138))	('testicular cancer', 'Phenotype', 'HP:0010788', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('testicular cancer', 'Disease', 'MESH:D013736', (48, 65))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TLRs', 'Gene', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('testicular cancer', 'Disease', 'MESH:D013736', (167, 184))	('testicular cancer', 'Phenotype', 'HP:0010788', (48, 65))	('cancer', 'Disease', (59, 65))	('testicular cancer', 'Disease', (167, 184))	('causes', 'Reg', (160, 166))
67101	24639717	Some studies have shown that polymorphisms of TLR2 and 4 may affect on the risk of cancer.	('TLR2', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TLR2 and 4', 'Gene', '7097;7099', (46, 56))	('affect', 'Reg', (61, 67))	('cancer', 'Disease', (83, 89))	('polymorphisms', 'Var', (29, 42))	('TLR2', 'Gene', '7097', (46, 50))
67108	24639717	Imperfections during male germ cell development can lead to the formation of testicular germ cell tumors (TGCTs), which are classified as teratomas, nonseminomas and seminomas.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('nonseminomas and seminomas', 'Disease', 'MESH:D018239', (149, 175))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('teratomas', 'Phenotype', 'HP:0009792', (138, 147))	('seminoma', 'Disease', 'MESH:D018239', (152, 160))	('seminoma', 'Disease', 'MESH:D018239', (166, 174))	('teratomas', 'Disease', (138, 147))	('Imperfections', 'Var', (0, 13))	('teratomas', 'Disease', 'MESH:D013724', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('germ cell tumors', 'Phenotype', 'HP:0100728', (88, 104))	('lead to', 'Reg', (52, 59))	('seminoma', 'Disease', (152, 160))	('seminoma', 'Disease', (166, 174))
67126	24639717	SYBR Green Jump Start Taq Ready mix (Sigma) master mix [containing 10 mul SYBR Green, 7 mul of water, 1 mul of each primers (20 pmol/mul) and 1 mul of cDNA] was added to each well of PCR plate and amplification was performed under the following conditions: 50 cycles of 95oC for 30s, 58-60oC for 30s and 72oC for 30s.	('SYBR Green', 'Chemical', '-', (0, 10))	('95oC', 'Var', (270, 274))	('SYBR Green', 'Chemical', '-', (74, 84))	('mix', 'Gene', (32, 35))	('mix', 'Gene', '83881', (51, 54))	('mix', 'Gene', (51, 54))	('mix', 'Gene', '83881', (32, 35))
67160	23687617	In the absence of a functional BTB (through knockout of the major tight junction protein claudin-11), Sertoli cells proliferate and undergo apoptosis, while germ cells do not progress past early spermatocytes.	('Sertoli cells', 'Phenotype', 'HP:0100619', (102, 115))	('knockout', 'Var', (44, 52))	('Sertoli cell', 'Phenotype', 'HP:0100619', (102, 114))	('apoptosis', 'CPA', (140, 149))	('claudin-11', 'Gene', '5010', (89, 99))	('claudin-11', 'Gene', (89, 99))	('rat', 'Species', '10116', (123, 126))	('proliferate', 'CPA', (116, 127))
67196	23687617	Further to this, the hamster data show that replacement of FSH also promptly (within a week) and completely replenishes the Sertoli cell population as a result of increased proliferation and restored blood testis barrier protein localization.	('blood testis barrier protein localization', 'MPA', (200, 241))	('rat', 'Species', '10116', (180, 183))	('men', 'Species', '9606', (51, 54))	('increased', 'PosReg', (163, 172))	('Sertoli cell', 'MPA', (124, 136))	('hamster', 'Species', '10034', (21, 28))	('restored blood testis barrier', 'Phenotype', 'HP:0012870', (191, 220))	('FSH', 'Gene', (59, 62))	('Sertoli cell', 'Phenotype', 'HP:0100619', (124, 136))	('replenishes', 'NegReg', (108, 119))	('restored', 'PosReg', (191, 199))	('replacement', 'Var', (44, 55))
67220	23687617	A novel finding of the aberrant high expression of JAM-A in seminoma warrants further investigation, as the relevance of this to the disease process remains unknown.	('JAM-A', 'Gene', (51, 56))	('seminoma', 'Disease', (60, 68))	('seminoma', 'Disease', 'MESH:D018239', (60, 68))	('JAM-A', 'Gene', '50848', (51, 56))	('expression', 'MPA', (37, 47))	('aberrant', 'Var', (23, 31))
67272	21155977	It has been established that Plzf (promyelocyte leukaemia zinc-finger factor), a transcriptional repressor, is essential for SSCs self-renewal, as the loss of Plzf results in differentiation of SSCs at the cost of self-renewal.	('differentiation', 'CPA', (175, 190))	('SSCs', 'Disease', (194, 198))	('Plzf', 'Gene', '235320', (159, 163))	('Plzf', 'Gene', '235320', (29, 33))	('results in', 'Reg', (164, 174))	('promyelocyte leukaemia zinc-finger factor', 'Gene', (35, 76))	('promyelocyte leukaemia zinc-finger factor', 'Gene', '235320', (35, 76))	('Plzf', 'Gene', (29, 33))	('Plzf', 'Gene', (159, 163))	('promyelocyte leukaemia', 'Phenotype', 'HP:0004836', (35, 57))	('loss', 'Var', (151, 155))
67277	21155977	OCT4 knockdown SSCs could not colonize in both culture and transplanted testes.	('knockdown', 'Var', (5, 14))	('OCT4', 'Gene', (0, 4))	('OCT4', 'Gene', '18999', (0, 4))
67278	21155977	Further, it has been found that PLZF is not affected by knockdown of OCT4, which suggests that OCT4 and PLZF function in different pathways to maintain SSCs self-renewal.	('OCT4', 'Gene', (69, 73))	('OCT4', 'Gene', '18999', (69, 73))	('PLZF', 'Gene', (104, 108))	('PLZF', 'Gene', '235320', (104, 108))	('function', 'Reg', (109, 117))	('PLZF', 'Gene', (32, 36))	('OCT4', 'Gene', (95, 99))	('OCT4', 'Gene', '18999', (95, 99))	('PLZF', 'Gene', '235320', (32, 36))	('knockdown', 'Var', (56, 65))
67300	21155977	It has been demonstrated that removal of GDNF/GDNF family receptor (GFRA)1 from the culture medium for SSCs up-regulate expression of Neurog3 and proposed that Neurog3 may be an initiation signal for SSCs differentiation.	('expression', 'MPA', (120, 130))	('GFRA)1', 'Gene', '14585', (68, 74))	('Neurog3', 'Gene', (160, 167))	('rat', 'Species', '10116', (19, 22))	('Neurog3', 'Gene', (134, 141))	('up-regulate', 'PosReg', (108, 119))	('Neurog3', 'Gene', '11925', (160, 167))	('removal', 'Var', (30, 37))	('Neurog3', 'Gene', '11925', (134, 141))	('SSCs', 'Disease', (200, 204))
67305	21155977	Loss of any of these two genes blocks differentiation, resulting in infertility.	('resulting in', 'Reg', (55, 67))	('blocks', 'NegReg', (31, 37))	('infertility', 'Phenotype', 'HP:0000789', (68, 79))	('infertility', 'Disease', 'MESH:D007247', (68, 79))	('Loss', 'Var', (0, 4))	('infertility', 'Disease', (68, 79))	('differentiation', 'CPA', (38, 53))
67307	21155977	It is reported that male mice with juvenile spermatogonial depletion (jsd) mutation in UTP14b gene causes cessation of spermatogonial differentiation and in adults, only spermatogonial cells are remain, which suggest that it is involved in spermatogonial differentiation.	('mice', 'Species', '10090', (25, 29))	('mutation', 'Var', (75, 83))	('spermatogonial differentiation', 'CPA', (119, 149))	('UTP14b', 'Gene', '195434', (87, 93))	('UTP14b', 'Gene', (87, 93))	('cessation', 'NegReg', (106, 115))
67310	21155977	It has been shown that the gene encoding mouse cyclin A1, Ccna1, is highly expressed in late pachytene-diplotene spermatocytes and disruption of Ccna1 resulted in male infertility and complete spermatogenic arrest before first meiotic division (for references see).	('diplotene', 'Chemical', '-', (103, 112))	('spermatogenic arrest', 'Phenotype', 'HP:0031038', (193, 213))	('pachytene', 'Chemical', '-', (93, 102))	('mouse', 'Species', '10090', (41, 46))	('cyclin A1', 'Gene', '12427', (47, 56))	('infertility', 'Phenotype', 'HP:0000789', (168, 179))	('cyclin A1', 'Gene', (47, 56))	('Ccna1', 'Gene', (58, 63))	('resulted in', 'Reg', (151, 162))	('Ccna1', 'Gene', '12427', (58, 63))	('male infertility', 'Phenotype', 'HP:0003251', (163, 179))	('male infertility', 'Disease', (163, 179))	('male infertility', 'Disease', 'MESH:D007248', (163, 179))	('Ccna1', 'Gene', (145, 150))	('disruption', 'Var', (131, 141))	('spermatogenic arrest', 'CPA', (193, 213))	('Ccna1', 'Gene', '12427', (145, 150))
67344	21155977	Mutations in the USP26 (ubiquitin-specific protease 26) gene may play a role in male infertility and the Herc4 (E3 ubiquitin ligase), highly expressed in the testis, is also known to play a critical role in infertility by reducing motility of the spermatozoa.	('ubiquitin-specific protease 26', 'Gene', (24, 54))	('infertility', 'Disease', (207, 218))	('Herc4', 'Gene', '67345', (105, 110))	('male infertility', 'Phenotype', 'HP:0003251', (80, 96))	('male infertility', 'Disease', (80, 96))	('infertility', 'Disease', 'MESH:D007247', (207, 218))	('USP26', 'Gene', '83563', (17, 22))	('Mutations', 'Var', (0, 9))	('motility of the spermatozoa', 'CPA', (231, 258))	('infertility', 'Disease', (85, 96))	('reducing', 'NegReg', (222, 230))	('infertility', 'Phenotype', 'HP:0000789', (207, 218))	('infertility', 'Disease', 'MESH:D007247', (85, 96))	('male infertility', 'Disease', 'MESH:D007248', (80, 96))	('USP26', 'Gene', (17, 22))	('ubiquitin-specific protease 26', 'Gene', '83563', (24, 54))	('infertility', 'Phenotype', 'HP:0000789', (85, 96))	('Herc4', 'Gene', (105, 110))	('play', 'Reg', (65, 69))
67365	21155977	in vitro studies showed that impairment of STAT3 signalling increased SSC concentration specifically without affecting overall spermatogonial proliferation.	('rat', 'Species', '10116', (149, 152))	('men', 'Species', '9606', (35, 38))	('rat', 'Species', '10116', (81, 84))	('STAT3', 'Gene', '20848', (43, 48))	('SSC concentration', 'MPA', (70, 87))	('impairment', 'Var', (29, 39))	('STAT3', 'Gene', (43, 48))	('increased', 'PosReg', (60, 69))
67366	21155977	in vivo studies showed that SSCs deficient for STAT3 expression were incapable of re-establishing spermatogenesis after transplantation but could undergo initial colonization.	('undergo', 'Reg', (146, 153))	('STAT3', 'Gene', (47, 52))	('STAT3', 'Gene', '20848', (47, 52))	('deficient', 'Var', (33, 42))
67379	21155977	These include to determine the presence of SSCs in a cell population after positive or negative selection, the production of transgenic mice, evaluation of in vitro approaches to selectively culture SSCs, and importantly to determine if a gene mutation results in inadequate spermatogenesis and infertility.	('infertility', 'Phenotype', 'HP:0000789', (295, 306))	('gene mutation', 'Var', (239, 252))	('inadequate spermatogenesis', 'Phenotype', 'HP:0008669', (264, 290))	('infertility', 'Disease', (295, 306))	('results in', 'Reg', (253, 263))	('infertility', 'Disease', 'MESH:D007247', (295, 306))	('transgenic mice', 'Species', '10090', (125, 140))	('inadequate spermatogenesis', 'CPA', (264, 290))
67401	21155977	Recently, it has been reported that knockdown of Trp53 and Pten independently result in significantly higher expression levels of the pluripotency-associated gene Nanog.	('pluripotency', 'Disease', 'None', (134, 146))	('pluripotency', 'Disease', (134, 146))	('Trp53', 'Gene', (49, 54))	('Nanog', 'Gene', (163, 168))	('Trp53', 'Gene', '22059', (49, 54))	('higher', 'PosReg', (102, 108))	('Pten', 'Gene', (59, 63))	('knockdown', 'Var', (36, 45))	('Pten', 'Gene', '19211', (59, 63))	('expression levels', 'MPA', (109, 126))	('Nanog', 'Gene', '71950', (163, 168))
67413	21155977	Recent genetic studies show that abnormality of GDNF expression blocks sperm development and results in germ cell depletion.	('GDNF', 'Gene', (48, 52))	('blocks', 'NegReg', (64, 70))	('results in', 'Reg', (93, 103))	('sperm development', 'CPA', (71, 88))	('men', 'Species', '9606', (84, 87))	('abnormality', 'Var', (33, 44))	('germ cell depletion', 'CPA', (104, 123))
67414	21155977	It has been demonstrated that loss of BMP4 in mice results in degeneration of germ cells, reduced sperm counts, decreased sperm motility, and hence results in infertility.	('BMP4', 'Gene', '12159', (38, 42))	('infertility', 'Disease', 'MESH:D007247', (159, 170))	('results in', 'Reg', (148, 158))	('reduced', 'NegReg', (90, 97))	('sperm counts', 'CPA', (98, 110))	('infertility', 'Phenotype', 'HP:0000789', (159, 170))	('sperm motility', 'CPA', (122, 136))	('BMP4', 'Gene', (38, 42))	('infertility', 'Disease', (159, 170))	('rat', 'Species', '10116', (19, 22))	('degeneration', 'Disease', (62, 74))	('degeneration', 'Disease', 'MESH:D009410', (62, 74))	('mice', 'Species', '10090', (46, 50))	('rat', 'Species', '10116', (68, 71))	('reduced sperm', 'Phenotype', 'HP:0012207', (90, 103))	('decreased', 'NegReg', (112, 121))	('loss', 'Var', (30, 34))	('decreased sperm motility', 'Phenotype', 'HP:0012207', (112, 136))
67415	21155977	Disruption of fibroblast growth factor receptors (FGFR)1 signalling, which is important in normal spermiogenesis and male fertility, resulted in depletion of sperm production and incapacitated sperm.	('sperm', 'CPA', (158, 163))	('depletion', 'NegReg', (145, 154))	('FGFR', 'Gene', (50, 54))	('FGFR', 'Gene', '14182', (50, 54))	('Disruption', 'Var', (0, 10))
67416	21155977	It has been shown that c-KIT-induced activation of the PI3K pathway is critical in male fertility because mutant males with loss of PI3K bind to c-KIT are sterile, which is due to complete disruption of spermatogonial proliferation and early differentiation.	('loss', 'NegReg', (124, 128))	('mutant', 'Var', (106, 112))	('rat', 'Species', '10116', (225, 228))	('spermatogonial proliferation', 'CPA', (203, 231))	('c-KIT', 'Gene', (145, 150))	('bind', 'Interaction', (137, 141))	('PI3K', 'Gene', (132, 136))	('sterile', 'Disease', (155, 162))	('disruption', 'NegReg', (189, 199))	('early differentiation', 'CPA', (236, 257))
67418	21155977	There is a report that lack of expression of Steel (Sl) factor on Sertoli cells in infertile Sl mutant mice prevent the differentiation of spermatogonia, which express c-KIT receptor that result in azoospermia.	('differentiation', 'CPA', (120, 135))	('azoospermia', 'Disease', (198, 209))	('mutant', 'Var', (96, 102))	('mice', 'Species', '10090', (103, 107))	('azoospermia', 'Phenotype', 'HP:0000027', (198, 209))	('Steel (Sl) factor', 'Gene', '17311', (45, 62))	('azoospermia', 'Disease', 'MESH:D053713', (198, 209))	('result in', 'Reg', (188, 197))	('prevent', 'NegReg', (108, 115))	('Sertoli cell', 'Phenotype', 'HP:0100619', (66, 78))	('Sertoli cells', 'Phenotype', 'HP:0100619', (66, 79))	('Steel (Sl) factor', 'Gene', (45, 62))	('c-KIT', 'Protein', (168, 173))
67420	21155977	It is reported that genetic ablation of SIRT1 (Sirtuins class-III NAD-dependent histone deacetylases) in the mouse leads to male infertility.	('SIRT1', 'Gene', (40, 45))	('SIRT1', 'Gene', '93759', (40, 45))	('genetic ablation', 'Var', (20, 36))	('male infertility', 'Phenotype', 'HP:0003251', (124, 140))	('male infertility', 'Disease', 'MESH:D007248', (124, 140))	('leads to', 'Reg', (115, 123))	('male infertility', 'Disease', (124, 140))	('infertility', 'Phenotype', 'HP:0000789', (129, 140))	('mouse', 'Species', '10090', (109, 114))
67421	21155977	Further, loss of Dmc1, a Meiotic recombination protein, in mice result in infertility because of a defect in meiotic homologous chromosome pairing and an arrest in zygotene spermatocytes.	('mice', 'Species', '10090', (59, 63))	('Dmc1', 'Gene', '13404', (17, 21))	('result in', 'Reg', (64, 73))	('loss', 'Var', (9, 13))	('infertility', 'Disease', 'MESH:D007247', (74, 85))	('meiotic homologous chromosome pairing', 'CPA', (109, 146))	('infertility', 'Phenotype', 'HP:0000789', (74, 85))	('Dmc1', 'Gene', (17, 21))	('defect', 'NegReg', (99, 105))	('infertility', 'Disease', (74, 85))
67426	21155977	It has been found that defects in Sertoli cells compromise spermatogenesis and results in male infertility.	('spermatogenesis', 'CPA', (59, 74))	('Sertoli cell', 'Phenotype', 'HP:0100619', (34, 46))	('compromise', 'NegReg', (48, 58))	('Sertoli cells', 'Phenotype', 'HP:0100619', (34, 47))	('defects', 'Var', (23, 30))	('male infertility', 'Disease', 'MESH:D007248', (90, 106))	('infertility', 'Phenotype', 'HP:0000789', (95, 106))	('male infertility', 'Phenotype', 'HP:0003251', (90, 106))	('male infertility', 'Disease', (90, 106))	('results in', 'Reg', (79, 89))	('compromise spermatogenesis', 'Phenotype', 'HP:0008669', (48, 74))
67431	21155977	They found that transplantation of germ cells from infertile Sl/Sld mutant male mice to infertile W/Wv or Wv/W54 mutant male mice can revive the fertility to the recipient mice.	('Sl/Sld', 'Gene', (61, 67))	('mice', 'Species', '10090', (172, 176))	('mice', 'Species', '10090', (125, 129))	('mice', 'Species', '10090', (80, 84))	('fertility', 'CPA', (145, 154))	('mutant', 'Var', (68, 74))
67432	21155977	It has been shown that loss-of-function mutation in the KIT gene results in a severe spermatogenesis defect, which is turn led to infertility because of inability of its ligand, KITL, to stimulate spermatogonial proliferation and differentiation.	('mutation', 'Var', (40, 48))	('spermatogenesis', 'Disease', (85, 100))	('loss-of-function', 'NegReg', (23, 39))	('stimulate', 'PosReg', (187, 196))	('inability', 'NegReg', (153, 162))	('KITL', 'Gene', '17311', (178, 182))	('KIT', 'Gene', (56, 59))	('infertility', 'Disease', (130, 141))	('infertility', 'Phenotype', 'HP:0000789', (130, 141))	('infertility', 'Disease', 'MESH:D007247', (130, 141))	('led to', 'Reg', (123, 129))	('spermatogonial proliferation', 'CPA', (197, 225))	('rat', 'Species', '10116', (219, 222))	('spermatogenesis defect', 'Phenotype', 'HP:0008669', (85, 107))	('KITL', 'Gene', (178, 182))
67433	21155977	Long-term culture has been evaluated of rat SSCs following cryo-storage for their capacity to restore fertility to rats deficient in the DAZ-like (DAZL) gene, which show intact SSC compartment, but fail to produce mature sperm, resulted in infertility.	('infertility', 'Phenotype', 'HP:0000789', (240, 251))	('infertility', 'Disease', 'MESH:D007247', (240, 251))	('rat', 'Species', '10116', (115, 118))	('deficient', 'Var', (120, 129))	('infertility', 'Disease', (240, 251))	('rat', 'Species', '10116', (40, 43))	('DAZL', 'Gene', (147, 151))	('DAZ-like', 'Gene', (137, 145))	('rats', 'Species', '10116', (115, 119))	('DAZ-like', 'Gene', '680486', (137, 145))	('men', 'Species', '9606', (188, 191))	('resulted in', 'Reg', (228, 239))
67469	21155977	Their results show that 12p gain is resulted in activation of proliferation and maintenance of stem cell function via activation of key stem cell genes.	('activation', 'PosReg', (118, 128))	('proliferation', 'CPA', (62, 75))	('12p gain', 'Var', (24, 32))	('stem cell genes', 'Gene', (136, 151))	('activation', 'PosReg', (48, 58))	('rat', 'Species', '10116', (69, 72))
67479	21155977	There are several reports where alternation in expression of signalling molecules or pathways may result in an increased risk of testicular cancer.	('alternation', 'Var', (32, 43))	('testicular cancer', 'Phenotype', 'HP:0010788', (129, 146))	('pathways', 'Pathway', (85, 93))	('testicular cancer', 'Disease', 'MESH:D013736', (129, 146))	('result in', 'Reg', (98, 107))	('testicular cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('expression', 'MPA', (47, 57))
67484	21155977	The epigenetic mechanism that is involved in all cancers including TGCT is aberrant DNA methylation at gene promoters leading to silencing of tumour suppressor genes.	('involved', 'Reg', (33, 41))	('tumour', 'Disease', (142, 148))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('aberrant DNA methylation', 'Var', (75, 99))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('silencing', 'MPA', (129, 138))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('cancers', 'Disease', (49, 56))	('TGCT', 'Disease', (67, 71))
67487	21155977	It has been demonstrated that the loss of Dnd1 (dead end) results in loss of germ cells and development of TGCTs.	('loss', 'NegReg', (69, 73))	('loss', 'Var', (34, 38))	('development of TGCTs', 'CPA', (92, 112))	('rat', 'Species', '10116', (19, 22))	('men', 'Species', '9606', (99, 102))	('Dnd1', 'Gene', (42, 46))	('Dnd1', 'Gene', '213236', (42, 46))
67493	21155977	Their results show that transplantation resulted in a locally invasive solid tumour, with a cellular component that generated secondary tumours upon serial transplantation.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('resulted in', 'Reg', (40, 51))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (77, 83))	('tumour', 'Disease', (136, 142))	('tumours', 'Disease', (136, 143))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('rat', 'Species', '10116', (120, 123))	('transplantation', 'Var', (24, 39))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
67636	31597402	Small non-coding RNAs, also known as microRNAs (miRs), are frequently dysregulated in cancer cells and an oncogenic role of the miR-371 cluster has been described.	('miR-371', 'Gene', '442916', (128, 135))	('miR', 'Gene', '29116', (128, 131))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Small non-coding', 'Var', (0, 16))	('miR-371', 'Gene', (128, 135))	('miR', 'Gene', (128, 131))	('miR', 'Gene', (48, 51))	('dysregulated', 'Reg', (70, 82))	('miR', 'Gene', '29116', (48, 51))	('cancer', 'Disease', (86, 92))
67803	29436261	An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer.	('alteration', 'Var', (198, 208))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (109, 115))	('lead to', 'Reg', (213, 220))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('cancer', 'Disease', (257, 263))
67808	29436261	Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444).	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('BX641110', 'Var', (129, 137))	('epigenetic', 'Var', (19, 29))	('cisplatin resistance', 'MPA', (66, 86))	('AF198444', 'Var', (143, 151))	('RP11', 'Gene', (112, 116))	('RP11', 'Gene', '26121', (112, 116))	('involved', 'Reg', (54, 62))
67813	29436261	Because lncRNAs are involved in several processes important to the normal functioning of the cell, alterations in lncRNAs have been shown to contribute to the development and progression of various human diseases, including cancer.	('lncRNAs', 'Gene', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('alterations', 'Var', (99, 110))	('human', 'Species', '9606', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('contribute', 'Reg', (141, 151))
67816	29436261	Overexpression of MALAT1 plays an oncogenic role in ovarian cancer, increasing cell viability, colony formation, and migration, together with a metastatic phenotype in patients with ovarian cancer.	('ovarian cancer', 'Disease', (52, 66))	('migration', 'CPA', (117, 126))	('cell viability', 'CPA', (79, 93))	('MALAT1', 'Gene', '378938', (18, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('colony formation', 'CPA', (95, 111))	('increasing', 'PosReg', (68, 78))	('MALAT1', 'Gene', (18, 24))	('ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (168, 176))	('ovarian cancer', 'Disease', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
67824	29436261	In the present study, we integrated a global methylation analysis with lncRNA and mRNA transcriptomics to identify the epigenetic regulation of lncRNAs that could contribute to the development of acquired CDDP resistance in NSCLC and ovarian cancer cells.	('lncRNAs', 'Gene', (144, 151))	('CDDP', 'Chemical', '-', (205, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (234, 248))	('NSCLC', 'Disease', (224, 229))	('epigenetic regulation', 'Var', (119, 140))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('ovarian cancer', 'Disease', 'MESH:D010051', (234, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('ovarian cancer', 'Disease', (234, 248))	('contribute', 'Reg', (163, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))
67825	29436261	All data are based on eight CDDP-sensitive and CDDP-resistant NSCLC (H23S/R and H460S/R) and ovarian cancer (A2780S/R and OVCAR3S/R) cell lines previously established in our laboratory (Supplementary Figure 1).	('H460S', 'Var', (80, 85))	('CDDP', 'Chemical', '-', (28, 32))	('A2780S', 'SUBSTITUTION', 'None', (109, 115))	('ovarian cancer', 'Disease', (93, 107))	('NSCLC', 'Disease', (62, 67))	('A2780S', 'Var', (109, 115))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('H460S', 'SUBSTITUTION', 'None', (80, 85))	('CDDP', 'Chemical', '-', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('H23S', 'Var', (69, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('H23S', 'SUBSTITUTION', 'None', (69, 73))
67828	29436261	We further tested the expression of six transcripts in a selection of two additional paired CDDP-resistant/sensitive cancer cell lines, a different pair A2780/A2780CP, and the pair OV2008/OVC13 (Supplementary Figure 2D).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('A2780/A2780CP', 'Var', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tested', 'Reg', (11, 17))	('CDDP', 'Chemical', '-', (92, 96))	('cancer', 'Disease', (117, 123))
67839	29436261	For overlapping lncRNAs, the methylation pattern is associated with downregulation in platinum resistance, 73% of all differentially methylated overlapping lncRNAs in comparison with the 50% observed for cis-acting lncRNAs (Supplementary Figure 3C).	('methylation', 'Var', (29, 40))	('platinum', 'Chemical', 'MESH:D010984', (86, 94))	('platinum resistance', 'CPA', (86, 105))	('downregulation', 'NegReg', (68, 82))
67842	29436261	These candidates were AC091814.2, AC141928.1, RP11-65J3.1-002, RP11-65J3.1-003, BX641110, AF198444, XLOC_005125, and RP11-100E13.1 (Table 3).	('RP11', 'Gene', (63, 67))	('AF198444', 'Var', (90, 98))	('RP11', 'Gene', (117, 121))	('AC141928.1', 'Var', (34, 44))	('XLOC_005125', 'Var', (100, 111))	('BX641110', 'Var', (80, 88))	('RP11', 'Gene', '26121', (63, 67))	('RP11', 'Gene', (46, 50))	('RP11', 'Gene', '26121', (117, 121))	('RP11', 'Gene', '26121', (46, 50))	('AC091814.2', 'Var', (22, 32))
67843	29436261	Our first approach included the validation of general changes in expression after epigenetic reactivation treatment in the resistant cells, combining 5-Aza-2-deoxycytidine (5Aza-dC), a demethylating agent, and trichostatin A (TSA), a histone deacetylase inhibitor.	('epigenetic reactivation', 'Var', (82, 105))	('changes', 'Reg', (54, 61))	('TSA', 'Chemical', 'MESH:C012589', (226, 229))	('expression', 'MPA', (65, 75))	('5-Aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (150, 171))	('trichostatin A', 'Chemical', 'MESH:C012589', (210, 224))	('5Aza-dC', 'Chemical', 'MESH:D000077209', (173, 180))
67844	29436261	RT-PCR (Figure 4(A)) and qRT-PCR (Figure 4(B)) confirmed our first expression results observed in the cell lines for the six candidates, AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, AF198444, and XLOC_005125.	('RP11', 'Gene', '26121', (161, 165))	('XLOC_005125', 'Var', (202, 213))	('AC091814.2', 'Var', (137, 147))	('AF198444', 'Var', (188, 196))	('AC141928.1', 'Var', (149, 159))	('BX641110', 'Var', (178, 186))	('RP11', 'Gene', (161, 165))
67845	29436261	Bisulfite sequencing of the differentially methylated positions between sensitive (S) and resistant (R) cells confirmed the gain of methylation in the resistant subtypes for candidates AC091814.2, AC141928.1, and RP11-65J3.1-002, and loss of methylation for AF198444 and BX641110 (Figure 5).	('AC091814.2', 'Var', (185, 195))	('RP11', 'Gene', '26121', (213, 217))	('gain', 'PosReg', (124, 128))	('methylation', 'MPA', (132, 143))	('loss', 'NegReg', (234, 238))	('methylation', 'MPA', (242, 253))	('BX641110', 'Var', (271, 279))	('AC141928.1', 'Var', (197, 207))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('AF198444', 'Var', (258, 266))	('RP11', 'Gene', (213, 217))
67852	29436261	Some of the targets identified in the current study, AC091814.2, AC000035.3, XLOC_005125, BX641110, and RP11-384P7.7, are associated with coding genes that have been previously reported in the cancer literature; however, they have not been previously related to cancer development or cisplatin-resistance, which increases their interest for further studies.	('cancer', 'Disease', (262, 268))	('BX641110', 'Var', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('RP11', 'Gene', '26121', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cisplatin', 'Chemical', 'MESH:D002945', (284, 293))	('AC091814.2', 'Var', (53, 63))	('AC000035.3', 'Var', (65, 75))	('XLOC_005125', 'Var', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('RP11', 'Gene', (104, 108))
67857	29436261	Conversely, cis-acting lncRNAs may promote or interfere with the expression of their ACG, as has been previously shown.	('ACG', 'Gene', '139818', (85, 88))	('ACG', 'Gene', (85, 88))	('expression', 'MPA', (65, 75))	('promote', 'PosReg', (35, 42))	('cis-acting', 'Var', (12, 22))	('interfere', 'NegReg', (46, 55))
67863	29436261	Furthermore, bisulfite sequencing of the regions identified by WGBS confirmed hypermethylation in resistance for AC091814.2, AC141928.1, and RP11-65J3.1-002 lncRNAs.	('RP11', 'Gene', (141, 145))	('RP11', 'Gene', '26121', (141, 145))	('AC141928.1', 'Var', (125, 135))	('bisulfite', 'Chemical', 'MESH:C042345', (13, 22))	('hypermethylation', 'Var', (78, 94))	('AC091814.2', 'Gene', (113, 123))
67864	29436261	In addition, we identified several positions that lost methylation in the resistant subtypes of our models in the regulatory regions of AF198444 and BX641110, suggesting that CDDP also leads to epigenetic changes that decrease methylation levels.	('BX641110', 'Var', (149, 157))	('decrease', 'NegReg', (218, 226))	('leads to', 'Reg', (185, 193))	('CDDP', 'Var', (175, 179))	('methylation', 'MPA', (55, 66))	('methylation levels', 'MPA', (227, 245))	('CDDP', 'Chemical', '-', (175, 179))	('AF198444', 'Var', (136, 144))	('epigenetic changes', 'MPA', (194, 212))
67869	29436261	To analyze the changes in the transcriptome as a result of CDDP treatment, we established the CDDP-resistant variants of H23-R, H460-R, A2780-R, and OVCAR3-R from the parental-sensitive variants H23, H460, A2780, and OVCAR3, after exposure to increasing doses of CDDP treatment over a time period of 6-18 months.	('H460-R', 'Mutation', 'rs1482237484', (128, 134))	('H23-R', 'Mutation', 'rs765471409', (121, 126))	('H460-R', 'Var', (128, 134))	('H23-R', 'Gene', (121, 126))	('A2780-R', 'Var', (136, 143))	('CDDP', 'Chemical', '-', (94, 98))	('CDDP', 'Chemical', '-', (263, 267))	('CDDP-resistant', 'Disease', (94, 108))	('A2780-R', 'Mutation', 'p.A2780R', (136, 143))	('CDDP', 'Chemical', '-', (59, 63))
67870	29436261	In order to unmask epigenetic silencing caused by cisplatin, resistant cells received a combination of the epigenetic reactivation drugs 5-Aza-2-deoxycytidine (5Aza-dC) and trichostatin A (TSA) [as previously described as an epigenetic reactivating treatment to generate the resistant-treated subtypes (H23RT, H460RT, A2780RT and OVCAR3RT)].	('5Aza-dC', 'Chemical', 'MESH:D000077209', (160, 167))	('A2780RT', 'Var', (318, 325))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('TSA', 'Chemical', 'MESH:C012589', (189, 192))	('5-Aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (137, 158))	('H460RT', 'Var', (310, 316))	('H23RT', 'Var', (303, 308))	('trichostatin A', 'Chemical', 'MESH:C012589', (173, 187))
67880	29436261	The RNA obtained from the paired A2780/A2780CP and OV2008/OVC13 cell lines was generously provided by Dr. Cheng (Moffitt Cancer Center) and was used for further validations.	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Moffitt Cancer Center', 'Disease', 'MESH:D009369', (113, 134))	('Moffitt Cancer Center', 'Disease', (113, 134))	('A2780/A2780CP', 'Var', (33, 46))
67881	29436261	The DNA from H23S/R, H460S/R, A2780S/R, and OVCAR3S/R was isolated as described and sent to the National Centre for Genome Analysis [Centro Nacional de Analisis Genomico (CNAG)] for WGBS (GSE109317).	('A2780S', 'SUBSTITUTION', 'None', (30, 36))	('H460S', 'SUBSTITUTION', 'None', (21, 26))	('A2780S', 'Var', (30, 36))	('H23S', 'SUBSTITUTION', 'None', (13, 17))	('H23S', 'Var', (13, 17))	('H460S', 'Var', (21, 26))
67884	29436261	Isolated DNA from the H23S/R, H460S/R, A2780S/R, and OVCAR3S/R samples was bisulfite-modified and used for bisulfite sequencing as previously described.	('A2780S', 'Var', (39, 45))	('bisulfite', 'Chemical', 'MESH:C042345', (75, 84))	('H23S', 'Var', (22, 26))	('H460S', 'Var', (30, 35))	('H23S', 'SUBSTITUTION', 'None', (22, 26))	('bisulfite', 'Chemical', 'MESH:C042345', (107, 116))	('A2780S', 'SUBSTITUTION', 'None', (39, 45))	('H460S', 'SUBSTITUTION', 'None', (30, 35))
67912	25605631	During their development these cell types each undergo a specialised unique genetic process; nuclear fusion, gastrulation, meiosis, immunoglobulin/T cell receptor gene VDJ rearrangement, somatic hypermutation and class switching.	('somatic hypermutation', 'CPA', (187, 208))	('T cell receptor', 'Gene', (147, 162))	('rearrangement', 'Var', (172, 185))	('undergo', 'Reg', (47, 54))	('T cell receptor', 'Gene', '6962', (147, 162))	('VDJ', 'Gene', (168, 171))	('class switching', 'CPA', (213, 228))	('nuclear fusion', 'CPA', (93, 107))	('gastrulation', 'CPA', (109, 121))	('meiosis', 'CPA', (123, 130))	('men', 'Species', '9606', (181, 184))	('men', 'Species', '9606', (20, 23))
67929	25605631	Historical explanations for this extreme sensitivity to chemotherapy and the divergence in curability have been based on concepts including a higher growth rate for the curable cancers, the mutation of cells into drug resistant clones, the development of drug efflux pumps and the relationship of curable cancers to stem cells.	('mutation', 'Var', (190, 198))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancers', 'Disease', (305, 312))	('cancers', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('growth', 'MPA', (149, 155))	('men', 'Species', '9606', (247, 250))	('higher', 'PosReg', (142, 148))
67977	25605631	In Ewings tumours there is the characteristic translocation EWS/ETS transformation which leads to the transformation and the malignant phenotype.	('Ewings tumours', 'Disease', (3, 17))	('leads to', 'Reg', (89, 97))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('EWS', 'Gene', '2130', (60, 63))	('EWS', 'Gene', (60, 63))	('translocation', 'Var', (46, 59))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('malignant phenotype', 'CPA', (125, 144))	('Ewings tumours', 'Disease', 'MESH:C563168', (3, 17))
67994	25605631	In contrast in males at the start of gonadal development at approximately 6 to 7 weeks gestation, the action of sex-determining region Y (SRY) leads to Sertoli cell differentiation and production of cytochrome p450 26B1 which degrades retinoic acid which inhibits the progression to meiosis.	('action', 'Var', (102, 108))	('inhibits', 'NegReg', (255, 263))	('leads to', 'Reg', (143, 151))	('retinoic acid', 'Chemical', 'MESH:D014212', (235, 248))	('men', 'Species', '9606', (52, 55))	('Sertoli cell differentiation', 'Phenotype', 'HP:0100619', (152, 180))	('cytochrome p450 26B1', 'Enzyme', (199, 219))	('SRY', 'Gene', (138, 141))	('Sertoli cell', 'Phenotype', 'HP:0100619', (152, 164))	('to 7', 'Species', '1214577', (76, 80))	('Sertoli cell differentiation', 'CPA', (152, 180))	('degrades', 'MPA', (226, 234))	('progression to meiosis', 'CPA', (268, 290))
68034	25605631	From a clinical perspective it would also appear that the varying B cell malignancies of acute undifferentiated leukemia all the way through to myeloma also retain their then current natural level of apoptotic potential associated with the unique genetic processes of; VDJ rearrangement, somatic hypermutation and class switching that were occurring at the time of malignant transformation.	('leukemia', 'Phenotype', 'HP:0001909', (112, 120))	('B cell malignancies of acute undifferentiated leukemia', 'Phenotype', 'HP:0004812', (66, 120))	('myeloma', 'Disease', 'MESH:D009101', (144, 151))	('men', 'Species', '9606', (282, 285))	('myeloma', 'Disease', (144, 151))	('malignancies of acute undifferentiated leukemia', 'Disease', (73, 120))	('apoptotic potential', 'MPA', (200, 219))	('rearrangement', 'Var', (273, 286))	('malignancies of acute undifferentiated leukemia', 'Disease', 'MESH:D002277', (73, 120))
68040	25605631	There is also significantly VDJ activity occurring early in the development of hematopoietic stem cell that go on to the pathway of myeloid differentiation with VDJ rearrangement present in many cases of AML and also occurring later in development prior to acute lymphoid blast crisis in CML.	('AML', 'Disease', 'MESH:D015470', (204, 207))	('go on', 'Reg', (108, 113))	('rearrangement', 'Var', (165, 178))	('lymphoid blast crisis', 'Phenotype', 'HP:0005526', (263, 284))	('VDJ', 'Gene', (161, 164))	('CML', 'Disease', (288, 291))	('AML', 'Disease', (204, 207))	('men', 'Species', '9606', (71, 74))	('acute lymphoid blast crisis', 'Phenotype', 'HP:0006721', (257, 284))	('VDJ', 'Gene', (28, 31))	('men', 'Species', '9606', (243, 246))	('men', 'Species', '9606', (174, 177))	('CML', 'Disease', 'MESH:D015464', (288, 291))
68043	25605631	These processes are mediated by activation induced cytidine deaminase (AID) that produces mutations, insertions and deletions within the immunoglobulin hypervariable regions during somatic hypermutation.	('mutations', 'Var', (90, 99))	('deletions', 'Var', (116, 125))	('activation induced cytidine deaminase', 'Gene', (32, 69))	('AID', 'Gene', (71, 74))	('activation induced cytidine deaminase', 'Gene', '57379', (32, 69))	('AID', 'Gene', '57379', (71, 74))	('insertions', 'Var', (101, 111))
68045	25605631	These complexes processes of immunoglobulin gene VDJ rearrangement and somatic hypermutation are recognised to be associated with the induction of lymphomagenesis, with VDJ rearrangements particularly linked to malignancy associated translocations including t, t[14:18] and BCL2, whilst somatic hypermutation is linked to the myc translocations seen in Burkitt's lymphoma.	('lymphoma', 'Disease', (363, 371))	('lymphoma', 'Disease', 'MESH:D008223', (363, 371))	('linked', 'Reg', (201, 207))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (353, 371))	('BCL2', 'Gene', (274, 278))	('lymphoma', 'Disease', (147, 155))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (353, 371))	('lymphoma', 'Disease', 'MESH:D008223', (147, 155))	('rearrangements', 'Var', (173, 187))	("Burkitt's lymphoma", 'Disease', (353, 371))	('malignancy', 'Disease', 'MESH:D009369', (211, 221))	('men', 'Species', '9606', (182, 185))	('VDJ', 'Gene', (169, 172))	('men', 'Species', '9606', (62, 65))	('t[14:18]', 'Var', (261, 269))	('lymphoma', 'Phenotype', 'HP:0002665', (363, 371))	('malignancy', 'Disease', (211, 221))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('associated', 'Reg', (114, 124))	('BCL2', 'Gene', '596', (274, 278))	('translocations', 'Var', (233, 247))	('rearrangement', 'Var', (53, 66))
68066	25605631	The malignancies that arise from B cells that have completed VDJ rearrangement but not undergone somatic hypermutation include mantle cell lymphoma and chronic lymphocytic leukemia [CLL].	('cell lymphoma', 'Phenotype', 'HP:0012191', (134, 147))	('malignancies', 'Disease', 'MESH:D009369', (4, 16))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (127, 147))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('mantle cell lymphoma', 'Disease', (127, 147))	('VDJ', 'Gene', (61, 64))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('rearrangement', 'Var', (65, 78))	('malignancies', 'Disease', (4, 16))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (152, 180))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (152, 180))	('men', 'Species', '9606', (74, 77))	('CLL', 'Phenotype', 'HP:0005550', (182, 185))	('chronic lymphocytic leukemia', 'Disease', (152, 180))
68070	25605631	In mantle cell lymphoma the impact on the hyper-mutated status of the variable domain is significant as those with mutated genes have a 5 year event free survival of 75% vs only 23% for those with classical unmutated Mantle cell lymphoma.	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (3, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (229, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('cell lymphoma', 'Phenotype', 'HP:0012191', (224, 237))	('mantle cell lymphoma', 'Disease', (3, 23))	('cell lymphoma', 'Phenotype', 'HP:0012191', (10, 23))	('mutated genes', 'Var', (115, 128))	('Mantle cell lymphoma', 'Disease', 'MESH:D020522', (217, 237))	('Mantle cell lymphoma', 'Disease', (217, 237))
68074	25605631	The action of AID is focused predominantly on the variable regions of the immunoglobulin genes and it is estimated that the AID leads to a mutation rate in the variable regions that is approximately 1 million times higher than would occur by spontaneous mutation alone.	('AID', 'Gene', '57379', (14, 17))	('AID', 'Gene', (14, 17))	('mutation', 'Var', (139, 147))	('higher', 'PosReg', (215, 221))	('AID', 'Gene', (124, 127))	('AID', 'Gene', '57379', (124, 127))
68081	25605631	Burkitt's lymphoma appears to arise in germinal centre B cells that have undergone somatic hypermutation of the VH genes and is characterised by translocation of the c-myc oncogene.	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (0, 18))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (0, 18))	('c-myc', 'Gene', '4609', (166, 171))	('translocation', 'Var', (145, 158))	('c-myc', 'Gene', (166, 171))	("Burkitt's lymphoma", 'Disease', (0, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))
68087	25605631	However in Hodgkin's lymphoma these cells with these 'crippling' mutations of the immunoglobulin chain are generally viewed as failed germinal centre B Cells that are pre-apoptotic but prevented from progressing to an apoptotic death by EBV infection It may be that the loss of the classical B cell phenotype seen in Hodgkin's disease is a result of the cell moving part of the way down the apoptotic pathways but with the completion of the normal apoptotic pathway blocked as a result of EBV infection.	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (11, 29))	('EBV infection', 'Disease', 'MESH:D020031', (489, 502))	('failed germinal centre B Cells', 'Phenotype', 'HP:0002849', (127, 157))	('EBV infection', 'Disease', (237, 250))	('EBV infection', 'Disease', 'MESH:D020031', (237, 250))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (11, 29))	('EBV infection', 'Disease', (489, 502))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (317, 334))	("Hodgkin's lymphoma", 'Disease', (11, 29))	("Hodgkin's disease", 'Disease', (317, 334))	("Hodgkin's disease", 'Phenotype', 'HP:0012189', (317, 334))	('apoptotic', 'Pathway', (391, 400))	('mutations', 'Var', (65, 74))
68093	25605631	In terms of the unique genetic events, follicular lymphoma is demonstrated to carry rearranged immunoglobulin genes that have undergone somatic hypermutation.	('follicular lymphoma', 'Disease', (39, 58))	('rearranged', 'Var', (84, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('immunoglobulin genes', 'Gene', (95, 115))	('follicular lymphoma', 'Disease', 'MESH:D008224', (39, 58))
68107	25605631	Similarly lymphoplasmacytic lymphoma (Waldenstroms macroglobulinaemia) arises from mature B cells that have rearranged VH genes, have undergone somatic hypermutation but have failed to complete class switching This malignancy also has a good response rate to chemotherapy but is not chemotherapy curable and has a shorter natural history that follicular NHL or MALT with a median survival of approximately 8 years.	('MALT', 'Disease', (361, 365))	('Waldenstroms macroglobulinaemia', 'Disease', (38, 69))	('VH genes', 'Gene', (119, 127))	('rearranged', 'Var', (108, 118))	('NHL', 'Disease', 'MESH:D008228', (354, 357))	('NHL', 'Disease', (354, 357))	('malignancy', 'Disease', 'MESH:D009369', (215, 225))	('lymphoplasmacytic lymphoma', 'Disease', 'MESH:D008223', (10, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (28, 36))	('Waldenstroms macroglobulinaemia', 'Phenotype', 'HP:0005508', (38, 69))	('Waldenstroms macroglobulinaemia', 'Disease', 'MESH:D008258', (38, 69))	('lymphoplasmacytic lymphoma', 'Disease', (10, 36))	('malignancy', 'Disease', (215, 225))	('MALT', 'Disease', 'MESH:D018442', (361, 365))
68113	25605631	More recent data has indicated that the BRAF protein that is involved in signal transduction from the B cell receptor has a characteristic V[600]E mutation in nearly all cases of HCL a finding that is not present in any other lymphoid malignancy.	('BRAF', 'Gene', '673', (40, 44))	('V[600]E', 'Var', (139, 146))	('BRAF', 'Gene', (40, 44))	('lymphoid malignancy', 'Disease', 'MESH:D008223', (226, 245))	('HCL a', 'Disease', (179, 184))	('lymphoid malignancy', 'Disease', (226, 245))	('lymphoid malignancy', 'Phenotype', 'HP:0002665', (226, 245))
68116	25605631	The dramatic response to chemotherapy suggests that the DNA damage can shift the balance to highly effective apoptosis, using the mechanisms that are still partially in place linked to the AID activity that is on-going, albeit at a lower level than is present in DLBCL.	('DNA', 'Var', (56, 59))	('shift', 'Reg', (71, 76))	('AID', 'Gene', '57379', (189, 192))	('AID', 'Gene', (189, 192))
68123	25605631	In contrast to the three processes of VDJ rearrangement, somatic hypermutation and class switching occurring in B cells, T cells have a simpler pattern of genetic activity to achieve their variation in antigenic recognition with only rearrangement of the V and J regions in the TCR alpha chain whilst the TCR beta has the fuller rearrangement of the VDJ components similarly to a B cell.	('rearrangement', 'Var', (234, 247))	('men', 'Species', '9606', (338, 341))	('men', 'Species', '9606', (51, 54))	('antigenic recognition', 'MPA', (202, 223))	('TCR alpha', 'Gene', '28755', (278, 287))	('TCR beta', 'Gene', (305, 313))	('TCR beta', 'Gene', '6962', (305, 313))	('men', 'Species', '9606', (243, 246))	('TCR alpha', 'Gene', (278, 287))
68124	25605631	In a parallel fashion to that seen in B cell malignancies the rise in chemotherapy curability coincides with the onset of V[D]J rearrangements in the T cell receptor genes.	('T cell receptor', 'Gene', (150, 165))	('T cell receptor', 'Gene', '6962', (150, 165))	('malignancies', 'Disease', 'MESH:D009369', (45, 57))	('rise', 'PosReg', (62, 66))	('malignancies', 'Disease', (45, 57))	('chemotherapy curability', 'CPA', (70, 93))	('V[D]J rearrangements', 'Var', (122, 142))	('men', 'Species', '9606', (137, 140))
68131	25605631	ALK + ve large cell lymphoma arise from T cells that have undergone V[D]J recombination but have failed to produce a functional T cell receptor.	('lymphoma', 'Disease', (20, 28))	('lymphoma', 'Disease', 'MESH:D008223', (20, 28))	('V[D]J', 'Var', (68, 73))	('ALK', 'Gene', (0, 3))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('T cell receptor', 'Gene', (128, 143))	('T cell receptor', 'Gene', '6962', (128, 143))	('cell lymphoma', 'Phenotype', 'HP:0012191', (15, 28))	('ALK', 'Gene', '238', (0, 3))
68143	25605631	A number of studies have confirmed that these unique genetic events of VDJ rearrangement that are associated with B cell and T cell development are occurring at significant levels in the cells that develop into AML.	('VDJ', 'Gene', (71, 74))	('AML', 'Disease', (211, 214))	('men', 'Species', '9606', (139, 142))	('men', 'Species', '9606', (84, 87))	('rearrangement', 'Var', (75, 88))	('AML', 'Disease', 'MESH:D015470', (211, 214))
68144	25605631	In studies of AML, genetic analysis indicates that the immunoglobulin heavy chains genes have undergone VDJ rearrangement in 40-50% of cases and that the expression of the VDJ recombinase associated proteins RAG1 and RAG2 was also detectable in approximately 50% of cases.	('RAG1', 'Gene', '5896', (208, 212))	('undergone', 'Reg', (94, 103))	('AML', 'Disease', (14, 17))	('men', 'Species', '9606', (117, 120))	('RAG2', 'Gene', '5897', (217, 221))	('AML', 'Disease', 'MESH:D015470', (14, 17))	('rearrangement', 'Var', (108, 121))	('RAG2', 'Gene', (217, 221))	('RAG1', 'Gene', (208, 212))
68145	25605631	More recent data confirms that VDJ recombination had occurred in the AML myeloblasts of 50% of patients and that there was also limited evidence of somatic hypermutation occurring.	('AML', 'Disease', (69, 72))	('patients', 'Species', '9606', (95, 103))	('recombination', 'Var', (35, 48))	('occurred', 'Reg', (53, 61))	('VDJ', 'Gene', (31, 34))	('AML', 'Disease', 'MESH:D015470', (69, 72))
68155	25605631	In contrast to other malignancies, including B ALL and T ALL and AML, which arise in cells around the time of VDJ rearrangement, CML in lymphoid blast crisis is not chemotherapy curable.	('AML', 'Disease', (65, 68))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('lymphoid blast crisis', 'Phenotype', 'HP:0005526', (136, 157))	('ALL', 'Phenotype', 'HP:0006721', (47, 50))	('CML', 'Disease', (129, 132))	('lymphoid blast crisis', 'Disease', (136, 157))	('ALL', 'Phenotype', 'HP:0006721', (57, 60))	('malignancies', 'Disease', (21, 33))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('rearrangement', 'Var', (114, 127))	('men', 'Species', '9606', (123, 126))	('CML', 'Disease', 'MESH:D015464', (129, 132))
68161	25605631	The major impact of this protein on inhibiting apoptosis is seen in studies where BCR/ABL has been transfected into chemotherapy sensitive cells lines leading to high levels drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (174, 189))	('inhibiting', 'NegReg', (36, 46))	('BCR/ABL', 'Gene', (82, 89))	('apoptosis', 'CPA', (47, 56))	('drug resistance', 'MPA', (174, 189))	('transfected', 'Var', (99, 110))	('BCR/ABL', 'Gene', '25;613', (82, 89))
68162	25605631	As a result the presence of the BCR/ABL activity may be sufficient to override the apoptotic sensitivity normally seen with active VDJ rearrangement.	('BCR/ABL', 'Gene', (32, 39))	('men', 'Species', '9606', (144, 147))	('BCR/ABL', 'Gene', '25;613', (32, 39))	('override', 'PosReg', (70, 78))	('apoptotic sensitivity', 'CPA', (83, 104))	('presence', 'Var', (16, 24))
68179	25605631	It has previously been noted that radiotherapy treatment to fibroblast and lymphoma cells can result in the expression of meiosis related proteins and that the combination of DNA damage and meiosis related proteins can only be tolerated by cells with mutated p53 pathways.	('result in', 'Reg', (94, 103))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('men', 'Species', '9606', (52, 55))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('meiosis', 'Protein', (122, 129))	('p53', 'Gene', (259, 262))	('p53', 'Gene', '7157', (259, 262))	('expression', 'MPA', (108, 118))	('mutated', 'Var', (251, 258))	('lymphoma', 'Disease', (75, 83))
68219	25590623	In the "chronic" exposure setting, a T-test was performed on gene expression levels obtained from samples exposed to the drugs (IC10 cisplatin or IC10 bleomycin) versus the untreated control samples that were collected after 30 days incubation.	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('IC10 cisplatin', 'Var', (128, 142))	('IC10', 'Var', (146, 150))	('bleomycin', 'Chemical', 'MESH:D001761', (151, 160))
68315	29853869	Encouraged by favorable early oncologic and safety outcomes for treatment of clinical stage (CS) I nonseminomatous germ cell tumor (NSGCT), the R-RPLND affords the same recovery advantages as the laparoscopic retroperitoneal lymph node dissection (L-RPLND) while offering greater dexterity, superior visualization, and a theoretically shorter learning curve for the surgeon.	('CS', 'Chemical', '-', (93, 95))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('nonseminomatous germ cell tumor', 'Disease', (99, 130))	('R-RPLND', 'Var', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('nonseminomatous germ cell tumor', 'Disease', 'MESH:C537844', (99, 130))	('germ cell tumor', 'Phenotype', 'HP:0100728', (115, 130))	('GCT', 'Phenotype', 'HP:0100728', (134, 137))
68486	27652227	Sexual behavior was severely disrupted if bilateral lesions were positioned in the preoptic area/anterior hypothalamus, whereas posterior hypothalamic lesions (including mammillary bodies) did not interfere with sexual behavior.	('disrupted', 'NegReg', (29, 38))	('Sexual behavior', 'CPA', (0, 15))	('Sexual behavior', 'Phenotype', 'HP:0030214', (0, 15))	('anterior hypothalamus', 'Disease', (97, 118))	('anterior hypothalamus', 'Disease', 'MESH:D007029', (97, 118))	('hypothalamic lesions', 'Disease', (138, 158))	('hypothalamic lesions', 'Phenotype', 'HP:0025058', (138, 158))	('sexual behavior', 'Phenotype', 'HP:0030214', (212, 227))	('hypothalamic lesions', 'Disease', 'MESH:D007027', (138, 158))	('lesions', 'Var', (52, 59))
68501	27652227	With the introduction of successful medical treatment of ED with phosphodiesterase type 5, many men experience erections without adequate psycho-emotional arousal and experience difficulty achieving orgasm since they had not experienced sufficient erotic stimulation before and during coitus.	('men', 'Species', '9606', (96, 99))	('men', 'Species', '9606', (49, 52))	('man', 'Species', '9606', (91, 94))	('experience erections', 'Phenotype', 'HP:0000802', (100, 120))	('phosphodiesterase', 'Var', (65, 82))	('erections', 'Disease', (111, 120))	('experience', 'Reg', (100, 110))
68528	27652227	Woffian duct abnormalities may affect the strictures between the efferent ducts of the testis to the prostate, specifically the epididymis, the vas deference and the seminal vesicle, and also can affect ejaculation.	('affect', 'Reg', (31, 37))	('epididymis', 'Disease', (128, 138))	('strictures', 'MPA', (42, 52))	('ejaculation', 'CPA', (203, 214))	('epididymis', 'Disease', 'MESH:D004823', (128, 138))	('affect', 'Reg', (196, 202))	('abnormalities', 'Var', (13, 26))
68571	27652227	Fewer than 5% of patients with complete upper motor neuron lesions retained the ability to ejaculate.	('ability', 'MPA', (80, 87))	('motor neuron lesion', 'Phenotype', 'HP:0007373', (46, 65))	('motor neuron lesions', 'Phenotype', 'HP:0007373', (46, 66))	('lesions', 'Var', (59, 66))	('patients', 'Species', '9606', (17, 25))
68572	27652227	Ejaculation rates were higher (15%) in patients with both lower motor neuron lesions and an intact thoracolumbar sympathetic outflow.	('Ejaculation rates', 'MPA', (0, 17))	('lesions', 'Var', (77, 84))	('lower', 'Protein', (58, 63))	('rat', 'Species', '10116', (12, 15))	('patients', 'Species', '9606', (39, 47))	('motor neuron lesion', 'Phenotype', 'HP:0007373', (64, 83))	('higher', 'PosReg', (23, 29))	('motor neuron lesions', 'Phenotype', 'HP:0007373', (64, 84))	('lower motor neuron', 'Phenotype', 'HP:0002366', (58, 76))
68636	27652227	The majority of those disorders were related to sperm volume (9% DT36 group; 8% DT24 + D12 group), decreased libido (5% DT36 group; 6% DT24 + D12 group), impotence (5% DT36 group; 4% DT24 + D12 group), and malaise and fatigue (5% DT36 group; 1% DT24 + D12 group).	('malaise', 'Phenotype', 'HP:0012378', (206, 213))	('decreased', 'NegReg', (99, 108))	('DT24 + D12', 'Var', (80, 90))	('impotence', 'Disease', 'MESH:D007172', (154, 163))	('sperm volume', 'CPA', (48, 60))	('impotence', 'Phenotype', 'HP:0000802', (154, 163))	('malaise and fatigue', 'Disease', 'MESH:D005221', (206, 225))	('impotence', 'Disease', (154, 163))	('libido', 'CPA', (109, 115))	('fatigue', 'Phenotype', 'HP:0012378', (218, 225))
68652	27652227	In one double blind, placebo-controlled study, imipramine and phenelzine were associated with a high incidence of adverse changes in sexual function, particularly impaired orgasm and ejaculation.	('phenelzine', 'Gene', (62, 72))	('phenelzine', 'Chemical', 'MESH:D010624', (62, 72))	('impaired', 'NegReg', (163, 171))	('imipramine', 'Chemical', 'MESH:D007099', (47, 57))	('sexual function', 'MPA', (133, 148))	('ejaculation', 'CPA', (183, 194))	('imipramine', 'Var', (47, 57))
68733	24369133	One example, although recently challenged, is the observation that exposure to vinclozolin, a fungicide and antiandrogenic agent, during embryogenesis decreases the adult sperm motility and concentration, and this effect is transferred through several generations of male offspring and is associated with alterations in the sperm methylation profile.	('vinclozolin', 'Chemical', 'MESH:C025643', (79, 90))	('rat', 'Species', '10116', (197, 200))	('rat', 'Species', '10116', (256, 259))	('vinclozolin', 'Var', (79, 90))	('decreases', 'NegReg', (151, 160))	('alterations', 'Reg', (305, 316))	('rat', 'Species', '10116', (309, 312))
68749	24369133	Such disorders can be caused by deficient androgen production or action and are among the most common congenital disorders in male children.	('deficient', 'Var', (32, 41))	('children', 'Species', '9606', (131, 139))	('congenital disorders', 'Disease', 'MESH:D000013', (102, 122))	('deficient androgen production', 'Phenotype', 'HP:0008226', (32, 61))	('action', 'MPA', (65, 71))	('caused', 'Reg', (22, 28))	('androgen', 'Protein', (42, 50))	('congenital disorders', 'Disease', (102, 122))
68752	24369133	Several androgen-dependent genes, such as AR, steroid-5-alpha-reductase, alpha polypeptide 2 (SRD5A2), hydroxysteroid (17-beta) dehydrogenase 3 (HSD17B3) and FK506 binding protein 4 (FKBP52), are associated with the regulation of the external genitalia formation and defects in these genes significantly increase the risk of developing hypospadias.	('SRD5A2', 'Gene', (94, 100))	('FKBP52', 'Gene', (183, 189))	('hydroxysteroid (17-beta) dehydrogenase 3', 'Gene', '3293', (103, 143))	('AR', 'Gene', '367', (42, 44))	('HSD17B3', 'Gene', '3293', (145, 152))	('FK506 binding protein 4', 'Gene', '2288', (158, 181))	('FK506 binding protein 4', 'Gene', (158, 181))	('steroid', 'Chemical', 'MESH:D013256', (110, 117))	('HSD17B3', 'Gene', (145, 152))	('steroid', 'Chemical', 'MESH:D013256', (46, 53))	('hypospadias', 'Phenotype', 'HP:0000047', (336, 347))	('regulation of the external genitalia formation', 'Phenotype', 'HP:0003247', (216, 262))	('increase', 'Reg', (304, 312))	('SRD5A2', 'Gene', '6716', (94, 100))	('hypospadias', 'Disease', (336, 347))	('external genitalia', 'Disease', 'MESH:D012734', (234, 252))	('FKBP52', 'Gene', '2288', (183, 189))	('external genitalia', 'Disease', (234, 252))	('defects', 'Var', (267, 274))	('hypospadias', 'Disease', 'MESH:D007021', (336, 347))
68753	24369133	Deficient androgen action within this early programming window in males can induce the common congenital disorders of cryptorchidism and hypospadias in rats.	('Deficient', 'Var', (0, 9))	('hypospadias', 'Phenotype', 'HP:0000047', (137, 148))	('induce', 'Reg', (76, 82))	('rats', 'Species', '10116', (152, 156))	('androgen', 'Protein', (10, 18))	('cryptorchidism', 'Phenotype', 'HP:0000028', (118, 132))	('congenital disorders of cryptorchidism and hypospadias', 'Disease', 'MESH:D003456', (94, 148))	('Deficient androgen action', 'Phenotype', 'HP:0008226', (0, 25))
68761	24369133	Disruption of steroidogenesis in FLCs by environmental xenobiotics and/or metabolic endogenous factors during the masculinization programming window may cause undermasculinization and malformation of the male reproductive organs.	('steroidogenesis', 'MPA', (14, 29))	('men', 'Species', '9606', (48, 51))	('steroid', 'Chemical', 'MESH:D013256', (14, 21))	('malformation', 'Disease', (184, 196))	('cause', 'Reg', (153, 158))	('undermasculinization', 'Disease', (159, 179))	('Disruption', 'Var', (0, 10))
68767	24369133	Defects in several key genes that control phallus development, androgen biosynthesis and action can be enhanced by the environment; this promotes the development of hypospadias.	('men', 'Species', '9606', (126, 129))	('promotes', 'PosReg', (137, 145))	('hypospadias', 'Disease', (165, 176))	('Defects', 'Var', (0, 7))	('hypospadias', 'Phenotype', 'HP:0000047', (165, 176))	('men', 'Species', '9606', (157, 160))	('men', 'Species', '9606', (57, 60))	('hypospadias', 'Disease', 'MESH:D007021', (165, 176))
68768	24369133	Experimental animal models have demonstrated the importance of the homeobox genes A (HOXA) and D (HOXD) in the development of the phallus because deletion of these genes in mice induces malformation of the external genitalia consistent with hypospadias.	('deletion', 'Var', (146, 154))	('malformation of the external genitalia', 'Disease', 'MESH:C564563', (186, 224))	('induces', 'Reg', (178, 185))	('hypospadias', 'Disease', (241, 252))	('HOXA', 'Gene', (85, 89))	('hypospadias', 'Disease', 'MESH:D007021', (241, 252))	('men', 'Species', '9606', (118, 121))	('hypospadias', 'Phenotype', 'HP:0000047', (241, 252))	('rat', 'Species', '10116', (39, 42))	('HOXA', 'Gene', '111336', (85, 89))	('malformation of the external genitalia', 'Disease', (186, 224))	('malformation of the external genitalia', 'Phenotype', 'HP:0000811', (186, 224))	('mice', 'Species', '10090', (173, 177))	('men', 'Species', '9606', (6, 9))
68770	24369133	In humans, polymorphisms of FGF8, FGF10 and FGFR2 may be associated with an increased risk of hypospadias.	('FGF10', 'Gene', (34, 39))	('hypospadias', 'Disease', 'MESH:D007021', (94, 105))	('FGF8', 'Gene', (28, 32))	('FGF8', 'Gene', '2253', (28, 32))	('hypospadias', 'Disease', (94, 105))	('polymorphisms', 'Var', (11, 24))	('humans', 'Species', '9606', (3, 9))	('FGFR2', 'Gene', '2263', (44, 49))	('hypospadias', 'Phenotype', 'HP:0000047', (94, 105))	('FGFR2', 'Gene', (44, 49))	('associated', 'Reg', (57, 67))
68771	24369133	Mutations in the genes controlling androgen biosynthesis by the Leydig cells (e.g., the luteinizing hormone (LH) receptor and 5alpha-reductase genes) also induce hypospadias, which can be associated with cryptorchidism and micropenis.	('cryptorchidism and micropenis', 'Disease', 'MESH:C536649', (204, 233))	('LH', 'Gene', (109, 111))	('associated', 'Reg', (188, 198))	('hypospadias', 'Disease', 'MESH:D007021', (162, 173))	('LH', 'Chemical', 'MESH:D007986', (109, 111))	('hypospadias', 'Disease', (162, 173))	('induce', 'Reg', (155, 161))	('Mutations', 'Var', (0, 9))	('cryptorchidism', 'Phenotype', 'HP:0000028', (204, 218))	('micropenis', 'Phenotype', 'HP:0000054', (223, 233))	('hypospadias', 'Phenotype', 'HP:0000047', (162, 173))
68773	24369133	These mutations are typically found in AIS cases with severe hypospadias and they may not be common causes of isolated hypospadias.	('hypospadias', 'Disease', (119, 130))	('hypospadias', 'Phenotype', 'HP:0000047', (61, 72))	('isolated hypospadias', 'Disease', 'MESH:D007021', (110, 130))	('isolated hypospadias', 'Disease', (110, 130))	('hypospadias', 'Phenotype', 'HP:0000047', (119, 130))	('found', 'Reg', (30, 35))	('hypospadias', 'Disease', 'MESH:D007021', (61, 72))	('AIS', 'Disease', 'OMIM:181800', (39, 42))	('hypospadias', 'Disease', 'MESH:D007021', (119, 130))	('hypospadias', 'Disease', (61, 72))	('AIS', 'Disease', (39, 42))	('mutations', 'Var', (6, 15))
68775	24369133	A recent study reported that a higher number of the CAG repeat sequence in the AR gene may increase the risk of hypospadias in Caucasians.	('hypospadias', 'Disease', (112, 123))	('hypospadias', 'Phenotype', 'HP:0000047', (112, 123))	('increase', 'PosReg', (91, 99))	('hypospadias', 'Disease', 'MESH:D007021', (112, 123))	('AR', 'Gene', '367', (79, 81))	('CAG repeat sequence', 'Var', (52, 71))
68779	24369133	In humans, mutations in these genes are associated with the development of disorders of sex development (DSD) syndrome, including micropenis, a bifid scrotum, penoscrotal hypospadias and cryptorchidism.	('micropenis', 'Disease', 'MESH:C536649', (130, 140))	('mutations', 'Var', (11, 20))	('bifid scrotum', 'Phenotype', 'HP:0000048', (144, 157))	('penoscrotal hypospadias', 'Phenotype', 'HP:0000808', (159, 182))	('micropenis', 'Disease', (130, 140))	('bifid scrotum', 'Disease', (144, 157))	('men', 'Species', '9606', (67, 70))	('hypospadias', 'Phenotype', 'HP:0000047', (171, 182))	('cryptorchidism', 'Disease', (187, 201))	('penoscrotal hypospadias', 'Disease', 'MESH:C566526', (159, 182))	('micropenis', 'Phenotype', 'HP:0000054', (130, 140))	('humans', 'Species', '9606', (3, 9))	('disorders of sex development (DSD) syndrome', 'Disease', 'MESH:D012734', (75, 118))	('men', 'Species', '9606', (99, 102))	('cryptorchidism', 'Phenotype', 'HP:0000028', (187, 201))	('associated', 'Reg', (40, 50))	('penoscrotal hypospadias', 'Disease', (159, 182))
68781	24369133	Exposure of male fetuses in utero to different environmental chemicals such as vinclozolin, polychlorinated biphenyls (PCBs), phthalates and dioxins has been shown to induce hypospadias in boys of the resident families.	('boys', 'Species', '9606', (189, 193))	('vinclozolin', 'Chemical', 'MESH:C025643', (79, 90))	('hypospadias', 'Phenotype', 'HP:0000047', (174, 185))	('polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (92, 117))	('dioxins', 'Chemical', 'MESH:D004147', (141, 148))	('men', 'Species', '9606', (54, 57))	('PCBs', 'Chemical', 'MESH:D011078', (119, 123))	('hypospadias', 'Disease', 'MESH:D007021', (174, 185))	('induce', 'Reg', (167, 173))	('polychlorinated biphenyls', 'Var', (92, 117))	('phthalates', 'Chemical', 'MESH:C032279', (126, 136))	('hypospadias', 'Disease', (174, 185))
68805	24369133	Low birth weight, preterm delivery and small for gestational age weight are associated with a substantial increase in the incidence of cryptorchidism, which may reach 20%-25% in boys with birth weight less than 2.5 kg.	('boys', 'Species', '9606', (178, 182))	('Low birth', 'Var', (0, 9))	('small for gestational age', 'Phenotype', 'HP:0001518', (39, 64))	('cryptorchidism', 'Disease', (135, 149))	('Low birth weight', 'Phenotype', 'HP:0001518', (0, 16))	('cryptorchidism', 'Phenotype', 'HP:0000028', (135, 149))	('preterm delivery', 'Phenotype', 'HP:0001622', (18, 34))
68810	24369133	Dysfunction of the FLCs leading to androgen and Insl3 deficiency retains the testis either in the abdomen or in the inguinal canals.	('Dysfunction', 'Var', (0, 11))	('deficiency retains the testis', 'Disease', (54, 83))	('deficiency retains the testis', 'Disease', 'MESH:D013736', (54, 83))	('Insl3', 'Gene', (48, 53))	('androgen', 'Gene', (35, 43))	('Insl3 deficiency', 'Phenotype', 'HP:0031037', (48, 64))	('men', 'Species', '9606', (102, 105))
68814	24369133	Patients with inactivating mutations in the LH receptor gene exhibit cryptorchidism and other phenotypic features.	('inactivating mutations', 'Var', (14, 36))	('cryptorchidism', 'Disease', (69, 83))	('LH receptor', 'Gene', (44, 55))	('LH receptor', 'Gene', '3973', (44, 55))	('Patients', 'Species', '9606', (0, 8))	('cryptorchidism', 'Phenotype', 'HP:0000028', (69, 83))
68818	24369133	Mutations in the AR gene, steroidogenic enzymes and hypothalamic-pituitary regulators needed for testicular stimulation have been reported as rare causes of cryptorchidism.	('cryptorchidism', 'Phenotype', 'HP:0000028', (157, 171))	('causes', 'Reg', (147, 153))	('hypothalamic-pituitary', 'Disease', 'MESH:D007029', (52, 74))	('Mutations', 'Var', (0, 9))	('cryptorchidism', 'Disease', (157, 171))	('AR', 'Gene', '367', (17, 19))	('hypothalamic-pituitary', 'Disease', (52, 74))	('steroid', 'Chemical', 'MESH:D013256', (26, 33))
68822	24369133	The phenotypes of men with INSL3 and RXFP2 mutations vary between unilateral to bilateral cryptorchidism, indicating differences of the penetrance of the genetic changes to the gubernaculum development.	('vary', 'Reg', (53, 57))	('RXFP2', 'Gene', (37, 42))	('RXFP2', 'Gene', '122042', (37, 42))	('men', 'Species', '9606', (18, 21))	('INSL3', 'Gene', (27, 32))	('men', 'Species', '9606', (197, 200))	('mutations', 'Var', (43, 52))	('cryptorchidism', 'Phenotype', 'HP:0000028', (90, 104))	('unilateral to bilateral cryptorchidism', 'Phenotype', 'HP:0012741', (66, 104))	('bilateral cryptorchidism', 'Phenotype', 'HP:0008689', (80, 104))	('INSL3', 'Gene', '3640', (27, 32))
68827	24369133	The levels of phthalates in mother's breast milk were not linked with a risk of cryptorchidism in their sons, even though EDCs have been found to cause an antiandrogenic effect on the anogenital index in boys.	('cryptorchidism', 'Disease', (80, 94))	('phthalates', 'Chemical', 'MESH:C032279', (14, 24))	('EDCs', 'Var', (122, 126))	('boys', 'Species', '9606', (204, 208))	('anogenital', 'MPA', (184, 194))	('cryptorchidism', 'Phenotype', 'HP:0000028', (80, 94))	('antiandrogenic effect', 'MPA', (155, 176))
68830	24369133	These congenital malformations can be associated with the suppression of production of androgen and Insl3 by FLCs.	('congenital malformations', 'Disease', 'MESH:D000013', (6, 30))	('congenital malformations', 'Disease', (6, 30))	('production of androgen', 'MPA', (73, 95))	('FLCs', 'Var', (109, 113))	('suppression', 'NegReg', (58, 69))
68840	24369133	Testicular germ cell tumors are known to be connected to mutations in several genes, including kit-ligand (KITLG), sprouty homolog 4 (SPRY4), BCL2-antagonist/killer 1 (BAK1), telomerase reverse transcriptase (TERT), doublesex and mab-3 related transcription factor 1 (DMRT1) and activating transcription factor 7 interacting protein (ATF7IP).	('DMRT1', 'Gene', (268, 273))	('kit-ligand', 'Gene', '4254', (95, 105))	('germ cell tumors', 'Phenotype', 'HP:0100728', (11, 27))	('mutations', 'Var', (57, 66))	('kit-ligand', 'Gene', (95, 105))	('KITLG', 'Gene', (107, 112))	('connected', 'Reg', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('SPRY4', 'Gene', '81848', (134, 139))	('KITLG', 'Gene', '4254', (107, 112))	('telomerase reverse transcriptase', 'Gene', (175, 207))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('ATF7IP', 'Gene', (334, 340))	('BCL2', 'Gene', '596', (142, 146))	('TERT', 'Gene', (209, 213))	('BAK1', 'Gene', '578', (168, 172))	('sprouty homolog 4', 'Gene', '81848', (115, 132))	('TERT', 'Gene', '7015', (209, 213))	('DMRT1', 'Gene', '1761', (268, 273))	('BAK1', 'Gene', (168, 172))	('cell tumors', 'Disease', (16, 27))	('cell tumors', 'Disease', 'MESH:D005935', (16, 27))	('activating transcription factor 7 interacting protein', 'Gene', '55729', (279, 332))	('sprouty homolog 4', 'Gene', (115, 132))	('telomerase reverse transcriptase', 'Gene', '7015', (175, 207))	('BCL2', 'Gene', (142, 146))	('doublesex and mab-3 related transcription factor 1', 'Gene', '1761', (216, 266))	('ATF7IP', 'Gene', '55729', (334, 340))	('SPRY4', 'Gene', (134, 139))
68841	24369133	Detection of these malignant cells can be achieved by showing positive expression for placental alkaline phosphatase (PLAP); tyrosine-protein kinase Kit (C-KIT); POU domain, class 5, transcription factor 1 (POU5F1, also termed as OCT3/4); activating enhancer binding protein 2-gamma (AP-2gamma); and homeobox transcription factor NANOG (NANOG).	('PLAP', 'Gene', (118, 122))	('placental alkaline phosphatase', 'Gene', '250', (86, 116))	('POU', 'Var', (162, 165))	('AP-2gamma', 'Gene', (284, 293))	('PLAP', 'Gene', '250', (118, 122))	('C-KIT', 'Gene', '3815', (154, 159))	('POU5F1', 'Gene', '5460', (207, 213))	('POU5F1', 'Gene', (207, 213))	('C-KIT', 'Gene', (154, 159))	('placental alkaline phosphatase', 'Gene', (86, 116))	('NANOG', 'Gene', '79923', (337, 342))	('NANOG', 'Gene', (337, 342))	('NANOG', 'Gene', '79923', (330, 335))	('NANOG', 'Gene', (330, 335))	('homeobox', 'Gene', (300, 308))	('AP-2gamma', 'Gene', '7022', (284, 293))
68842	24369133	Recent and earlier studies demonstrate the role of KITLG and DMRT1 gene alterations as the main factors involved in TGCT formation.	('KITLG', 'Gene', (51, 56))	('TGCT', 'Disease', (116, 120))	('rat', 'Species', '10116', (76, 79))	('alterations', 'Var', (72, 83))	('DMRT1', 'Gene', '1761', (61, 66))	('involved', 'Reg', (104, 112))	('DMRT1', 'Gene', (61, 66))	('rat', 'Species', '10116', (34, 37))	('KITLG', 'Gene', '4254', (51, 56))
68849	24369133	Because EDCs comprise a large number of different substances with dissimilar structures and diverse toxicities, some EDCs may directly affect spermatogenesis, for instance, by changing the structure or motility of spermatozoa, damaging the spermatogonia or destroying Sertoli cells; while most other pesticides act indirectly through endocrine disruption.	('damaging', 'Reg', (227, 235))	('toxicities', 'Disease', (100, 110))	('changing', 'Reg', (176, 184))	('Sertoli cells', 'CPA', (268, 281))	('affect', 'Reg', (135, 141))	('structure', 'MPA', (189, 198))	('spermatogenesis', 'CPA', (142, 157))	('spermatogonia', 'CPA', (240, 253))	('toxicities', 'Disease', 'MESH:D064420', (100, 110))	('Sertoli cell', 'Phenotype', 'HP:0100619', (268, 280))	('Sertoli cells', 'Phenotype', 'HP:0100619', (268, 281))	('EDCs', 'Var', (117, 121))	('destroying', 'NegReg', (257, 267))
68856	24369133	A recent study reported that organophosphate pesticide sprayers had reduced percentages of morphologically normal sperm and motile sperm and decreased serum levels of LH and testosterone.	('organophosphate', 'Var', (29, 44))	('testosterone', 'Chemical', 'MESH:D013739', (174, 186))	('organophosphate', 'Chemical', 'MESH:D010755', (29, 44))	('LH', 'Chemical', 'MESH:D007986', (167, 169))	('decreased', 'NegReg', (141, 150))	('reduced percentages of morphologically normal sperm', 'Phenotype', 'HP:0012207', (68, 119))	('morphologically normal sperm', 'CPA', (91, 119))	('reduced', 'NegReg', (68, 75))	('motile sperm', 'CPA', (124, 136))
68866	24369133	Exposure to dexamethasone from e15 to e21 reduced the plasma testosterone and LH levels between e19 and e21.	('reduced', 'NegReg', (42, 49))	('plasma testosterone', 'MPA', (54, 73))	('reduced the plasma testosterone', 'Phenotype', 'HP:0040171', (42, 73))	('testosterone', 'Chemical', 'MESH:D013739', (61, 73))	('LH levels', 'MPA', (78, 87))	('LH', 'Chemical', 'MESH:D007986', (78, 80))	('e19', 'Var', (96, 99))	('e21', 'Var', (104, 107))	('dexamethasone', 'Chemical', 'MESH:D003907', (12, 25))
68917	24369133	The exposure of male rats to Aroclor 1254, a PCB, was reported to cause decreased testicular weight, sperm count, sperm motility and daily sperm production and was associated with a depletion of mitochondrial antioxidant enzymes.	('daily sperm production', 'CPA', (133, 155))	('testicular weight', 'CPA', (82, 99))	('decreased', 'NegReg', (72, 81))	('sperm count', 'CPA', (101, 112))	('rats', 'Species', '10116', (21, 25))	('PCB', 'Gene', '25104', (45, 48))	('sperm motility', 'CPA', (114, 128))	('PCB', 'Gene', (45, 48))	('decreased testicular', 'Phenotype', 'HP:0008734', (72, 92))	('Aroclor 1254', 'Chemical', 'MESH:D020111', (29, 41))	('depletion', 'MPA', (182, 191))	('Aroclor 1254', 'Var', (29, 41))	('mitochondrial antioxidant', 'MPA', (195, 220))
69104	18288311	Furthermore hypospadias, cryptorchidism, and testicular cancer have all been found to be associated with low birth weight, suggesting a potential association with an underlying placental defect.	('cryptorchidism', 'Disease', (25, 39))	('low birth', 'Var', (105, 114))	('testicular cancer', 'Disease', (45, 62))	('hypospadias', 'Disease', 'MESH:D007021', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('low birth weight', 'Phenotype', 'HP:0001518', (105, 121))	('hypospadias', 'Disease', (12, 23))	('cryptorchidism', 'Phenotype', 'HP:0000028', (25, 39))	('testicular cancer', 'Phenotype', 'HP:0010788', (45, 62))	('testicular cancer', 'Disease', 'MESH:D013736', (45, 62))	('placental defect', 'Phenotype', 'HP:0100767', (177, 193))	('hypospadias', 'Phenotype', 'HP:0000047', (12, 23))
69114	18288311	Interactions between genetic susceptibility and the environment have been the focus of research in this area, and advances in genomics have allowed the identification of polymorphisms associated with hypospadias, cryptorchidism, and testicular cancer.	('testicular cancer', 'Disease', (233, 250))	('hypospadias', 'Disease', 'MESH:D007021', (200, 211))	('cryptorchidism', 'Phenotype', 'HP:0000028', (213, 227))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('hypospadias', 'Disease', (200, 211))	('associated', 'Reg', (184, 194))	('testicular cancer', 'Disease', 'MESH:D013736', (233, 250))	('testicular cancer', 'Phenotype', 'HP:0010788', (233, 250))	('polymorphisms', 'Var', (170, 183))	('hypospadias', 'Phenotype', 'HP:0000047', (200, 211))	('cryptorchidism', 'Disease', (213, 227))
69115	18288311	This is well illustrated by the recent identification of the association of a variant of the gene for the ER-alpha with hypospadias and cryptorchidism in Japanese cohorts that has now been found to be associated with a decreased incidence of hypospadias in a European cohort.	('hypospadias', 'Disease', (120, 131))	('cryptorchidism', 'Phenotype', 'HP:0000028', (136, 150))	('hypospadias', 'Phenotype', 'HP:0000047', (120, 131))	('hypospadias', 'Disease', 'MESH:D007021', (242, 253))	('variant', 'Var', (78, 85))	('rat', 'Species', '10116', (19, 22))	('ER-alpha', 'Gene', (106, 114))	('cryptorchidism', 'Disease', (136, 150))	('hypospadias', 'Disease', (242, 253))	('hypospadias', 'Disease', 'MESH:D007021', (120, 131))	('hypospadias', 'Phenotype', 'HP:0000047', (242, 253))	('association', 'Interaction', (61, 72))
69126	33489210	Several researchers have recommended cryopreservation of sperm before treatment for TGCT, 3 ,  4 ,  5  as infertility can harm the mental health of young patients, and these patients may not have considered their fertility or plans to have children at the time of their TGCT diagnosis.	('infertility', 'Disease', (106, 117))	('harm', 'NegReg', (122, 126))	('men', 'Species', '9606', (131, 134))	('cryopreservation', 'Var', (37, 53))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (174, 182))	('men', 'Species', '9606', (75, 78))	('men', 'Species', '9606', (30, 33))	('infertility', 'Phenotype', 'HP:0000789', (106, 117))	('children', 'Species', '9606', (240, 248))	('infertility', 'Disease', 'MESH:D007247', (106, 117))	('mental health', 'MPA', (131, 144))
69127	33489210	Thus, pre-treatment cryopreservation of sperm may improve these patients' quality of life, even if the sperm is not ultimately used for assisted reproductive therapy.	('patients', 'Species', '9606', (64, 72))	('men', 'Species', '9606', (15, 18))	('quality of life', 'CPA', (74, 89))	('cryopreservation', 'Var', (20, 36))	('improve', 'PosReg', (50, 57))
69192	33172093	Clinically, high expression of FGF9 is associated with poor prognosis in patients who have non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (91, 117))	('FGF9', 'Gene', (31, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('non-small cell lung cancer', 'Disease', (91, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (95, 117))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (91, 117))	('NSCLC', 'Disease', (119, 124))	('patients', 'Species', '9606', (73, 81))	('high expression', 'Var', (12, 27))
69209	33172093	In the 12 h control group, the expression of cyclin A1 and cyclin B1 were also significantly reduced by cordycepin (Figure 4A,D,E).	('cyclin B1', 'Gene', (59, 68))	('cyclin A1', 'Gene', (45, 54))	('reduced', 'NegReg', (93, 100))	('cyclin B1', 'Gene', '268697', (59, 68))	('expression', 'MPA', (31, 41))	('cordycepin', 'Chemical', 'MESH:C058120', (104, 114))	('cordycepin', 'Var', (104, 114))	('cyclin A1', 'Gene', '12427', (45, 54))
69211	33172093	In addition, cordycepin did reduce protein basal levels of cyclin B1 and E1 proteins whether treated with FGF9 or not at 12 h after treatment (Figure 4A,D,E).	('cyclin B1', 'Gene', (59, 68))	('cordycepin', 'Chemical', 'MESH:C058120', (13, 23))	('protein basal levels of', 'MPA', (35, 58))	('cyclin B1', 'Gene', '268697', (59, 68))	('E1 proteins', 'Protein', (73, 84))	('reduce', 'NegReg', (28, 34))	('men', 'Species', '9606', (137, 140))	('FGF9', 'Var', (106, 110))
69231	33172093	On day 9 after initiation of drug administration, the tumor volumes of the FGF9/PBS group were significantly increased compared to the BSA/PBS and Control/PBS groups (Figure 7A), which was consistent with our previous finding in a NOD-SCID model.	('SCID', 'Disease', (235, 239))	('SCID', 'Disease', 'MESH:D053632', (235, 239))	('SCID', 'Phenotype', 'HP:0004430', (235, 239))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('FGF9/PBS', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('PBS', 'Chemical', 'MESH:D007854', (155, 158))	('tumor', 'Disease', (54, 59))	('increased', 'PosReg', (109, 118))	('PBS', 'Chemical', 'MESH:D007854', (80, 83))	('PBS', 'Chemical', 'MESH:D007854', (139, 142))
69237	33172093	Results showed that the tumor tissue expression of Ki-67 decreased and cleaved caspase-3 increased in FGF9/cordycepin and Control/cordycepin groups (Figure 7D-G), whereas the tumor tissue expression of Ki-67 increased and cleaved as caspase-3 decreased in the FGF9/PBS group (Figure 7D-G).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Ki-67', 'Gene', (202, 207))	('cleaved', 'MPA', (71, 78))	('Ki-67', 'Gene', (51, 56))	('cordycepin', 'Chemical', 'MESH:C058120', (107, 117))	('PBS', 'Chemical', 'MESH:D007854', (265, 268))	('caspase-3', 'Gene', (79, 88))	('decreased', 'NegReg', (57, 66))	('cordycepin', 'Chemical', 'MESH:C058120', (130, 140))	('caspase-3', 'Gene', '12367', (233, 242))	('cleaved', 'MPA', (222, 229))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (24, 29))	('caspase-3', 'Gene', '12367', (79, 88))	('increased', 'PosReg', (208, 217))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('increased', 'PosReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Ki-67', 'Gene', '17345', (202, 207))	('Ki-67', 'Gene', '17345', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('FGF9/cordycepin', 'Var', (102, 117))	('caspase-3', 'Gene', (233, 242))
69238	33172093	These data indicated that, in vivo, cordycepin decreased the tumor mass by decreasing MA-10 cell proliferation and increasing cell apoptosis.	('cordycepin', 'Var', (36, 46))	('cordycepin', 'Chemical', 'MESH:C058120', (36, 46))	('decreasing', 'NegReg', (75, 85))	('MA-10', 'Chemical', '-', (86, 91))	('cell apoptosis', 'CPA', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MA-10 cell proliferation', 'CPA', (86, 110))	('increasing', 'PosReg', (115, 125))	('tumor', 'Disease', (61, 66))	('decreased', 'NegReg', (47, 56))
69239	33172093	Furthermore, the immunohistochemical expressions of p-ERK1/2 and p-Rb in MA-10 tumors were significantly inhibited in FGF9/cordycepin and Control/cordycepin groups while the p-ERK1/2 and p-Rb expressions were increased in the FGF9/PBS group (Figure 8A-D).	('FGF9/cordycepin', 'Var', (118, 133))	('p-ERK1/2', 'Gene', (52, 60))	('MA-10', 'Gene', (73, 78))	('Rb', 'Gene', '19645', (189, 191))	('cordycepin', 'Chemical', 'MESH:C058120', (123, 133))	('inhibited', 'NegReg', (105, 114))	('Rb', 'Gene', '19645', (67, 69))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('MA-10', 'Chemical', '-', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cordycepin', 'Chemical', 'MESH:C058120', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('PBS', 'Chemical', 'MESH:D007854', (231, 234))
69244	33172093	In the present study, we have a novel finding that cordycepin inhibited MA-10 cell proliferation in vitro and tumor growth in vivo through suppressing the FGF9 signaling pathway, which upregulated the phosphorylation of ERK1/2 and Rb, the expressions of E2F1 and the cell cycle related proteins, cyclins and CDKs (Figure 10).	('expressions', 'MPA', (239, 250))	('MA-10', 'Chemical', '-', (72, 77))	('cordycepin', 'Var', (51, 61))	('cyclins', 'Gene', '268697', (296, 303))	('FGF9 signaling pathway', 'Pathway', (155, 177))	('E2F1', 'Gene', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cordycepin', 'Chemical', 'MESH:C058120', (51, 61))	('MA-10 cell proliferation', 'CPA', (72, 96))	('ERK1/2', 'Protein', (220, 226))	('suppressing', 'NegReg', (139, 150))	('CDKs', 'Gene', (308, 312))	('cyclins', 'Gene', (296, 303))	('upregulated', 'PosReg', (185, 196))	('CDKs', 'Gene', '12534;1017;12566;12567', (308, 312))	('tumor', 'Disease', (110, 115))	('inhibited', 'NegReg', (62, 71))	('Rb', 'Gene', '19645', (231, 233))	('phosphorylation', 'MPA', (201, 216))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
69251	33172093	Here, from the microarray analysis of cordycepin-mediated alteration of gene expression levels in testicular cancer cells, the clustering of the microarray data identified that the mRNA level of FGF9 and FGF18 were reduced in 100 mug/mL cordycepin-treated MA-10 cells (Table 1).	('FGF9', 'Gene', (195, 199))	('mRNA level', 'MPA', (181, 191))	('100 mug/mL', 'Var', (226, 236))	('cordycepin', 'Chemical', 'MESH:C058120', (38, 48))	('testicular cancer', 'Phenotype', 'HP:0010788', (98, 115))	('testicular cancer', 'Disease', 'MESH:D013736', (98, 115))	('cordycepin', 'Chemical', 'MESH:C058120', (237, 247))	('reduced', 'NegReg', (215, 222))	('FGF18', 'Gene', '14172', (204, 209))	('FGF18', 'Gene', (204, 209))	('testicular cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MA-10', 'Chemical', '-', (256, 261))
69256	33172093	FGFs and FGFRs would alter in cancer cells associated with receptor overexpression and/or the aberrant FGFs secretion.	('receptor', 'Protein', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('FGF', 'Gene', '2254;14180;14165;14172', (9, 12))	('FGF', 'Gene', '2254;14180;14165;14172', (0, 3))	('overexpression', 'PosReg', (68, 82))	('FGF', 'Gene', (0, 3))	('alter', 'Reg', (21, 26))	('FGF', 'Gene', '2254;14180;14165;14172', (103, 106))	('secretion', 'MPA', (108, 117))	('FGFR', 'Gene', '14182;14183;14184;14186', (9, 13))	('aberrant', 'Var', (94, 102))	('FGFR', 'Gene', (9, 13))	('FGF', 'Gene', (103, 106))	('FGF', 'Gene', (9, 12))
69263	33172093	We also illustrate that cordycepin could induce apoptosis through p38 MAPKs, PI3K/AKT, cell cycle arrest and caspase signaling pathways, and promote unfolded protein response-dependent cell death through FoxO/P15/P27, PERK-eIF2alpha and the IRE1-XBP1 pathways in MA-10 cells.	('eIF2alpha', 'Gene', (223, 232))	('IRE1', 'Gene', (241, 245))	('AKT', 'Gene', '11651', (82, 85))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('XBP1', 'Gene', (246, 250))	('PERK', 'Gene', '13666', (218, 222))	('P27', 'Gene', (213, 216))	('P15', 'Gene', '12579', (209, 212))	('induce', 'PosReg', (41, 47))	('PERK', 'Gene', (218, 222))	('XBP1', 'Gene', '22433', (246, 250))	('p38', 'Var', (66, 69))	('promote', 'PosReg', (141, 148))	('caspase signaling pathways', 'Pathway', (109, 135))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))	('cordycepin', 'Chemical', 'MESH:C058120', (24, 34))	('P27', 'Gene', '12576', (213, 216))	('cell cycle', 'CPA', (87, 97))	('AKT', 'Gene', (82, 85))	('arrest', 'Disease', (98, 104))	('eIF2alpha', 'Gene', '229317', (223, 232))	('unfolded protein response-dependent', 'MPA', (149, 184))	('MA-10', 'Chemical', '-', (263, 268))	('P15', 'Gene', (209, 212))	('apoptosis', 'CPA', (48, 57))	('IRE1', 'Gene', '26918', (241, 245))
69264	33172093	Moreover, FGF9 could activate the FGFR2 signaling pathway to induce MA-10 cell proliferation.	('FGFR2', 'Gene', (34, 39))	('FGFR2', 'Gene', '14183', (34, 39))	('induce', 'PosReg', (61, 67))	('MA-10', 'Chemical', '-', (68, 73))	('FGF9', 'Var', (10, 14))	('activate', 'PosReg', (21, 29))	('MA-10 cell proliferation', 'CPA', (68, 92))
69402	28036409	Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 329 controls.	('single nucleotide polymorphism', 'Var', (24, 54))	('rs995030', 'Mutation', 'rs995030', (61, 69))	('rs995030', 'Var', (61, 69))	('KITLG', 'Gene', '4254', (18, 23))	('KITLG', 'Gene', (18, 23))
69403	28036409	Testicular cancer was associated with the number of children fathered 5 years before diagnosis (odds ratio (OR) per additional child: 0.78, 95% confidence interval (CI): 0.58-1.04) and sibship size (OR per additional sibling: 0.76, 95% CI: 0.66-0.88).	('associated', 'Interaction', (22, 32))	('children', 'Species', '9606', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Testicular cancer', 'Disease', (0, 17))	('child', 'Species', '9606', (127, 132))	('Testicular cancer', 'Disease', 'MESH:D013736', (0, 17))	('sibship', 'Var', (185, 192))	('child', 'Species', '9606', (52, 57))	('Testicular cancer', 'Phenotype', 'HP:0010788', (0, 17))
69405	28036409	The SNP rs995030 was strongly associated with risk of testicular cancer (per allele OR: 1.83; 95%CI: 1.26-2.64), but it did not modify the association between number of children and the risk of testicular cancer.	('associated', 'Reg', (30, 40))	('testicular cancer', 'Phenotype', 'HP:0010788', (54, 71))	('testicular cancer', 'Phenotype', 'HP:0010788', (194, 211))	('testicular cancer', 'Disease', 'MESH:D013736', (194, 211))	('testicular cancer', 'Disease', 'MESH:D013736', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SNP rs995030', 'Var', (4, 16))	('testicular cancer', 'Disease', (54, 71))	('children', 'Species', '9606', (169, 177))	('testicular cancer', 'Disease', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('rs995030', 'Mutation', 'rs995030', (8, 16))
69422	28036409	Notably, two independent GWAS found that allele variations in KITLG (the unique ligand for the receptor tyrosine kinase KIT) were the strongest genetic risk factors for testicular germ cell tumors.	('KITLG', 'Gene', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('KITLG', 'Gene', '4254', (62, 67))	('germ cell tumors', 'Phenotype', 'HP:0100728', (180, 196))	('germ cell tumor', 'Phenotype', 'HP:0100728', (180, 195))	('tumors', 'Disease', (190, 196))	('allele variations', 'Var', (41, 58))	('receptor tyrosine kinase', 'Gene', (95, 119))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('receptor tyrosine kinase', 'Gene', '5979', (95, 119))	('risk factors', 'Reg', (152, 164))
69423	28036409	These studies showed that the KITLG single nucleotide polymorphism (SNP) rs995030 was associated with an at least 2-fold increased risk of testicular cancer.	('rs995030', 'Mutation', 'rs995030', (73, 81))	('rs995030', 'Var', (73, 81))	('single nucleotide polymorphism', 'Var', (36, 66))	('testicular cancer', 'Phenotype', 'HP:0010788', (139, 156))	('testicular cancer', 'Disease', 'MESH:D013736', (139, 156))	('KITLG', 'Gene', '4254', (30, 35))	('KITLG', 'Gene', (30, 35))	('testicular cancer', 'Disease', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
69424	28036409	The other identified SNPs were in strong linkage disequilibrium with each other and with rs995030 (r2>0.8), which may thus serve as a TagSNP.	('linkage', 'Interaction', (41, 48))	('rs995030', 'Var', (89, 97))	('rs995030', 'Mutation', 'rs995030', (89, 97))
69425	28036409	Apart from these SNPs, other genetic alterations of the KIT/KITLG pathway have been linked to an increased susceptibility to testicular germ cell tumors.	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('genetic alterations', 'Var', (29, 48))	('germ cell tumor', 'Phenotype', 'HP:0100728', (136, 151))	('KITLG', 'Gene', '4254', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('susceptibility', 'Reg', (107, 121))	('linked', 'Reg', (84, 90))	('KITLG', 'Gene', (60, 65))	('tumors', 'Disease', (146, 152))	('germ cell tumors', 'Phenotype', 'HP:0100728', (136, 152))
69426	28036409	The KIT-KITLG system is also crucial for germ cell survival, proliferation, motility, and migration, and its alterations may impair fertility.	('KITLG', 'Gene', '4254', (8, 13))	('KITLG', 'Gene', (8, 13))	('impair', 'NegReg', (125, 131))	('alterations', 'Var', (109, 120))	('impair fertility', 'Phenotype', 'HP:0000144', (125, 141))	('fertility', 'CPA', (132, 141))
69427	28036409	Indeed, mutations, complete or partial deletions of KIT or KITLG sequences and altered expression of either genes have been reported to be involved in the disruption of normal germ cell development, in increased spermatocyte apoptosis, and in microenvironment alterations.	('increased', 'PosReg', (202, 211))	('disruption', 'NegReg', (155, 165))	('KIT', 'Gene', (52, 55))	('men', 'Species', '9606', (255, 258))	('complete', 'Var', (19, 27))	('men', 'Species', '9606', (193, 196))	('mutations', 'Var', (8, 17))	('spermatocyte apoptosis', 'CPA', (212, 234))	('KITLG', 'Gene', '4254', (59, 64))	('expression', 'MPA', (87, 97))	('partial deletions', 'Var', (31, 48))	('KITLG', 'Gene', (59, 64))	('involved', 'Reg', (139, 147))	('normal germ cell development', 'CPA', (169, 197))	('increased spermatocyte apoptosis', 'Phenotype', 'HP:0030887', (202, 234))
69430	28036409	In order to disentangle the possible roles of shared environmental and genetic risk factors, we also assessed interactions the KITLG SNP rs995030 may have with subfertility in its association with the risk of testicular cancer.	('testicular cancer', 'Disease', (209, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('rs995030', 'Mutation', 'rs995030', (137, 145))	('subfertility', 'Disease', (160, 172))	('testicular cancer', 'Phenotype', 'HP:0010788', (209, 226))	('testicular cancer', 'Disease', 'MESH:D013736', (209, 226))	('KITLG', 'Gene', '4254', (127, 132))	('rs995030', 'Var', (137, 145))	('men', 'Species', '9606', (60, 63))	('association', 'Interaction', (180, 191))	('KITLG', 'Gene', (127, 132))
69441	28036409	Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 342 controls.	('single', 'Var', (24, 30))	('rs995030', 'Mutation', 'rs995030', (61, 69))	('rs995030', 'Var', (61, 69))	('KITLG', 'Gene', '4254', (18, 23))	('KITLG', 'Gene', (18, 23))
69444	28036409	Genotyping of the SNP rs995030 within the 3'UTR of the KITLG gene (Chromosome 12, NCBI Nucleotide Reference Sequence: NG_012098.1) was performed.	('rs995030', 'Mutation', 'rs995030', (22, 30))	('rs995030', 'Var', (22, 30))	('KITLG', 'Gene', (55, 60))	('KITLG', 'Gene', '4254', (55, 60))
69453	28036409	For the analyses on the KITLG SNP rs995030, we first tested for the Hardy-Weinberg equilibrium (HWE) among controls.	('tested', 'Reg', (53, 59))	('rs995030', 'Mutation', 'rs995030', (34, 42))	('KITLG', 'Gene', '4254', (24, 29))	('Hardy-Weinberg equilibrium', 'Disease', (68, 94))	('rs995030', 'Var', (34, 42))	('KITLG', 'Gene', (24, 29))
69478	28036409	Sibship size has also been repeatedly associated with a decreased risk of testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (74, 91))	('testicular cancer', 'Disease', 'MESH:D013736', (74, 91))	('decreased', 'NegReg', (56, 65))	('testicular cancer', 'Disease', (74, 91))	('Sibship', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
69487	28036409	We did not test our samples for the gr/gr microdeletion on the Y chromosome, which is largely associated with impaired spermatogenesis and the risk of testicular tumors because it is a rare, low-penetrance allele (carrier frequency 2-3%) and thus accounts for a limited number of cases.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('testicular tumors', 'Disease', (151, 168))	('impaired spermatogenesis', 'Phenotype', 'HP:0008669', (110, 134))	('microdeletion', 'Var', (42, 55))	('associated', 'Reg', (94, 104))	('testicular tumors', 'Disease', 'MESH:D013736', (151, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('testicular tumors', 'Phenotype', 'HP:0010788', (151, 168))
69488	28036409	The rs995030 SNP of the KITLG gene, which has been highly and consistently associated with risk of testicular cancer and is in strong linkage disequilibrium (r2>0.8) with other susceptibility SNPs was selected for the present analyses.	('rs995030 SNP', 'Var', (4, 16))	('testicular cancer', 'Phenotype', 'HP:0010788', (99, 116))	('testicular cancer', 'Disease', 'MESH:D013736', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('KITLG', 'Gene', '4254', (24, 29))	('rs995030', 'Mutation', 'rs995030', (4, 12))	('associated', 'Reg', (75, 85))	('KITLG', 'Gene', (24, 29))	('testicular cancer', 'Disease', (99, 116))
69524	33710779	9  Potential harms associated with screening include false-positive results, anxiety, and harms from diagnostic tests or procedures.	('anxiety', 'Disease', (77, 84))	('false-positive results', 'Var', (53, 75))	('anxiety', 'Phenotype', 'HP:0000739', (77, 84))	('anxiety', 'Disease', 'MESH:D001007', (77, 84))
69572	33710779	Generally, in cancer screening, overdiagnosis and false positives are the most important harms.	('cancer', 'Disease', (14, 20))	('false positives', 'Var', (50, 65))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
69654	27172897	Here we show that inhibition of HDAC1-3 is sufficient for LTR12 activation.	('HDAC1', 'Gene', (32, 37))	('LTR12', 'Gene', (58, 63))	('HDAC1', 'Gene', '3065', (32, 37))	('activation', 'PosReg', (64, 74))	('inhibition', 'Var', (18, 28))
69672	27172897	The molecular responses to alterations in HDAC activity range from apoptosis, migration and differentiation to angiogenesis.	('HDAC', 'Gene', (42, 46))	('angiogenesis', 'CPA', (111, 123))	('apoptosis', 'CPA', (67, 76))	('HDAC', 'Gene', '9734', (42, 46))	('migration', 'CPA', (78, 87))	('differentiation', 'CPA', (92, 107))	('alterations', 'Var', (27, 38))
69676	27172897	In some cancers, particular HDACs are overexpressed, and inhibition of HDAC activity can represent an efficient anticancer treatment.	('HDAC', 'Gene', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('inhibition', 'Var', (57, 67))	('cancer', 'Disease', (8, 14))	('cancers', 'Disease', (8, 15))	('HDAC', 'Gene', '9734', (28, 32))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('HDAC', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HDAC', 'Gene', '9734', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
69701	27172897	On the other hand, LTR12s do not depend on their specific integration site to function as HDAC inhibitor-responsive promoters.	('HDAC', 'Gene', (90, 94))	('HDAC', 'Gene', '9734', (90, 94))	('LTR12s', 'Var', (19, 25))
69720	27172897	Figure S4B, S4C) of NF-Y by shRNA-mediated knockdown, followed by TSA-treatment.	('NF-Y', 'Gene', (20, 24))	('knockdown', 'Var', (43, 52))	('TSA', 'Chemical', 'MESH:C012589', (66, 69))
69721	27172897	The removal of NFY-A resulted in a decreased expression of the LTR12-driven genes CGREF1, DHRS2 and SEMA4D, both in TSA- and in DMSO-treated cells (Figure 6A).	('CGREF1', 'Gene', (82, 88))	('removal', 'Var', (4, 11))	('DHRS2', 'Gene', '10202', (90, 95))	('SEMA4D', 'Gene', '10507', (100, 106))	('TSA', 'Chemical', 'MESH:C012589', (116, 119))	('DHRS2', 'Gene', (90, 95))	('decreased', 'NegReg', (35, 44))	('SEMA4D', 'Gene', (100, 106))	('expression', 'MPA', (45, 55))	('NFY-A', 'Chemical', '-', (15, 20))	('NFY-A', 'Gene', (15, 20))	('CGREF1', 'Gene', '10669', (82, 88))	('DMSO', 'Chemical', 'MESH:D004121', (128, 132))
69722	27172897	Depletion of NF-YB also reduced the levels of LTR12-driven mRNAs, but with lower significance (Suppl.	('reduced', 'NegReg', (24, 31))	('NF-YB', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('levels', 'MPA', (36, 42))	('LTR12-driven mRNAs', 'MPA', (46, 64))	('NF-YB', 'Gene', '4801', (13, 18))
69723	27172897	LTR12-driven TNFRSF10B expression, in contrast, was augmented by removal of NF-YA, but not NF-YB.	('removal', 'Var', (65, 72))	('NF-YB', 'Gene', (91, 96))	('augmented', 'PosReg', (52, 61))	('TNFRSF10B', 'Gene', (13, 22))	('NF-YA', 'Gene', '4800', (76, 81))	('NF-YB', 'Gene', '4801', (91, 96))	('TNFRSF10B', 'Gene', '8795', (13, 22))	('NF-YA', 'Gene', (76, 81))	('expression', 'MPA', (23, 33))
69724	27172897	This is in line with a proapoptotic effect of NF-YA inactivation, possibly secondary to the activation of p53.	('p53', 'Gene', '7157', (106, 109))	('activation', 'PosReg', (92, 102))	('inactivation', 'Var', (52, 64))	('NF-YA', 'Gene', '4800', (46, 51))	('p53', 'Gene', (106, 109))	('NF-YA', 'Gene', (46, 51))
69726	27172897	NF-YA depletion reduced the cleavage of poly-ADP-Ribose Polymerase (PARP) and caspase 3 upon treatment with TSA (Figure 6B).	('NF-YA', 'Gene', '4800', (0, 5))	('PARP', 'Gene', (68, 72))	('reduced', 'NegReg', (16, 23))	('caspase 3', 'Gene', (78, 87))	('NF-YA', 'Gene', (0, 5))	('cleavage', 'MPA', (28, 36))	('depletion', 'Var', (6, 15))	('TSA', 'Chemical', 'MESH:C012589', (108, 111))	('PARP', 'Gene', '142', (68, 72))	('caspase 3', 'Gene', '836', (78, 87))	('poly-ADP-Ribose Polymerase', 'Gene', '142', (40, 66))	('poly-ADP-Ribose Polymerase', 'Gene', (40, 66))
69730	27172897	Strikingly, the enormous upregulation of LTR12-driven genes by HDAC inhibitors is not confined to cells from germline tumors.	('HDAC', 'Gene', (63, 67))	('HDAC', 'Gene', '9734', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('inhibitors', 'Var', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', (118, 124))	('upregulation', 'PosReg', (25, 37))	('LTR12-driven genes', 'Gene', (41, 59))
69744	27172897	HDACs remove acetyl groups from histone tails, and hypoacetylated chromatin is overall associated with transcriptional silencing.	('HDAC', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (0, 4))	('hypoacetylated', 'Var', (51, 65))	('transcriptional', 'MPA', (103, 118))	('associated', 'Reg', (87, 97))	('acetyl groups', 'MPA', (13, 26))
69745	27172897	Histone deacetylation is commonly observed in human cancer and might stimulate the repression of important tumorsuppressive genes, thereby supporting tumorigenesis and possibly invasion and metastasis.	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('supporting', 'PosReg', (139, 149))	('Histone', 'Protein', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (46, 51))	('stimulate', 'PosReg', (69, 78))	('deacetylation', 'Var', (8, 21))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('invasion', 'CPA', (177, 185))	('tumors', 'Disease', (107, 113))	('repression', 'MPA', (83, 93))	('cancer', 'Disease', (52, 58))	('tumor', 'Disease', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
69751	27172897	The exception, the proapototic TNFRSF10B, shows an opposite behavior upon NF-YA vs NF-YB inactivation and joins a discrete set of pro-apoptotic mRNA genes which are differentially regulated upon inactivation of the two subunits.	('NF-YB', 'Gene', '4801', (83, 88))	('NF-YA', 'Gene', (74, 79))	('inactivation', 'Var', (89, 101))	('TNFRSF10B', 'Gene', (31, 40))	('NF-YA', 'Gene', '4800', (74, 79))	('NF-YB', 'Gene', (83, 88))	('TNFRSF10B', 'Gene', '8795', (31, 40))
69770	27172897	In contrast, when using xenograft models, derived from patients or cell lines, HDAC inhibitors may reveal their full potential for treating a broad spectrum of human cancers.	('inhibitors', 'Var', (84, 94))	('HDAC', 'Gene', (79, 83))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('HDAC', 'Gene', '9734', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (55, 63))	('human', 'Species', '9606', (160, 165))
69783	27172897	GSM935429, GSM935433, GSM935408, GSM935508, GSM935506 and GSM935507.	('GSM935429', 'Chemical', '-', (0, 9))	('GSM935507', 'Chemical', '-', (58, 67))	('GSM935507', 'Var', (58, 67))	('GSM935433', 'Var', (11, 20))	('GSM935506', 'Chemical', '-', (44, 53))	('GSM935433', 'Chemical', '-', (11, 20))	('GSM935506', 'Var', (44, 53))	('GSM935429', 'Var', (0, 9))	('GSM935508', 'Chemical', '-', (33, 42))	('GSM935408', 'Var', (22, 31))	('GSM935508', 'Var', (33, 42))	('GSM935408', 'Chemical', '-', (22, 31))
69788	27172897	Knockdown and treatment efficiency were assayed by PCR on cDNAs and by Western blot analysis on whole cell protein extracts using anti-NF-YA (Santa Cruz), anti NF-YB (GeneSpin), anti H3K9Ac (Abcam) and anti-Vinculin (Sigma) antibodies.	('NF-YB', 'Gene', (160, 165))	('anti H3K9Ac', 'Var', (178, 189))	('Vinculin', 'Gene', '7414', (207, 215))	('NF-YA', 'Gene', '4800', (135, 140))	('NF-YB', 'Gene', '4801', (160, 165))	('Vinculin', 'Gene', (207, 215))	('NF-YA', 'Gene', (135, 140))
69799	26604070	Men with sperm concentration and count in the 90th percentile of the distribution (>=178 M/ml and >=579, respectively) and total motile count (TMC) have an increased risk of melanoma (HRConcentration=2.1; HRCount=2.7; HRTMC=2.0).	('>=579', 'Var', (98, 103))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('TMC', 'Chemical', '-', (143, 146))	('melanoma', 'Disease', (174, 182))	('TMC', 'Chemical', '-', (220, 223))	('Men', 'Species', '9606', (0, 3))
69808	26604070	In brief, Y-chromosome deletions, epigenetic hypermethylation, DNA mismatch repair gene deletions/mutations, and aneuploidy are all mechanisms identified in cell culture, animal models, and human tissues, which have been shown to contribute to infertility and cancer.	('aneuploidy', 'Disease', 'MESH:D000782', (113, 123))	('DNA mismatch repair gene', 'Gene', (63, 87))	('infertility', 'Disease', 'MESH:D007247', (244, 255))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('infertility', 'Phenotype', 'HP:0000789', (244, 255))	('cancer', 'Disease', (260, 266))	('deletions/mutations', 'Var', (88, 107))	('infertility', 'Disease', (244, 255))	('epigenetic hypermethylation', 'Var', (34, 61))	('aneuploidy', 'Disease', (113, 123))	('contribute', 'Reg', (230, 240))	('human', 'Species', '9606', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Y-chromosome', 'Gene', (10, 22))
69913	26604070	Jacobsen and colleagues linked multiple Danish health registries with a large cohort of men with semen analyses, and the risk of testicular cancer was greater for men with low concentration, poor motility, and abnormal morphology.	('abnormal', 'Var', (210, 218))	('testicular cancer', 'Disease', 'MESH:D013736', (129, 146))	('men', 'Species', '9606', (163, 166))	('testicular cancer', 'Phenotype', 'HP:0010788', (129, 146))	('low', 'NegReg', (172, 175))	('men', 'Species', '9606', (88, 91))	('poor motility', 'CPA', (191, 204))	('testicular cancer', 'Disease', (129, 146))	('men', 'Species', '9606', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
69915	26604070	Our findings also improve upon previous research by showing that abnormal morphology, viability, and TMC are also associated with an increased risk of testicular cancer.	('testicular cancer', 'Disease', (151, 168))	('abnormal', 'Var', (65, 73))	('TMC', 'Chemical', '-', (101, 104))	('viability', 'CPA', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('testicular cancer', 'Disease', 'MESH:D013736', (151, 168))	('associated', 'Reg', (114, 124))	('testicular cancer', 'Phenotype', 'HP:0010788', (151, 168))
69922	26604070	The association between high levels of sperm concentration and TMC and melanoma is also a novel finding.	('TMC', 'Disease', (63, 66))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('high', 'Var', (24, 28))	('TMC', 'Chemical', '-', (63, 66))
69932	26604070	In future studies, we plan to select a cohort of men who later developed testicular cancer after semen analysis to locate associated genetic or epigenetic changes based on semen parameters.	('men', 'Species', '9606', (49, 52))	('testicular cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('men', 'Species', '9606', (99, 102))	('epigenetic', 'Var', (144, 154))	('testicular cancer', 'Phenotype', 'HP:0010788', (73, 90))	('testicular cancer', 'Disease', 'MESH:D013736', (73, 90))	('men', 'Species', '9606', (174, 177))
70127	23169336	To explore the positive predictive values (PPVs) for sperm counts of s-FSH and s-inhibin B, we used specified cut-off levels previously reported to predict oligo- (s-inhibin B<80 ng l-1 and s-FSH>10 IU l-1) and azoospermia (<50 ng l-1 and >10.9 IU l-1, respectively).	('azoospermia', 'Disease', (211, 222))	('>10', 'Var', (195, 198))	('l-1', 'Gene', '3897', (182, 185))	('oligo-', 'Disease', (156, 162))	('l-1', 'Gene', (231, 234))	('l-1', 'Gene', '3897', (202, 205))	('azoospermia', 'Phenotype', 'HP:0000027', (211, 222))	('l-1', 'Gene', (182, 185))	('s-FSH>10', 'Var', (190, 198))	('l-1', 'Gene', '3897', (248, 251))	('azoospermia', 'Disease', 'MESH:D053713', (211, 222))	('l-1', 'Gene', (202, 205))	('l-1', 'Gene', (248, 251))	('l-1', 'Gene', '3897', (231, 234))
70132	23169336	Overall, 42% had elevated s-FSH (>=12 IU l-1), varying from 30% in the Surgery group to 75% in the Cis>850 mg group (P<0.001; Figure 1A).	('l-1', 'Gene', '3897', (41, 44))	('s-FSH', 'MPA', (26, 31))	('Cis>850 mg', 'Var', (99, 109))	('elevated', 'PosReg', (17, 25))	('l-1', 'Gene', (41, 44))	('elevated s-FSH', 'Phenotype', 'HP:0008232', (17, 31))
70136	23169336	The s-inhibin B was significantly lower in the Cis>850 mg than the Cis<=850 mg group (-42 ng l-1, P=0.006).	('s-inhibin', 'MPA', (4, 13))	('l-1', 'Gene', (93, 96))	('lower', 'NegReg', (34, 39))	('Cis>850 mg', 'Var', (47, 57))	('l-1', 'Gene', '3897', (93, 96))
70148	23169336	Post-treatment paternity varied significantly according to treatment (Surgery 80%, RT 66%, Cis <=850 mg 73%, and Cis>850 mg 42% P=0.001).	('men', 'Species', '9606', (10, 13))	('paternity', 'CPA', (15, 24))	('Post', 'Gene', (0, 4))	('Cis <=850 mg', 'Var', (91, 103))	('Cis>850 mg', 'Var', (113, 123))	('men', 'Species', '9606', (64, 67))	('Post', 'Gene', '159371', (0, 4))
70157	23169336	The s-FSH, s-inhibin B, and sperm counts assessed at follow-up were all associated with post-treatment paternity.	('post', 'Gene', (88, 92))	('associated', 'Reg', (72, 82))	('sperm counts', 'CPA', (28, 40))	('men', 'Species', '9606', (98, 101))	('post', 'Gene', '159371', (88, 92))	('s-inhibin', 'Var', (11, 20))
70169	23169336	In the Cis>850 mg group, 43% had azoospermia, very similar to that reported by in their high-dose group (47%).	('Cis>850 mg', 'Var', (7, 17))	('azoospermia', 'Disease', (33, 44))	('azoospermia', 'Phenotype', 'HP:0000027', (33, 44))	('azoospermia', 'Disease', 'MESH:D053713', (33, 44))
70177	23169336	The correlations between sperm counts, s-inhibin B, and s-FSH were similar or slightly lower than that reported in men with impaired fertility, but higher than that reported in the general population.	('s-FSH', 'Gene', (56, 61))	('lower', 'NegReg', (87, 92))	('men', 'Species', '9606', (115, 118))	('s-inhibin', 'Var', (39, 48))	('correlations', 'MPA', (4, 16))	('sperm counts', 'CPA', (25, 37))	('impaired fertility', 'Phenotype', 'HP:0000144', (124, 142))	('higher', 'PosReg', (148, 154))
70178	23169336	The s-inhibin B has been proposed to be a better marker of spermatogenesis than s-FSH, and found that s-inhibin B, but not s-FSH, significantly correlated with sperm concentration in cancer patients referred for sperm cryopreservation before treatment.	('correlated with', 'Reg', (144, 159))	('cancer', 'Disease', (183, 189))	('patients', 'Species', '9606', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('sperm concentration', 'CPA', (160, 179))	('s-inhibin', 'Var', (102, 111))	('men', 'Species', '9606', (247, 250))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
70179	23169336	We applied cut-off levels for s-inhibin B and s-FSH that previously have been reported to be of predictive value for oligozoospermia (<20 millions per ml) in the general population or subfertile men, and for azoospermia in childhood cancer survivors.	('azoospermia', 'Disease', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('s-FSH', 'Var', (46, 51))	('azoospermia', 'Phenotype', 'HP:0000027', (208, 219))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('oligozoospermia', 'Disease', 'MESH:D009845', (117, 132))	('s-inhibin', 'Var', (30, 39))	('azoospermia', 'Disease', 'MESH:D053713', (208, 219))	('child', 'Species', '9606', (223, 228))	('men', 'Species', '9606', (195, 198))	('oligozoospermia', 'Disease', (117, 132))
70187	23169336	Post-treatment paternity seemed to vary less with s-inhibin B.	('s-inhibin', 'Var', (50, 59))	('men', 'Species', '9606', (10, 13))	('Post', 'Gene', (0, 4))	('Post', 'Gene', '159371', (0, 4))
70211	32459453	Thus, the insertion in the 12p chromosome leads to a relevant functional alteration, promoting the stem cell maintenance and proliferation by the key genes activations, as: POU5F1/OCT3/4, SOX2 e NANOG.	('NANOG', 'Gene', '79923', (195, 200))	('stem cell maintenance', 'CPA', (99, 120))	('POU5F1', 'Gene', '5460', (173, 179))	('POU5F1', 'Gene', (173, 179))	('OCT3/4', 'Gene', '5460', (180, 186))	('proliferation', 'CPA', (125, 138))	('NANOG', 'Gene', (195, 200))	('insertion', 'Var', (10, 19))	('activations', 'PosReg', (156, 167))	('SOX2', 'Gene', (188, 192))	('OCT3/4', 'Gene', (180, 186))	('SOX2', 'Gene', '6657', (188, 192))	('promoting', 'PosReg', (85, 94))
70212	32459453	Mutations in the SRY gene are connected to the gonadal tumor development, gonadal dysgenesis and infertility, which may occur in approximately 52.5% of the individuals presenting an alteration in this gene.	('gonadal tumor', 'Disease', 'MESH:D006058', (47, 60))	('gonadal tumor', 'Disease', (47, 60))	('infertility', 'Disease', 'MESH:D007247', (97, 108))	('SRY', 'Gene', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('connected', 'Reg', (30, 39))	('infertility', 'Phenotype', 'HP:0000789', (97, 108))	('Mutations', 'Var', (0, 9))	('infertility', 'Disease', (97, 108))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (74, 92))	('gonadal dysgenesis', 'Disease', (74, 92))	('men', 'Species', '9606', (68, 71))	('SRY', 'Gene', '6736', (17, 20))	('gonadal tumor', 'Phenotype', 'HP:0010785', (47, 60))
70213	32459453	Another studied gene is the tumor suppressor p53, which has an important role in spermatogenesis; it is know that p53 mutations leads to a genomic and chromosomal instability that can compromise sperm fecundity ability in the oocyte; further, it is related to TCGTs pathogenesis.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('tumor', 'Disease', (28, 33))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('chromosomal instability', 'Phenotype', 'HP:0040012', (151, 174))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (118, 127))	('leads to', 'Reg', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('compromise', 'NegReg', (184, 194))	('sperm fecundity ability in the oocyte', 'CPA', (195, 232))
70235	32459453	It is believed that testicular tumors promote a negative effect on the spermatogenesis due to disruptions in the blood-testicular barrier, followed by antibodies formation against the sperm and long lymphocytic infiltrates into the parenchyma adjacent to tumor germ cells; it is known that antisperm antibodies are associated with count decrease, low motility and morphological anomalies of the sperm.	('morphological anomalies of the sperm', 'Phenotype', 'HP:0012864', (364, 400))	('testicular tumors', 'Disease', (20, 37))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('antisperm', 'Var', (290, 299))	('tumor', 'Disease', (255, 260))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('testicular tumor', 'Phenotype', 'HP:0010788', (20, 36))	('count decrease', 'CPA', (331, 345))	('tumor', 'Disease', (31, 36))	('testicular tumors', 'Disease', 'MESH:D013736', (20, 37))	('spermatogenesis', 'CPA', (71, 86))	('testicular tumors', 'Phenotype', 'HP:0010788', (20, 37))	('low motility', 'CPA', (347, 359))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
70238	32459453	However, it was also reported that even before treatment, some patients already had poor semen quality, which leads us to believe that the presence of the tumor interferes with spermatogenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('interferes', 'NegReg', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('semen quality', 'CPA', (89, 102))	('men', 'Species', '9606', (52, 55))	('tumor', 'Disease', (155, 160))	('men', 'Species', '9606', (91, 94))	('presence', 'Var', (139, 147))	('spermatogenesis', 'CPA', (177, 192))	('patients', 'Species', '9606', (63, 71))
70266	32459453	There are evidences from the literature that after unilateral orchiectomy, sperm concentration becomes reduced (average sperm concentration: 16.6 x 106/mL), compared to the results from the pre-surgery time (average sperm concentration: 26.7 x 106/mL) (22, 29); at the same time, the resection of retroperitoneal lymph nodes promotes a dry ejaculation in virtually 100% of the patients.	('promotes', 'PosReg', (325, 333))	('sperm concentration', 'MPA', (75, 94))	('reduced', 'NegReg', (103, 110))	('patients', 'Species', '9606', (377, 385))	('resection', 'Var', (284, 293))	('unilateral orchiectomy', 'Phenotype', 'HP:0012741', (51, 73))	('dry ejaculation', 'MPA', (336, 351))
70301	27487789	Mutations in the gene for fibrillin-1 cause autosomal dominant disorder Marfan syndrome and other related diseases of connective tissue collectively named type-1 fibrillinopathies.	('autosomal dominant disorder Marfan syndrome', 'Disease', (44, 87))	('fibrillinopathies', 'Disease', (162, 179))	('cause', 'Reg', (38, 43))	('fibrillinopathies', 'Disease', 'None', (162, 179))	('Mutations', 'Var', (0, 9))	('fibrillin-1', 'Gene', '2200', (26, 37))	('fibrillin-1', 'Gene', (26, 37))	('autosomal dominant disorder Marfan syndrome', 'Disease', 'MESH:D008382', (44, 87))
70357	27487789	PARP1 positivity was the highest in GCNIS and among germ cell tumours its expression was higher in less differentiated subtypes of tumours, seminoma and embryonal carcinoma, with decreased positivity in more differentiated subtypes.	('GCNIS', 'Chemical', '-', (36, 41))	('tumours', 'Disease', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('germ cell tumours', 'Disease', (52, 69))	('germ cell tumours', 'Disease', 'MESH:D009373', (52, 69))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('expression', 'MPA', (74, 84))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (153, 172))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (153, 172))	('positivity', 'Var', (6, 16))	('embryonal carcinoma', 'Disease', (153, 172))	('highest', 'Reg', (25, 32))	('seminoma', 'Disease', (140, 148))	('PARP1', 'Gene', (0, 5))	('tumours', 'Disease', (62, 69))	('seminoma', 'Disease', 'MESH:D018239', (140, 148))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('higher', 'PosReg', (89, 95))	('germ cell tumour', 'Phenotype', 'HP:0100728', (52, 68))	('PARP1', 'Gene', '142', (0, 5))	('GCNIS', 'Disease', (36, 41))
70363	27487789	While mutations in the gene for fibrillin-1 cause Marfan syndrome, there is limited data of association between Marfan syndrome and risk of testicular germ cell tumors.	('cause', 'Reg', (44, 49))	('tumors', 'Disease', (161, 167))	('Marfan syndrome', 'Disease', (50, 65))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('germ cell tumors', 'Phenotype', 'HP:0100728', (151, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('Marfan syndrome', 'Disease', (112, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('fibrillin-1', 'Gene', '2200', (32, 43))	('fibrillin-1', 'Gene', (32, 43))	('mutations', 'Var', (6, 15))	('Marfan syndrome', 'Disease', 'MESH:D008382', (50, 65))	('Marfan syndrome', 'Disease', 'MESH:D008382', (112, 127))
70384	26461055	The two SNPs were each coded as a categorical variable, while the interaction term (SNP1 x SNP2) were included as continuous covariates; for each pairwise combination of SNPs, the joint risk was consistent with the product of the individual risks.	('SNP1', 'Gene', (84, 88))	('SNPs', 'Var', (170, 174))	('SNP1', 'Gene', '6625', (84, 88))
70451	26816750	Although the exact mechanism by which cancer affects semen quality is not known, it is likely that pre-existing defects due to flawed development of the testes could contribute to testicular cancer, while abnormal cytokine secretion in the presence of cancer could result in Hodgkin's lymphoma.	('contribute', 'Reg', (166, 176))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('abnormal', 'Var', (205, 213))	('defects', 'MPA', (112, 119))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (275, 293))	('cancer', 'Disease', (191, 197))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (275, 293))	('lymphoma', 'Phenotype', 'HP:0002665', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (38, 44))	('abnormal cytokine secretion', 'Phenotype', 'HP:0011113', (205, 232))	('testicular cancer', 'Disease', 'MESH:D013736', (180, 197))	('result in', 'Reg', (265, 274))	('men', 'Species', '9606', (141, 144))	('men', 'Species', '9606', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('abnormal cytokine', 'Phenotype', 'HP:0031406', (205, 222))	('cancer', 'Disease', (252, 258))	("Hodgkin's lymphoma", 'Disease', (275, 293))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('testicular cancer', 'Disease', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('testicular cancer', 'Phenotype', 'HP:0010788', (180, 197))
70459	26816750	In addition to disrupting spermatogenesis, cytotoxic chemotherapy may also contribute to erectile or ejaculatory dysfunction or directly damage sperm DNA, resulting in the transmission of defective DNA and abnormal chromosomes to offspring.	('erectile or ejaculatory dysfunction', 'Disease', 'MESH:D007172', (89, 124))	('defective', 'Var', (188, 197))	('abnormal', 'Var', (206, 214))	('contribute', 'Reg', (75, 85))	('erectile or ejaculatory dysfunction', 'Disease', (89, 124))	('sperm DNA', 'CPA', (144, 153))	('abnormal chromosomes', 'Phenotype', 'HP:0031411', (206, 226))	('disrupting', 'Reg', (15, 25))	('disrupting spermatogenesis', 'Phenotype', 'HP:0008669', (15, 41))	('spermatogenesis', 'CPA', (26, 41))	('damage', 'NegReg', (137, 143))
70461	26816750	Alkylating agents, such as cyclophosphamide, procarbazine and chlorambucil, are the most gonadotoxic drugs because they interfere with DNA synthesis and RNA transcription, thus causing new mutations that may lead to apoptosis.	('DNA synthesis', 'MPA', (135, 148))	('chlorambucil', 'Chemical', 'MESH:D002699', (62, 74))	('lead to', 'Reg', (208, 215))	('interfere', 'NegReg', (120, 129))	('apoptosis', 'CPA', (216, 225))	('RNA transcription', 'MPA', (153, 170))	('causing', 'Reg', (177, 184))	('procarbazine', 'Chemical', 'MESH:D011344', (45, 57))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (27, 43))	('mutations', 'Var', (189, 198))
70465	26816750	Unfortunately, the effect of newer drugs like the taxanes and multikinase inhibitors are still unknown, although there have been indications that when used as an adjuvant, taxanes may enable cyclophosphamide to become more toxic.	('cyclophosphamide', 'MPA', (191, 207))	('enable', 'PosReg', (184, 190))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (191, 207))	('taxanes', 'Var', (172, 179))	('taxanes', 'Chemical', 'MESH:D043823', (50, 57))	('more toxic', 'MPA', (218, 228))	('taxanes', 'Chemical', 'MESH:D043823', (172, 179))
70519	26816750	Men with ejaculatory dysfunction due to spinal cord injuries, anejaculation or retrograde ejaculation are also unable to produce a semen sample.	('anejaculation', 'Phenotype', 'HP:0012879', (62, 75))	('anejaculation', 'Var', (62, 75))	('retrograde ejaculation', 'Phenotype', 'HP:0012877', (79, 101))	('ejaculatory dysfunction', 'Disease', (9, 32))	('unable', 'NegReg', (111, 117))	('men', 'Species', '9606', (133, 136))	('spinal cord injuries', 'Disease', (40, 60))	('spinal cord injuries', 'Phenotype', 'HP:0100561', (40, 60))	('spinal cord injuries', 'Disease', 'MESH:D013119', (40, 60))	('Men', 'Species', '9606', (0, 3))
70618	26816821	Cancer related sexual dysfunction in this population of male cancer patients includes erectile dysfunction (ED), structural changes within the penis, ejaculatory dysfunction and hypogonadism among many others.	('dysfunction', 'Disease', (162, 173))	('dysfunction', 'Disease', 'MESH:D006331', (22, 33))	('sexual dysfunction', 'Disease', (15, 33))	('erectile dysfunction', 'Disease', 'MESH:D007172', (86, 106))	('hypogonadism', 'Disease', 'MESH:D007006', (178, 190))	('dysfunction', 'Disease', (95, 106))	('patients', 'Species', '9606', (68, 76))	('dysfunction', 'Disease', 'MESH:D006331', (162, 173))	('sexual dysfunction', 'Disease', 'MESH:D012735', (15, 33))	('hypogonadism', 'Disease', (178, 190))	('dysfunction', 'Disease', (22, 33))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('structural', 'Var', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ED', 'Phenotype', 'HP:0000802', (108, 110))	('male cancer', 'Disease', (56, 67))	('male cancer', 'Disease', 'MESH:D018567', (56, 67))	('dysfunction', 'Disease', 'MESH:D006331', (95, 106))	('hypogonadism', 'Phenotype', 'HP:0000135', (178, 190))	('erectile dysfunction', 'Phenotype', 'HP:0000802', (86, 106))	('erectile dysfunction', 'Disease', (86, 106))
70634	26816821	The resulting tool was able to stratify patients into three groups according to the relative preoperative risk of post-RP ED: low (age <=65 years, IIEF-EF >=26, CCI <=1), intermediate (age 66-69 years or IIEF-EF 11-25, CCI <=1), and high risk (age >=70 years or IIEF-EF <=10 or CCI >=2).	('age <=65 years', 'Var', (131, 145))	('RP', 'Gene', '399694', (119, 121))	('IIEF-EF 11-25', 'Var', (204, 217))	('patients', 'Species', '9606', (40, 48))	('ED', 'Phenotype', 'HP:0000802', (122, 124))	('age >=70 years', 'Var', (244, 258))
70670	26816821	Although the exact cause of orgasmic dysfunction after RP is unknown, it is clear that removal of the prostate and the seminal vesicles may in itself impact orgasmic pleasure as ejaculation is no longer possible.	('orgasmic dysfunction', 'Disease', 'MESH:D020018', (28, 48))	('orgasmic pleasure', 'Phenotype', 'HP:0030015', (157, 174))	('removal', 'Var', (87, 94))	('impact', 'Reg', (150, 156))	('orgasmic dysfunction', 'Disease', (28, 48))	('orgasmic pleasure', 'MPA', (157, 174))	('RP', 'Gene', '399694', (55, 57))
70677	26816821	They have found that Age >65 yrs, androgen deprivation therapy (ADT), prostate <40 g, each year post-RT and dose >100 Gy were independent risk factor for anejaculation.	('ADT', 'Chemical', '-', (64, 67))	('anejaculation', 'Disease', (154, 167))	('androgen', 'Disease', (34, 42))	('anejaculation', 'Phenotype', 'HP:0012879', (154, 167))	('<40 g', 'Var', (79, 84))
70752	26816821	Due to prolonged absence of erections, ADT may lead to corporal fibrosis and decreased penile length.	('fibrosis', 'Disease', 'MESH:D005355', (64, 72))	('penile length', 'CPA', (87, 100))	('lead to', 'Reg', (47, 54))	('ADT', 'Var', (39, 42))	('absence', 'NegReg', (17, 24))	('absence of erections', 'Phenotype', 'HP:0000802', (17, 37))	('ADT', 'Chemical', '-', (39, 42))	('erections', 'CPA', (28, 37))	('fibrosis', 'Disease', (64, 72))	('decreased', 'NegReg', (77, 86))
70809	26691229	The effects of MOTILIPERM on cisplatin induced testicular toxicity in Sprague-Dawley rats Cisplatin causes male infertility but the exact mechanism have not been clarified, yet.	('infertility', 'Disease', (112, 123))	('Sprague-Dawley rats', 'Species', '10116', (70, 89))	('rats', 'Species', '10116', (85, 89))	('Cisplatin', 'Var', (90, 99))	('testicular toxicity', 'Disease', 'MESH:D013733', (47, 66))	('rat', 'Species', '10116', (85, 88))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('toxicity', 'Disease', (58, 66))	('MOTILIPERM', 'Chemical', '-', (15, 25))	('causes', 'Reg', (100, 106))	('infertility', 'Disease', 'MESH:D007247', (112, 123))	('male infertility', 'Phenotype', 'HP:0003251', (107, 123))	('male infertility', 'Disease', 'MESH:D007248', (107, 123))	('testicular toxicity', 'Disease', (47, 66))	('infertility', 'Phenotype', 'HP:0000789', (112, 123))	('Cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('male infertility', 'Disease', (107, 123))
70812	26691229	The decreased weight of epididymis and prostate were increased significantly in CIS 10 mg/kg + MOTILIPERM 100 mg/kg/day compared with CIS 10 mg/kg.	('decreased', 'NegReg', (4, 13))	('decreased weight', 'Phenotype', 'HP:0004325', (4, 20))	('weight of epididymis', 'Disease', (14, 34))	('CIS 10 mg/kg +', 'Var', (80, 94))	('increased', 'PosReg', (53, 62))	('weight of epididymis', 'Disease', 'MESH:D015431', (14, 34))
70841	26691229	Epididymis weight in CIS group was significantly decreased compared with CTR group, and in CIS + M 100 compared with CTR + M 200 and CIS groups.	('Epididymis weight', 'Disease', 'MESH:D015431', (0, 17))	('Epididymis weight', 'Disease', (0, 17))	('decreased', 'NegReg', (49, 58))	('CIS', 'Var', (21, 24))	('CIS + M 100', 'Var', (91, 102))
70902	26099672	Ferda et al demonstrated that initial uptake of lesions correlated with prognosis, with patients whose renal tumors exhibit SUVmax >10 having significantly worse survival than those with SUV max <1010.	('renal tumors', 'Disease', (103, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (88, 96))	('renal tumors', 'Phenotype', 'HP:0009726', (103, 115))	('renal tumors', 'Disease', 'MESH:D007674', (103, 115))	('SUVmax >10', 'Var', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('worse', 'NegReg', (156, 161))
70947	26099672	FDG PET/CT detects more malignant disease than conventional CT/MRI in 20-40% of patients, and FDG PET/CT may change the clinical management in up to 68% of the patients.	('FDG', 'Chemical', 'MESH:D019788', (0, 3))	('change', 'Reg', (109, 115))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (80, 88))	('FDG', 'Chemical', 'MESH:D019788', (94, 97))	('malignant disease', 'Disease', 'MESH:D009369', (24, 41))	('FDG', 'Var', (94, 97))	('malignant disease', 'Disease', (24, 41))	('detects', 'Reg', (11, 18))
70972	26099672	Recurrence free survival, OS and disease free survival (DSS) were all significantly poorer in the patients with positive FDG PET/CT than in those with negative FDG-PET/CT.	('Recurrence free survival', 'CPA', (0, 24))	('FDG', 'Chemical', 'MESH:D019788', (121, 124))	('patients', 'Species', '9606', (98, 106))	('FDG', 'Chemical', 'MESH:D019788', (160, 163))	('OS', 'Chemical', '-', (26, 28))	('disease free survival', 'CPA', (33, 54))	('positive FDG PET/CT', 'Var', (112, 131))	('poorer', 'NegReg', (84, 90))
70994	26099672	In a small study, methionine was superior to FDG, however, tumor was identified with a sensitivity of 78% (18/23) only with methionine PET.	('FDG', 'Chemical', 'MESH:D019788', (45, 48))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('methionine', 'Var', (124, 134))	('methionine', 'Chemical', 'MESH:D008715', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('methionine', 'Chemical', 'MESH:D008715', (124, 134))
71117	29259474	This result implies that RPLND eventually causes infertility in the survivors of TC.	('RPLND', 'Var', (25, 30))	('infertility', 'Phenotype', 'HP:0000789', (49, 60))	('infertility', 'Disease', 'MESH:D007247', (49, 60))	('infertility', 'Disease', (49, 60))	('causes', 'Reg', (42, 48))	('TC', 'Phenotype', 'HP:0010788', (81, 83))
71133	29259474	Testicular sperm extraction (TESE) is an effective method of sperm retrieval from patients with non-obstructive azoospermia (NOA),18 and has been used also for survivors of cancer with postchemotherapy azoospermia (PCA).89 Two types of method, conventional TESE (cTESE) and microdissection TESE (micro-TESE), are both widely practiced.90 In the cTESE procedure, the testis is exposed through a small incision and testicular tissue is dissected without identifying focal areas of spermatogenesis.91 In the micro-TESE procedure, the tunica albuginea is widely opened and the testicular tissue is seen with an operating microscope before dissection.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('azoospermia', 'Disease', (202, 213))	('azoospermia', 'Phenotype', 'HP:0000027', (202, 213))	('TESE', 'Chemical', '-', (29, 33))	('cTESE', 'Chemical', '-', (263, 268))	('TESE', 'Chemical', '-', (346, 350))	('TESE', 'Chemical', '-', (290, 294))	('azoospermia', 'Disease', 'MESH:D053713', (202, 213))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))	('TESE', 'Chemical', '-', (257, 261))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('non-obstructive azoospermia', 'Disease', (96, 123))	('TESE', 'Chemical', '-', (511, 515))	('micro-TESE', 'Var', (505, 515))	('cancer', 'Disease', (173, 179))	('patients', 'Species', '9606', (82, 90))	('azoospermia', 'Disease', (112, 123))	('TESE', 'Chemical', '-', (264, 268))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('small incision', 'Phenotype', 'HP:0005486', (394, 408))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('azoospermia', 'Disease', 'MESH:D053713', (112, 123))	('NOA', 'Phenotype', 'HP:0011961', (125, 128))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('TESE', 'Chemical', '-', (302, 306))	('cTESE', 'Chemical', '-', (345, 350))
71134	29259474	The micro-TESE procedure enables the surgeon to visualize the tubules that are more likely to contain active spermatogenesis.92  Various studies have reported the improvement of the sperm retrieval rate (SRR) in patients with NOA with micro-TESE.	('TESE', 'Chemical', '-', (10, 14))	('improvement', 'PosReg', (163, 174))	('sperm retrieval rate', 'CPA', (182, 202))	('TESE', 'Chemical', '-', (241, 245))	('patients', 'Species', '9606', (212, 220))	('men', 'Species', '9606', (170, 173))	('micro-TESE', 'Var', (235, 245))	('NOA', 'Phenotype', 'HP:0011961', (226, 229))
71194	29201487	Furthermore, supernumerary testes have more than a 30% incidence of histological abnormalities and 4-7% of polyorchidism cases may be associated with malignancy.	('associated', 'Reg', (134, 144))	('malignancy', 'Disease', (150, 160))	('supernumerary', 'Var', (13, 26))	('polyorchidism', 'Disease', 'None', (107, 120))	('polyorchidism', 'Disease', (107, 120))	('supernumerary testes', 'Phenotype', 'HP:0010470', (13, 33))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))	('histological abnormalities', 'Phenotype', 'HP:0002664', (68, 94))	('polyorchidism', 'Phenotype', 'HP:0010470', (107, 120))
71202	28545024	The expression of PL2L60 proteins was enhanced when host gene Piwil2 was genetically disrupted in a murine cell model.	('murine', 'Species', '10090', (100, 106))	('Piwil2', 'Gene', (62, 68))	('genetically disrupted', 'Var', (73, 94))	('expression', 'Species', '29278', (4, 14))	('enhanced', 'PosReg', (38, 46))	('expression', 'MPA', (4, 14))	('PL2L60', 'Gene', (18, 24))	('proteins', 'Protein', (25, 33))
71209	28545024	While full length PIWIL2 can mediate DNA repair acting as a barrier gene to the initiation of tumorigenesis and promote apoptotic cell death in tumor tissues, its variants such as PL2L60 and PL2L60A can promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (144, 149))	('promote', 'PosReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PL2L60A', 'Var', (191, 198))	('PL2L60', 'Var', (180, 186))	('tumor', 'Disease', (94, 99))	('apoptotic cell death', 'CPA', (120, 140))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('promote', 'PosReg', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
71210	28545024	Since the variants such as PL2L60 has opposite functions to full length PIWIL2 in tumor development, e.g., tumor promoting vs. tumor suppression, we have referred to the intragenic promoter-mediated activation as aberrant or alienated activation of host gene.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('variants', 'Var', (10, 18))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PL2L60', 'Gene', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (82, 87))
71211	28545024	Among the variants mentioned above, PL2L60 is predominantly expressed in precancerous stem cells (pCSCs) as well as in various types of human and murine tumor cell lines with a level much higher than full length of PIWIL2.	('human', 'Species', '9606', (136, 141))	('PL2L60', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('murine', 'Species', '10090', (146, 152))	('variants', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
71212	28545024	PL2L60 can promote tumor cell survival and proliferation in vitro through up-regulation of STAT3 and BCL2 genes.	('BCL2', 'Gene', '596', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PL2L60', 'Var', (0, 6))	('up-regulation', 'PosReg', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('STAT3', 'Gene', '6774', (91, 96))	('promote', 'PosReg', (11, 18))	('BCL2', 'Gene', (101, 105))	('proliferation', 'CPA', (43, 56))	('STAT3', 'Gene', (91, 96))	('tumor', 'Disease', (19, 24))
71215	28545024	Interestingly, while Piwil2, PL2L80 and PL2L60 were detected in the testicular cells of mice, knockout of Piwil2 by homologous recombination did not abrogate the expressions of PL2L60 and PL2L80 in the testis, implicating that PL2L60 and PL2L80 might be transcribed by alternative promoters in the host gene Piwil2.	('knockout', 'Var', (94, 102))	('PL2L60', 'Gene', (177, 183))	('abrogate', 'NegReg', (149, 157))	('expression', 'Species', '29278', (162, 172))	('PL2L80', 'Gene', (188, 194))	('expressions', 'MPA', (162, 173))	('mice', 'Species', '10090', (88, 92))
71220	28545024	We have found that while PIWIL2 is mainly detected in apoptotic cells of primary cancers, PL2L60, a variant of PIWIL2, is widely expressed in various types of proliferating cancer cells, promoting tumor growth.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('primary cancers', 'Disease', (73, 88))	('PL2L60', 'Var', (90, 96))	('cancer', 'Disease', (81, 87))	('primary cancers', 'Disease', 'MESH:D009369', (73, 88))	('promoting', 'PosReg', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (197, 202))
71223	28545024	A series of PL2L60-luciferase (p60-Luc) promoter reporting vectors (V-2409/+155, V-3688/-2280, V-6228/-3633, V-8673/-6193, V-11225/-8643, and V-13707/-11190) were constructed, using pGL3-basic vectors inserted with tiling fragments (Figure 1A & 1B).	('pGL3', 'Gene', (182, 186))	('V-11225/-8643', 'Var', (123, 136))	('pGL3', 'Gene', '6391', (182, 186))	('V-3688/-2280', 'Var', (81, 93))	('V-13707/-11190', 'Var', (142, 156))	('V-6228/-3633', 'Var', (95, 107))	('V-8673/-6193', 'Var', (109, 121))	('V-2409/+155', 'Var', (68, 79))
71226	28545024	The luciferase activity of V-2409/+155, V-6228/-3633, V-8673/-6193, V-11225/-8643 and V-13707/-11190 was almost the same as or even lower than the pGL3-basic negative control vector (Figure 1C).	('V-11225/-8643', 'Var', (68, 81))	('V-13707/-11190', 'Var', (86, 100))	('pGL3', 'Gene', '6391', (147, 151))	('V-8673/-6193', 'Var', (54, 66))	('pGL3', 'Gene', (147, 151))	('activity', 'MPA', (15, 23))	('V-6228/-3633', 'Var', (40, 52))	('lower', 'NegReg', (132, 137))	('luciferase', 'Enzyme', (4, 14))	('V-2409/+155', 'Var', (27, 38))
71227	28545024	Since enhancer has bidirectional or reverse transcription activity, we constructed four vectors with the fragments-3688/-2680, which were amplified by PCR and inserted at the up-stream or down-stream of luciferase gene in pGL3-basic reporting vector in a direction of 5' to 3' and 3' to 5', respectively (Figure 2A; Supplementary Table 1).	('pGL3', 'Gene', (222, 226))	('fragments-3688/-2680', 'Var', (105, 125))	('pGL3', 'Gene', '6391', (222, 226))
71230	28545024	To further validate the results above, the fragment -3688/-2680 in forward or reverse direction was cloned into the upstream (EV-UF and EV-UR) or downstream (EV-DF and EV-DR) of luciferase gene in the pGL3-enhancer vectors, which were absent of promoter.	('EV-DR', 'Chemical', '-', (168, 173))	('pGL3', 'Gene', (201, 205))	('EV-DF', 'Chemical', '-', (158, 163))	('fragment -3688/-2680', 'Var', (43, 63))	('EV-UR', 'Chemical', '-', (136, 141))	('pGL3', 'Gene', '6391', (201, 205))	('EV-UF', 'Chemical', '-', (126, 131))	('luciferase', 'Gene', (178, 188))
71231	28545024	As shown in Figure 2C, among the vectors of EV-UF, EV-UR, EV-DF, EV-DR, only the vector EV-UF demonstrated luciferase activity higher than pGL3-enhancer vectors.	('EV-DR', 'Chemical', '-', (65, 70))	('EV-UR', 'Chemical', '-', (51, 56))	('activity', 'MPA', (118, 126))	('pGL3', 'Gene', (139, 143))	('EV-UF', 'Chemical', '-', (88, 93))	('EV-DF', 'Chemical', '-', (58, 63))	('pGL3', 'Gene', '6391', (139, 143))	('higher', 'PosReg', (127, 133))	('EV-UF', 'Chemical', '-', (44, 49))	('luciferase', 'Enzyme', (107, 117))	('EV-UF', 'Var', (88, 93))
71233	28545024	To further exclude the enhancer activity, the fragment -3688/-2680 was inserted into the up or down stream of pGL3-promoter and the vectors of PV-UF, PV-UR, PV-DF and PV-DR were constructed.	('pGL3', 'Gene', (110, 114))	('fragment -3688/-2680', 'Var', (46, 66))	('pGL3', 'Gene', '6391', (110, 114))
71235	28545024	Interestingly, PV-DF and PV-DR significantly inhibited the pGL3-promoter activity (Figure 2D), implicating that the fragment might also suppress canonical promoter of PIWIL2 gene.	('PV-DR', 'Var', (25, 30))	('PIWIL2 gene', 'Gene', (167, 178))	('pGL3', 'Gene', '6391', (59, 63))	('PV-DF', 'Var', (15, 20))	('canonical promoter', 'MPA', (145, 163))	('suppress', 'NegReg', (136, 144))	('inhibited', 'NegReg', (45, 54))	('pGL3', 'Gene', (59, 63))
71236	28545024	The fragment -3688/-2680 was further divided into of three fragments, which were amplified by PCR (Supplementary Table 1) and used to construct vectors: PGL3-5.2.1 (-2609/-2280), PGL3-5.2.2 (-3009/-2609) and PGL3-5.1 (-3688/-2959) (Figure 3A).	('PGL3', 'Gene', (153, 157))	('PGL3', 'Gene', '6391', (208, 212))	('-2609/-2280', 'Var', (165, 176))	('PGL3', 'Gene', (208, 212))	('PGL3', 'Gene', '6391', (179, 183))	('PGL3', 'Gene', (179, 183))	('-3688/-2959', 'Var', (218, 229))	('PGL3', 'Gene', '6391', (153, 157))	('-3009/-2609', 'Var', (191, 202))
71241	28545024	As shown in Figure 3F, the luciferase activity was significantly reduced when the putative binding sites specific for STAT3(-) and HLF were mutated, respectively.	('HLF', 'Gene', '3131', (131, 134))	('activity', 'MPA', (38, 46))	('reduced', 'NegReg', (65, 72))	('STAT3', 'Gene', '6774', (118, 123))	('HLF', 'Gene', (131, 134))	('STAT3', 'Gene', (118, 123))	('luciferase', 'Enzyme', (27, 37))	('binding', 'Interaction', (91, 98))	('mutated', 'Var', (140, 147))
71242	28545024	As shown in Figure 3E, the fragment -2380/-2330 was co-precipitated by antibodies to HLF and polymerase II (Pol II), although not by antibody to STAT3 (Figure 3H).	('fragment -2380/-2330', 'Var', (27, 47))	('HLF', 'Gene', '3131', (85, 88))	('STAT3', 'Gene', (145, 150))	('HLF', 'Gene', (85, 88))	('STAT3', 'Gene', '6774', (145, 150))
71244	28545024	Failure to co-precipitate the fragment -2380/-2330 by anti-STAT3 may be associated with STAT3 only binding to STAT3(-) site with low affinity in the complementary chain of the fragment -2380/2330 (Figure 3E, 3G & 3F).	('STAT3', 'Gene', '6774', (110, 115))	('STAT3', 'Gene', '6774', (88, 93))	('STAT3', 'Gene', (110, 115))	('STAT3', 'Gene', (88, 93))	('STAT3', 'Gene', '6774', (59, 64))	('STAT3', 'Gene', (59, 64))	('fragment -2380/-2330', 'Var', (30, 50))	('binding', 'Interaction', (99, 106))
71245	28545024	To determine whether the intragenic PL2L60-specific promoter was activated coordinately by STAT3 and HLF, we knocked down STAT3 or HLF mRNAs in HEK-293T cells using RNA interference techniques.	('HLF', 'Gene', '3131', (131, 134))	('knocked', 'Var', (109, 116))	('HLF', 'Gene', (131, 134))	('HLF', 'Gene', (101, 104))	('STAT3', 'Gene', '6774', (91, 96))	('STAT3', 'Gene', '6774', (122, 127))	('HEK-293T cells', 'CellLine', 'CVCL:0063', (144, 158))	('STAT3', 'Gene', (91, 96))	('STAT3', 'Gene', (122, 127))	('HLF', 'Gene', '3131', (101, 104))
71252	28545024	Interestingly, HLF and STAT3 might transactivate PL2L60-specific promoter interdependently, because co-transfection of shSTAT3 cell lines with HLF siRNAs and pGL3-basic vectors harboring the fragment -2380/-2330 had no additive effects on the luciferase activity and did not further reduce PL2L60 proteins expression (not shown).	('activity', 'MPA', (254, 262))	('STAT3', 'Gene', '6774', (121, 126))	('HLF', 'Gene', '3131', (15, 18))	('pGL3', 'Gene', '6391', (158, 162))	('STAT3', 'Gene', '6774', (23, 28))	('STAT3', 'Gene', (121, 126))	('expression', 'Species', '29278', (306, 316))	('fragment -2380/-2330', 'Var', (191, 211))	('STAT3', 'Gene', (23, 28))	('luciferase', 'Enzyme', (243, 253))	('expression', 'MPA', (306, 316))	('HLF', 'Gene', (15, 18))	('HLF', 'Gene', '3131', (143, 146))	('HLF', 'Gene', (143, 146))	('pGL3', 'Gene', (158, 162))
71261	28545024	Importantly, PL2L60 and probably PL2L80 or PL2L80A were remarkably up regulated in mili-/- MEFs, as compared to those in wt MEFs as well as in the testicular cells of human and wt mice (Figure 5B).	('PL2L60', 'Var', (13, 19))	('up regulated', 'PosReg', (67, 79))	('MEFs', 'CellLine', 'CVCL:9115', (91, 95))	('mili-/-', 'Var', (83, 90))	('PL2L80A', 'Var', (43, 50))	('mice', 'Species', '10090', (180, 184))	('MEFs', 'CellLine', 'CVCL:9115', (124, 128))	('PL2L80', 'Var', (33, 39))	('human', 'Species', '9606', (167, 172))
71262	28545024	As we had expected, the Piwil2 proteins (110 kDa) were detected in the testicular cells of human and mice as well as in the mili+/+ MEF, although very low in level, but not in the mili-/- MEF (Figure 5B).	('mili+/+', 'Var', (124, 131))	('110 kDa', 'Var', (41, 48))	('mice', 'Species', '10090', (101, 105))	('MEF', 'CellLine', 'CVCL:9115', (132, 135))	('human', 'Species', '9606', (91, 96))	('MEF', 'CellLine', 'CVCL:9115', (188, 191))
71264	28545024	As expected, knocking down of mRNAs using siE21 significantly inhibited the expression of PL2L60 proteins by about 45% and 50% in the tumor cells of cervix and breast, respectively.	('proteins', 'Protein', (97, 105))	('expression', 'Species', '29278', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('inhibited', 'NegReg', (62, 71))	('expression', 'MPA', (76, 86))	('mRNAs', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PL2L60', 'Gene', (90, 96))	('siE21', 'Gene', (42, 47))	('knocking', 'Var', (13, 21))	('tumor', 'Disease', (134, 139))
71265	28545024	In contrast, siE7, which was effective in knocking down full length PIWIL2 mRNAs and PL2L80 mRNAs (not shown), and siNC had no significant effects on PL2L60 protein expression (Figure 5C & 5D).	('expression', 'Species', '29278', (165, 175))	('knocking', 'Var', (42, 50))	('PL2L80', 'Gene', (85, 91))	('PIWIL2', 'Gene', (68, 74))	('PL2L60 protein expression', 'MPA', (150, 175))
71267	28545024	In addition to gametogenesis, PIWIL2 can promote tumorigenesis through upregulating several signal transduction pathways and inhibiting apoptotic death of tumor cells via activation of Stat3/Bcl-XL pathway.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('upregulating', 'PosReg', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('signal transduction pathways', 'Pathway', (92, 120))	('Bcl-XL', 'Gene', (191, 197))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (155, 160))	('promote', 'PosReg', (41, 48))	('activation', 'PosReg', (171, 181))	('Stat3', 'Gene', '6774', (185, 190))	('PIWIL2', 'Var', (30, 36))	('inhibiting', 'NegReg', (125, 135))	('Stat3', 'Gene', (185, 190))	('Bcl-XL', 'Gene', '598', (191, 197))
71270	28545024	In contrast, PIWIL2 variants PL2L proteins, such as PL2L60, were detected abundantly in various types of tumor tissues and tumor cell lines, suggesting that the tumorigenic functions of PIWIL2 might be mediated mainly by PIWIL2 variants.	('variants', 'Var', (228, 236))	('variants', 'Var', (20, 28))	('tumor', 'Disease', (123, 128))	('mediated', 'Reg', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('PIWIL2', 'Gene', (221, 227))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
71271	28545024	However, the mechanisms by which PL2L60 promotes tumorigenesis remain to be elucidated.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('PL2L60', 'Var', (33, 39))	('promotes', 'PosReg', (40, 48))
71275	28545024	To refine the PL2L60-specific intragenic promoter, a series of pGL3-basic report vectors were constructed with fragments from a 13,862 bp fragment (-13707/+155) surrounding the pTSS of the putative PL2L60-specific promoter.	('-13707/+155', 'Var', (148, 159))	('pGL3', 'Gene', '6391', (63, 67))	('pGL3', 'Gene', (63, 67))
71276	28545024	To further verify the promoter activity and exclude the intragenic enhancer activity of the fragment, pGL3-basic, pGL3-enhancer and pGL3-promoter vectors were used to test the promoter activity and enhancer activity of the fragment -3688/-2880, respectively.	('pGL3', 'Gene', (132, 136))	('promoter', 'MPA', (176, 184))	('pGL3', 'Gene', (114, 118))	('pGL3', 'Gene', '6391', (132, 136))	('enhancer', 'PosReg', (198, 206))	('fragment -3688/-2880', 'Var', (223, 243))	('pGL3', 'Gene', (102, 106))	('pGL3', 'Gene', '6391', (114, 118))	('pGL3', 'Gene', '6391', (102, 106))
71279	28545024	The promoter activity for PL2L60 was further verified by the specific recruitments of HLF and Pol II to the region, although STAT3 binding to its cis-element was not confirmed by ChIP assay.	('STAT3', 'Gene', (125, 130))	('recruitments', 'MPA', (70, 82))	('HLF', 'Gene', '3131', (86, 89))	('PL2L60', 'Var', (26, 32))	('Pol', 'Protein', (94, 97))	('STAT3', 'Gene', '6774', (125, 130))	('HLF', 'Gene', (86, 89))	('promoter', 'MPA', (4, 12))
71281	28545024	However, knockdown of STAT3 significantly reduced both luciferase activity of the promoter and PL2L60 protein expression (Figure 4B, 4D, 4F & 4H), similarly to knocking down of HLF (Figure 4A, 4C, 4E & 4G).	('reduced', 'NegReg', (42, 49))	('knockdown', 'Var', (9, 18))	('HLF', 'Gene', (177, 180))	('activity', 'MPA', (66, 74))	('PL2L60', 'Gene', (95, 101))	('STAT3', 'Gene', '6774', (22, 27))	('expression', 'Species', '29278', (110, 120))	('STAT3', 'Gene', (22, 27))	('luciferase', 'Enzyme', (55, 65))	('HLF', 'Gene', '3131', (177, 180))
71301	28545024	Moreover, the levels both PL2L80 and PL2L60 proteins in mili-/- MEFs were much higher than in mili+/+ MEFs (Figure 5B), suggesting that activation of the intragenic promoter is independent of the integrity of host gene, and even the activation be enhanced when the host gene is disrupted (Figure 5B).	('enhanced', 'PosReg', (247, 255))	('MEFs', 'CellLine', 'CVCL:9115', (64, 68))	('PL2L60 proteins', 'Var', (37, 52))	('MEFs', 'CellLine', 'CVCL:9115', (102, 106))	('mili-/-', 'Var', (56, 63))	('higher', 'PosReg', (79, 85))	('PL2L80', 'Var', (26, 32))
71302	28545024	This is of significance especially in the status of cancer gene mutations, which may result in aberrant activation of the host genes, leading to tumorigenesis.	('activation', 'PosReg', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('leading to', 'Reg', (134, 144))	('tumor', 'Disease', (145, 150))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
71303	28545024	This might be related to carcinogenic transformation of mili-/- MEFs, because we have observed that the mili-/- MEFs acquired tumorigenic capacity after long-term in vitro culture (unpublished data).	('MEFs', 'CellLine', 'CVCL:9115', (64, 68))	('MEFs', 'CellLine', 'CVCL:9115', (112, 116))	('mili-/- MEFs', 'Var', (104, 116))	('carcinogenic', 'Disease', 'MESH:D063646', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('carcinogenic', 'Disease', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
71344	28545024	Briefly, 5 x 106 cells were fixed with 1% formaldehyde in PBS for 10 min to cross-link DNA with associated proteins and the cells were then washed and harvested in PBS.	('proteins', 'Protein', (107, 115))	('PBS', 'Chemical', 'MESH:D007854', (58, 61))	('PBS', 'Chemical', 'MESH:D007854', (164, 167))	('formaldehyde', 'Chemical', 'MESH:D005557', (42, 54))	('DNA', 'Gene', (87, 90))	('cross-link', 'Var', (76, 86))
71353	26503584	We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 x 10-9), 11q14.1 (rs7107174, GAB2, P=9.7 x 10-11), 16p13.13 (rs4561483, GSPT1, P=1.6 x 10-8) and 16q24.2 (rs55637647, ZFPM1, P=3.4 x 10-9).	('rs4561483', 'Var', (132, 141))	('GSPT1', 'Gene', '2935', (143, 148))	('GAB2', 'Gene', (100, 104))	('rs7107174', 'Mutation', 'rs7107174', (89, 98))	('ZFPM1', 'Gene', '161882', (189, 194))	('ZFPM1', 'Gene', (189, 194))	('TFDP2', 'Gene', '7029', (58, 63))	('TGCT', 'Phenotype', 'HP:0010788', (32, 36))	('rs11705932', 'Mutation', 'rs11705932', (46, 56))	('rs55637647', 'Mutation', 'rs55637647', (177, 187))	('GSPT1', 'Gene', (143, 148))	('rs11705932', 'Var', (46, 56))	('rs4561483', 'Mutation', 'rs4561483', (132, 141))	('TFDP2', 'Gene', (58, 63))	('GAB2', 'Gene', '9846', (100, 104))	('rs7107174', 'Var', (89, 98))	('TGCT', 'Disease', (32, 36))	('rs55637647', 'Var', (177, 187))
71354	26503584	We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples.	('patient', 'Species', '9606', (192, 199))	('TGCT', 'Phenotype', 'HP:0010788', (187, 191))	('rs4561483', 'Var', (129, 138))	('GSPT1', 'Gene', (167, 172))	('TGCT', 'Disease', (187, 191))	('increased', 'PosReg', (157, 166))	('expression', 'MPA', (173, 183))	('rs4561483', 'Mutation', 'rs4561483', (129, 138))	('GSPT1', 'Gene', '2935', (167, 172))
71356	26503584	This genome-wide association study identifies four novel risk loci for testicular germ cell tumour, and provides functional correlation between a disease-associated variant and gene expression in patient samples for one of the identified loci.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('germ cell tumour', 'Phenotype', 'HP:0100728', (82, 98))	('patient', 'Species', '9606', (196, 203))	('variant', 'Var', (165, 172))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('testicular germ cell tumour', 'Phenotype', 'HP:0010788', (71, 98))
71361	26503584	First, rs11705932 (OR=1.18, confidence interval (CI)=1.09-1.28, P=1.5 x 10-9) which lies within a 240 kb region of linkage disequilibrium (LD) at 3q23, containing genes TFDP2 and ATP1B3.	('ATP1B3', 'Gene', (179, 185))	('rs11705932', 'Var', (7, 17))	('TFDP2', 'Gene', '7029', (169, 174))	('TFDP2', 'Gene', (169, 174))	('ATP1B3', 'Gene', '483', (179, 185))	('rs11705932', 'Mutation', 'rs11705932', (7, 17))
71362	26503584	Second, rs7107174 (OR=1.26, CI=1.16-1.37, P=9.7 x 10-11) which maps to intron 1 of GAB2 (11q14.1), in a 227 kb region of LD to which USP35 also localizes.	('GAB2', 'Gene', (83, 87))	('USP35', 'Gene', (133, 138))	('rs7107174', 'Var', (8, 17))	('GAB2', 'Gene', '9846', (83, 87))	('USP35', 'Gene', '57558', (133, 138))	('rs7107174', 'Mutation', 'rs7107174', (8, 17))
71363	26503584	Third, rs4561483 (OR=1.09, 95% CI=1.02-1.16, P=1.6 x 10-8) intronic to BCAR4 (16p13.13) within a 145 kb LD block also containing RSL1D1, GSPT1 and TNFRSF17.	('RSL1D1', 'Gene', (129, 135))	('GSPT1', 'Gene', '2935', (137, 142))	('TNFRSF17', 'Gene', '608', (147, 155))	('TNFRSF17', 'Gene', (147, 155))	('BCAR4', 'Gene', (71, 76))	('BCAR4', 'Gene', '400500', (71, 76))	('rs4561483', 'Mutation', 'rs4561483', (7, 16))	('RSL1D1', 'Gene', '26156', (129, 135))	('GSPT1', 'Gene', (137, 142))	('rs4561483', 'Var', (7, 16))
71364	26503584	Finally, rs55637647 (OR=1.17, CI=1.09-1.24, P=3.4 x 10-9) mapping within intron 1 of ZFPM1 (16q24.2), within a 40 kb LD block.	('ZFPM1', 'Gene', (85, 90))	('ZFPM1', 'Gene', '161882', (85, 90))	('rs55637647', 'Var', (9, 19))	('rs55637647', 'Mutation', 'rs55637647', (9, 19))
71365	26503584	We examined for evidence of genotype-specific effect for rs11705932, rs7107174, rs4561483 and rs55637647, however, no significant departure from a log-additive model was seen.	('rs7107174', 'Var', (69, 78))	('rs7107174', 'Mutation', 'rs7107174', (69, 78))	('rs55637647', 'Mutation', 'rs55637647', (94, 104))	('rs11705932', 'Mutation', 'rs11705932', (57, 67))	('rs4561483', 'Mutation', 'rs4561483', (80, 89))	('rs11705932', 'Var', (57, 67))	('rs55637647', 'Var', (94, 104))	('rs4561483', 'Var', (80, 89))
71366	26503584	We additionally tested for interaction between rs11705932, rs7107174, rs4561483 and rs55637647 and SNPs at previously identified risk loci for TGCT (Supplementary Table 2).	('TGCT', 'Disease', (143, 147))	('men', 'Species', '9606', (155, 158))	('rs55637647', 'Var', (84, 94))	('rs7107174', 'Mutation', 'rs7107174', (59, 68))	('tested', 'Reg', (16, 22))	('interaction', 'Interaction', (27, 38))	('rs55637647', 'Mutation', 'rs55637647', (84, 94))	('TGCT', 'Phenotype', 'HP:0010788', (143, 147))	('rs11705932', 'Mutation', 'rs11705932', (47, 57))	('rs4561483', 'Mutation', 'rs4561483', (70, 79))	('rs11705932', 'Var', (47, 57))	('rs4561483', 'Var', (70, 79))	('rs7107174', 'Var', (59, 68))
71367	26503584	Some evidence of interaction between rs11705932 and previously reported SNP rs12699477 (at 7p22.3) was shown (P=0.003), albeit nonsignificant after correcting for 84 tests.	('rs12699477', 'Var', (76, 86))	('interaction', 'Interaction', (17, 28))	('rs12699477', 'Mutation', 'rs12699477', (76, 86))	('rs11705932', 'Mutation', 'rs11705932', (37, 47))	('rs11705932', 'Var', (37, 47))
71368	26503584	To gain insight into the biological basis of associations at rs11705932, rs7107174, rs4561483 and rs55637647, we conducted expression quantitative trait loci (eQTL) analysis using RNA-seq expression and Affymetrix 6.0 SNP/exome sequencing data on 150 TGCT patients, which is publicly available through the cancer genome atlas (http://cancergenome.nih.gov/).	('rs7107174', 'Var', (73, 82))	('rs55637647', 'Var', (98, 108))	('cancer', 'Disease', (334, 340))	('rs4561483', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('rs7107174', 'Mutation', 'rs7107174', (73, 82))	('patients', 'Species', '9606', (256, 264))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('rs11705932', 'Mutation', 'rs11705932', (61, 71))	('rs55637647', 'Mutation', 'rs55637647', (98, 108))	('TGCT', 'Phenotype', 'HP:0010788', (251, 255))	('rs11705932', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('rs4561483', 'Mutation', 'rs4561483', (84, 93))	('cancer', 'Disease', (306, 312))
71369	26503584	Where the data for our sentinel SNP was not available, we analysed data for the best two proxy SNPs (defined as those with the highest r2 correlation) for which data were available, namely: 3q23 (sentinel SNP rs11705932), 11q14.1 (rs2450140, r2=0.88 and rs11237477, r2=0.86), 16p13.13 (rs2075158, r2=0.78 and rs2018199, r2=0.79) and 16q24.2 (rs3859027, r2=0.91 and rs12597021, r2=0.87).	('rs2075158', 'Mutation', 'rs2075158', (286, 295))	('rs12597021', 'Var', (365, 375))	('rs12597021', 'Mutation', 'rs12597021', (365, 375))	('rs2075158', 'Var', (286, 295))	('rs2450140', 'Var', (231, 240))	('rs2450140', 'Mutation', 'rs2450140', (231, 240))	('rs3859027', 'Mutation', 'rs3859027', (342, 351))	('rs2018199', 'Mutation', 'rs2018199', (309, 318))	('rs11237477', 'Var', (254, 264))	('rs3859027', 'Var', (342, 351))	('rs11237477', 'Mutation', 'rs11237477', (254, 264))	('rs2018199', 'Var', (309, 318))	('rs11705932', 'Mutation', 'rs11705932', (209, 219))
71371	26503584	However, a statistically significant association was found at 16p13.13, between genotype and expression of GSPT1 (proxy SNPs rs2075158 P=5.1 x 10-4, rs2018199 P=5.9 x 10-4), which remained significant after correction for multiple testing (Supplementary Table 1).	('rs2018199', 'Var', (149, 158))	('GSPT1', 'Gene', '2935', (107, 112))	('rs2075158', 'Var', (125, 134))	('men', 'Species', '9606', (246, 249))	('significant association', 'Reg', (25, 48))	('expression', 'MPA', (93, 103))	('GSPT1', 'Gene', (107, 112))	('rs2075158', 'Mutation', 'rs2075158', (125, 134))	('rs2018199', 'Mutation', 'rs2018199', (149, 158))
71372	26503584	Both SNPs rs2075158 and rs2018199 can be considered good proxy markers, having high r2 correlation with and closely comparable minor allelic frequencies to, the sentinel SNP.	('rs2075158', 'Var', (10, 19))	('rs2018199', 'Mutation', 'rs2018199', (24, 33))	('rs2075158', 'Mutation', 'rs2075158', (10, 19))	('r2 correlation', 'MPA', (84, 98))	('rs2018199', 'Var', (24, 33))
71373	26503584	Homozygosity for the risk allele at rs2075158 was associated a with 35% increase in GSPT1 expression compared with the reference homozygote genotype (Supplementary Fig.	('increase', 'PosReg', (72, 80))	('rs2075158', 'Mutation', 'rs2075158', (36, 45))	('men', 'Species', '9606', (156, 159))	('expression', 'MPA', (90, 100))	('GSPT1', 'Gene', '2935', (84, 89))	('rs2075158', 'Var', (36, 45))	('GSPT1', 'Gene', (84, 89))
71374	26503584	We used HaploReg and Roadmap Epigenome Mapping Consortium data on enhancer elements to examine whether rs11705932, rs7107174, rs4561483 and rs55637647 or their proxies (that is, r2>0.8 in 1000 Genomes CEU reference panel) lie at putative transcription factor binding/enhancer elements.	('rs11705932', 'Mutation', 'rs11705932', (103, 113))	('rs11705932', 'Var', (103, 113))	('men', 'Species', '9606', (279, 282))	('rs7107174', 'Var', (115, 124))	('rs55637647', 'Var', (140, 150))	('rs4561483', 'Mutation', 'rs4561483', (126, 135))	('rs4561483', 'Var', (126, 135))	('rs7107174', 'Mutation', 'rs7107174', (115, 124))	('men', 'Species', '9606', (78, 81))	('rs55637647', 'Mutation', 'rs55637647', (140, 150))
71376	26503584	At 11q14.1, which contains GAB2, there is evidence of strong evolutionary conservation, with 21 correlated SNPs having GERP score >2.0, the strongest of which is SNP rs2511156, which is in almost perfect LD with the sentinel SNP.	('GAB2', 'Gene', (27, 31))	('rs2511156', 'Var', (166, 175))	('SNP', 'Var', (162, 165))	('rs2511156', 'Mutation', 'rs2511156', (166, 175))	('GAB2', 'Gene', '9846', (27, 31))
71377	26503584	In addition, multiple correlated SNPs at 11q14.1 are predicted to be in strong enhancer regions, with four SNPs located within DNase hypersensitivity sites in the TGCT specific cell line NT2-D1.	('SNPs', 'Var', (33, 37))	('enhancer', 'PosReg', (79, 87))	('TGCT', 'Phenotype', 'HP:0010788', (163, 167))	('hypersensitivity', 'Disease', 'MESH:D004342', (133, 149))	('hypersensitivity', 'Disease', (133, 149))
71379	26503584	At 16q24.2, the sentinel SNP rs55637647 is conserved and EGR1 binding, an early growth response transcription factor linked to infertility and differential expression in germ cell tumours, was also reported within the LD block.	('EGR1', 'Gene', '1958', (57, 61))	('infertility', 'Disease', (127, 138))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumours', 'Disease', (180, 187))	('binding', 'Interaction', (62, 69))	('germ cell tumour', 'Phenotype', 'HP:0100728', (170, 186))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('rs55637647', 'Mutation', 'rs55637647', (29, 39))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('EGR1', 'Gene', (57, 61))	('infertility', 'Disease', 'MESH:D007247', (127, 138))	('rs55637647', 'Var', (29, 39))	('infertility', 'Phenotype', 'HP:0000789', (127, 138))
71384	26503584	The only recurring event, seen in >5% of tumours was a copy number deletion encompassing GAB2 and USP35 at 11q14.1 found in 7% of tumours.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('USP35', 'Gene', (98, 103))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumours', 'Disease', (130, 137))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('GAB2', 'Gene', '9846', (89, 93))	('copy number deletion', 'Var', (55, 75))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('USP35', 'Gene', '57558', (98, 103))	('tumours', 'Disease', (41, 48))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('GAB2', 'Gene', (89, 93))
71393	26503584	The OR effect sizes of TGCT SNPs have been among the highest reported in GWAS of any cancer type, hence suggesting a potential clinical utility for personalized risk profiling.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TGCT', 'Phenotype', 'HP:0010788', (23, 27))	('cancer', 'Disease', (85, 91))	('TGCT', 'Gene', (23, 27))	('SNPs', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
71400	26503584	Furthermore, inherited variants in GSPT1 have been reported to confer elevated risk of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('GSPT1', 'Gene', '2935', (35, 40))	('variants', 'Var', (23, 31))	('gastric cancer', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('GSPT1', 'Gene', (35, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))
71404	26503584	Our eQTL analysis did not demonstrate a link between rs7107174 and GAB2 expression, although this failure may be due to the imperfect correlation between the true functional SNP and proxy markers available.	('GAB2', 'Gene', '9846', (67, 71))	('rs7107174', 'Var', (53, 62))	('rs7107174', 'Mutation', 'rs7107174', (53, 62))	('GAB2', 'Gene', (67, 71))
71405	26503584	Alternatively, other functional mechanisms may underpin the association; of particular note, a missense variant (rs2510044) responsible for the P236M polymorphism in USP35 (ubiquitin-specific peptidase 35) is in perfect LD with our sentinel SNP.	('P236M', 'Mutation', 'p.P236M', (144, 149))	('rs2510044', 'Mutation', 'rs2510044', (113, 122))	('USP35', 'Gene', '57558', (166, 171))	('rs2510044', 'Var', (113, 122))	('ubiquitin-specific peptidase 35', 'Gene', '57558', (173, 204))	('ubiquitin-specific peptidase 35', 'Gene', (173, 204))	('USP35', 'Gene', (166, 171))	('P236M', 'Var', (144, 149))
71407	26503584	In our somatic data sets, a recurring deletion encompassing both GAB2 and USP35 was found in 7% of tumours; however, due to the large scale of these deletions there is no evidence to suggest they specifically relate to the 11q14.1 locus.	('USP35', 'Gene', (74, 79))	('GAB2', 'Gene', (65, 69))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('relate', 'Reg', (209, 215))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('USP35', 'Gene', '57558', (74, 79))	('tumours', 'Disease', (99, 106))	('deletion', 'Var', (38, 46))	('GAB2', 'Gene', '9846', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
71415	26503584	In this study, we therefore implicate FOG/GATA1 genes in TGCT susceptibility for the first time, highlighting a network of interlinked oncogenic pathways.	('FOG', 'Gene', (38, 41))	('TGCT', 'Disease', (57, 61))	('TGCT', 'Phenotype', 'HP:0010788', (57, 61))	('implicate', 'Reg', (28, 37))	('GATA1', 'Gene', '2623', (42, 47))	('FOG', 'Gene', '161882', (38, 41))	('genes', 'Var', (48, 53))	('GATA1', 'Gene', (42, 47))
71420	26503584	We constructed a PRS model to assess the clinical utility of TGCT risk SNPs, which demonstrated marked power in terms of risk discrimination, with men in the top 1% of genetic risk exhibiting a >10-fold increased risk of the disease.	('genetic', 'Var', (168, 175))	('TGCT', 'Phenotype', 'HP:0010788', (61, 65))	('PRS', 'Chemical', '-', (17, 20))	('TGCT', 'Gene', (61, 65))	('men', 'Species', '9606', (147, 150))
71437	26503584	Stage 2 QC was applied to the SNPs as follows: (i) discrepant calls in more than 2% of duplicate samples across COGS consortia, (ii) call rate <95%, MAF<1%, call rate <99% if MAF=1-5%, (iii) deviation from Hardy-Weinberg (P<10-5 in controls, P<10-12 in cases).	('MAF=1', 'Gene', (175, 180))	('MAF<1%', 'Gene', '84232', (149, 155))	('deviation', 'Var', (191, 200))	('MAF<1%', 'Gene', (149, 155))	('Hardy-Weinberg', 'Disease', (206, 220))	('MAF=1', 'Gene', '84232', (175, 180))
71444	26503584	We used data from the ENCODE project and HaploReg to investigate for evidence of transcriptional regulation at our identified locus to assess (i) whether the variant resides in a region in which modification of histone proteins is suggestive of enhancer and other regulatory activity (H3K4Me1 and H3K27A histone modification) or promoter activity (H3K4Me3 histone modification), (ii) whether the variant lies in a region where the chromatin is hypersensitive to cutting by the DNase enzyme (suggestive of regulatory region), (iii) whether the variant lies in a region of binding of transcription factor proteins (as assayed by chromatin immunoprecipitation with antibodies specific to the transcription factor followed by sequencing of the precipitated DNA (ChIP-seq)), (iv) whether the variant affects a specific regulatory motif, as evaluated from position weighted matrices assembled from TRANSFAC, JASPAR and protein-binding microarray experiments.	('variant', 'Var', (787, 794))	('affects', 'Reg', (795, 802))	('hypersensitive', 'Disease', 'MESH:D004342', (444, 458))	('hypersensitive', 'Disease', (444, 458))	('men', 'Species', '9606', (946, 949))
71445	26503584	We investigated for evidence of association between the SNPs at our locus and changes in gene expression using publicly available cancer genome atlas RNAseq and Affymetrix 6.0 SNP/exome sequencing data (http://cancergenome.nih.gov/).	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (130, 136))	('gene expression', 'MPA', (89, 104))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (210, 216))	('SNPs', 'Var', (56, 60))
71518	26560314	If the cases and controls are equally likely to either under- or over-report cannabis exposure, then the impact on the observed association between cannabis use and TGCT development would likely be to attenuate it.	('TGCT', 'Disease', (165, 169))	('men', 'Species', '9606', (177, 180))	('under-', 'Var', (55, 61))	('attenuate', 'NegReg', (201, 210))	('over-report', 'Var', (65, 76))
71556	28327516	In the past decade, many studies have demonstrated that unsaturated fatty acids of marine origin, such as omega (n)-3 and n-9 fatty acids, could play a beneficial role in brain functions.	('n-9', 'Var', (122, 125))	('beneficial', 'PosReg', (152, 162))	('brain functions', 'CPA', (171, 186))	('omega (n)-3 and n-9 fatty acids', 'Chemical', '-', (106, 137))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (56, 79))
71559	28327516	There are also data showing neuroprotective potential of monounsaturated fatty acids (MUFAs).	('monounsaturated fatty acids', 'Chemical', 'MESH:D005229', (57, 84))	('monounsaturated', 'Var', (57, 72))	('FAs', 'Chemical', 'MESH:D005227', (88, 91))	('neuroprotective potential', 'CPA', (28, 53))
71575	28327516	To be noted, the signals around 2.8 ppm indicated the presence of methylenes between two double bonds -CH=CH-CH2-CH=CH-, a typical feature of polyunsaturated fatty acids.	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (142, 169))	('methylenes', 'Var', (66, 76))	('CH=CH-CH2-CH', 'Disease', (103, 115))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('C', 'Chemical', 'MESH:D002244', (106, 107))	('CH=CH-CH2-CH', 'Disease', 'None', (103, 115))
71578	28327516	In the 13C-NMR spectrum (Figure 2B), the chemical shifts at 180.3 ppm indicated the carbons of C=O groups.	('C', 'Chemical', 'MESH:D002244', (9, 10))	('chemical shifts', 'MPA', (41, 56))	('C=O groups', 'Var', (95, 105))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('carbons', 'Chemical', 'MESH:D002244', (84, 91))	('13C', 'Chemical', '-', (7, 10))
71621	28327516	Abeta25-35, an active fragment corresponding to amino acids 25-35 in full-length Abeta, possesses the same beta-sheet structure and retains full toxicity of full-length Abeta1-42.	('Abeta', 'Gene', (81, 86))	('beta-sheet structure', 'MPA', (107, 127))	('Abeta', 'Gene', (0, 5))	('amino acids 25-35', 'Var', (48, 65))	('Abeta', 'Gene', '351', (169, 174))	('Abeta', 'Gene', '351', (81, 86))	('toxicity', 'Disease', 'MESH:D064420', (145, 153))	('toxicity', 'Disease', (145, 153))	('Abeta', 'Gene', (169, 174))	('Abeta', 'Gene', '351', (0, 5))
71653	28327516	Recent data from large epidemiological studies suggest a relationship between MSD adherence and significant reduction in incidence of Parkinson's disease and AD and mild cognitive decline or risk of dementia.	('MSD', 'Disease', 'MESH:D052517', (78, 81))	('reduction', 'NegReg', (108, 117))	('cognitive decline', 'Disease', (170, 187))	("Parkinson's disease", 'Disease', (134, 153))	('cognitive decline', 'Disease', 'MESH:D003072', (170, 187))	('AD', 'Disease', 'MESH:D000544', (158, 160))	('dementia', 'Disease', (199, 207))	('dementia', 'Phenotype', 'HP:0000726', (199, 207))	("Parkinson's disease", 'Disease', 'MESH:D010300', (134, 153))	('cognitive decline', 'Phenotype', 'HP:0001268', (170, 187))	('AD', 'Disease', (158, 160))	('adherence', 'Var', (82, 91))	('dementia', 'Disease', 'MESH:D003704', (199, 207))	('MSD', 'Disease', (78, 81))
71661	28327516	Studies in cultured hepatocytes and mouse models of diet-induced obesity suggest that palmitoleic acid has anti-inflammatory and insulin-sensitizing effects.	('diet-induced obesity', 'Phenotype', 'HP:0012743', (52, 72))	('obesity', 'Phenotype', 'HP:0001513', (65, 72))	('insulin', 'Gene', (129, 136))	('palmitoleic acid', 'Var', (86, 102))	('insulin', 'Gene', '3630', (129, 136))	('obesity', 'Disease', 'MESH:D009765', (65, 72))	('anti-inflammatory', 'MPA', (107, 124))	('obesity', 'Disease', (65, 72))	('palmitoleic acid', 'Chemical', 'MESH:C008757', (86, 102))	('mouse', 'Species', '10090', (36, 41))
71662	28327516	Moreover, both in vitro and in vivo studies have demonstrated that palmitoleic acid can decrease the level of pro-inflammatory mediators and reduce the level of C-reactive protein in mice.	('level of pro-inflammatory mediators', 'MPA', (101, 136))	('decrease', 'NegReg', (88, 96))	('palmitoleic acid', 'Chemical', 'MESH:C008757', (67, 83))	('reduce the level of C-reactive protein', 'Phenotype', 'HP:0032437', (141, 179))	('mice', 'Species', '10090', (183, 187))	('palmitoleic acid', 'Var', (67, 83))	('C', 'Chemical', 'MESH:D002244', (161, 162))	('reduce', 'NegReg', (141, 147))	('level of C-reactive protein', 'MPA', (152, 179))
71666	28327516	Our previous studies have confirmed that n-3 fatty acids possess broad spectrum of neuroprotective activities in both in vitro and in vivo experiments because of their anti-oxidant and anti-inflammatory properties.	('anti-inflammatory', 'CPA', (185, 202))	('anti-oxidant', 'MPA', (168, 180))	('n-3 fatty acids', 'Chemical', 'MESH:D015525', (41, 56))	('neuroprotective activities', 'CPA', (83, 109))	('n-3', 'Var', (41, 44))
71669	28327516	Moreover, there is evidence that dietary supplementation with DHA reduced the intraneuronal accumulation of not only amyloid-beta, but also tau, another important pathology marker for AD, in the 3xTg-AD mouse model via decreasing steady-state levels of presenilin 1.	('AD', 'Disease', 'MESH:D000544', (200, 202))	('reduced', 'NegReg', (66, 73))	('AD', 'Disease', (200, 202))	('mouse', 'Species', '10090', (203, 208))	('DHA', 'Var', (62, 65))	('presenilin 1', 'Gene', '19164', (253, 265))	('DHA', 'Chemical', 'MESH:D004281', (62, 65))	('tau', 'MPA', (140, 143))	('decreasing', 'NegReg', (219, 229))	('intraneuronal accumulation of', 'MPA', (78, 107))	('presenilin 1', 'Gene', (253, 265))	('AD', 'Disease', 'MESH:D000544', (184, 186))	('AD', 'Disease', (184, 186))
71754	25058905	Nine platinum analogues are currently in clinical trials around the world ormaplatin (tetraplatin), oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 (NK-121), 254-S, JM-216, and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (LNDDP)].	('ormaplatin', 'Chemical', 'MESH:C049777', (74, 84))	('cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum', 'Chemical', '-', (202, 264))	('CI-973', 'Var', (147, 153))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (100, 111))	('platinum', 'Chemical', 'MESH:D010984', (5, 13))	('DWA2114R', 'Var', (113, 121))	('platinum (II)', 'Chemical', '-', (256, 269))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('lobaplatin', 'Chemical', 'MESH:C066228', (135, 145))	('N', 'Chemical', 'MESH:D009584', (272, 273))	('tetraplatin', 'Chemical', 'MESH:C049777', (86, 97))	('enloplatin', 'Chemical', 'MESH:C060593', (123, 133))	('platinum', 'Chemical', 'MESH:D010984', (256, 264))	('LNDDP', 'Chemical', 'MESH:C054367', (271, 276))	('N', 'Chemical', 'MESH:D009584', (155, 156))
71780	25058905	In clinical trials, cisplatin is often selected due to its strong antitumor activity, but its adverse effects include renal toxicity, nausea and vomiting.	('vomiting', 'Disease', (145, 153))	('nausea', 'Disease', (134, 140))	('nausea', 'Disease', 'MESH:D009325', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('vomiting', 'Disease', 'MESH:D014839', (145, 153))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (134, 153))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('renal toxicity', 'Disease', (118, 132))	('tumor', 'Disease', (70, 75))	('renal toxicity', 'Disease', 'MESH:D007674', (118, 132))	('cisplatin', 'Var', (20, 29))	('vomiting', 'Phenotype', 'HP:0002013', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('nausea', 'Phenotype', 'HP:0002018', (134, 140))
71829	25058905	Metformin has been shown to enhance cisplatin cytotoxicity by suppressing Stat3 activity independently of the LKB1-AMPK pathway.	('AMPK', 'Gene', (115, 119))	('Stat3', 'Gene', '6774', (74, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('Stat3', 'Gene', (74, 79))	('LKB1', 'Gene', (110, 114))	('enhance', 'PosReg', (28, 35))	('Metformin', 'Var', (0, 9))	('suppressing', 'NegReg', (62, 73))	('LKB1', 'Gene', '6794', (110, 114))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cytotoxicity', 'Disease', (46, 58))	('AMPK', 'Gene', '5562', (115, 119))
71851	25058905	It has been further confirmed in human cells that cisplatin triggers rapid degradation of the copper membrane transporter CTR1, with diminished influx of cisplatin, resulting in resistance to the drug.	('CTR1', 'Gene', '1317', (122, 126))	('resistance to the drug', 'MPA', (178, 200))	('diminished', 'NegReg', (133, 143))	('influx of cisplatin', 'MPA', (144, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('CTR1', 'Gene', (122, 126))	('degradation', 'MPA', (75, 86))	('human', 'Species', '9606', (33, 38))	('copper membrane transporter', 'MPA', (94, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('cisplatin', 'Var', (50, 59))
71852	25058905	Genetic knockout of CTR1 results in cellular resistance to cisplatin in vivo.	('CTR1', 'Gene', '1317', (20, 24))	('CTR1', 'Gene', (20, 24))	('cellular resistance to cisplatin', 'MPA', (36, 68))	('results in', 'Reg', (25, 35))	('Genetic knockout', 'Var', (0, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
71857	25058905	Glucose Transporter 1 (Glut1) is not proposed to directly transport cisplatin, the mislocalization of the transporter exacerbates the cisplatin resistance phenotype.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('Glut1', 'Gene', '6513', (23, 28))	('exacerbates', 'PosReg', (118, 129))	('Glut1', 'Gene', (23, 28))	('cisplatin resistance phenotype', 'MPA', (134, 164))	('Glucose Transporter 1', 'Gene', '6513', (0, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('mislocalization', 'Var', (83, 98))	('Glucose Transporter 1', 'Gene', (0, 21))
71863	25058905	1,3-intrastrand d(GpXpG) adducts and other adducts such as inter-strand crosslinks and nonfunctional adducts have been reported to contribute to cisplatin's toxicity.	('toxicity', 'Disease', 'MESH:D064420', (157, 165))	('toxicity', 'Disease', (157, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('adducts', 'Var', (25, 32))	('contribute', 'Reg', (131, 141))	('cisplatin', 'MPA', (145, 154))
71875	25058905	Under certain conditions a thiol group may lead to formation of thiyl radicals that in turn can interact with molecular oxygen, therefore generating reactive oxygen species.	('oxygen', 'Chemical', 'MESH:D010100', (120, 126))	('thiyl radicals', 'MPA', (64, 78))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (149, 172))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('thiol', 'Var', (27, 32))	('generating', 'Reg', (138, 148))	('lead to', 'Reg', (43, 50))	('thiyl radicals', 'Chemical', '-', (64, 78))	('reactive oxygen species', 'MPA', (149, 172))	('thiol', 'Chemical', 'MESH:D013438', (27, 32))	('interact', 'Interaction', (96, 104))
71918	25058905	Iinhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin.	('Iinhibition', 'Var', (0, 11))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('sensitizes', 'Reg', (40, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('ovarian cancer', 'Disease', (51, 65))
71920	25058905	In addition, cisplatin induced phosphorylation of both BAD Ser-112 and Ser-136 is involved in maintaining cell viability after cisplatin treatment.	('involved', 'Reg', (82, 90))	('cell', 'CPA', (106, 110))	('Ser', 'Chemical', 'MESH:D012694', (59, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('phosphorylation', 'MPA', (31, 46))	('Ser', 'Chemical', 'MESH:D012694', (71, 74))	('Ser-136', 'Var', (71, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
71934	25058905	In vitro studies suggest that cisplatin resistance can result from epigenetic changes at the molecular and cellular levels, including reduced accumulation of the platinum compounds by either active efflux/sequestration/secretion or impaired influx, detoxification by GSH conjugates, metallothioneins and other antioxidants, increased levels of DNA damage repair (nucleotide excision repair and mismatch repair), changes in DNA methylation status, alterations of membrane protein trafficking as a result of defective organization and distribution of the cytoskeleton, overexpression of chaperones, up- or down-regulated expression of microRNA (miRNA1), transcription factors and small GTPases, inactivation.	('membrane protein trafficking', 'MPA', (462, 490))	('platinum', 'Chemical', 'MESH:D010984', (162, 170))	('increased', 'PosReg', (324, 333))	('down-regulated', 'NegReg', (604, 618))	('organization', 'MPA', (516, 528))	('changes', 'Reg', (412, 419))	('N', 'Chemical', 'MESH:D009584', (639, 640))	('defective', 'Var', (506, 515))	('N', 'Chemical', 'MESH:D009584', (345, 346))	('small GTPases', 'Protein', (678, 691))	('N', 'Chemical', 'MESH:D009584', (424, 425))	('up-', 'PosReg', (597, 600))	('GTP', 'Chemical', 'MESH:D006160', (684, 687))	('N', 'Chemical', 'MESH:D009584', (646, 647))	('microRNA', 'Protein', (633, 641))	('GSH', 'Chemical', 'MESH:D005978', (267, 270))	('metal', 'Chemical', 'MESH:D008670', (283, 288))	('reduced', 'NegReg', (134, 141))	('alterations', 'Reg', (447, 458))	('expression', 'MPA', (619, 629))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))
71938	25058905	Cisplatin also induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling.	('induces', 'Reg', (15, 22))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('nucleus-independent apoptotic signaling', 'CPA', (56, 95))	('endoplasmic reticulum stress', 'MPA', (23, 51))	('Cisplatin', 'Var', (0, 9))
71946	25058905	Moreover, ectopic L37 over expression can attenuate the DNA damage response mediated by p53.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('L37', 'Gene', '6167', (18, 21))	('attenuate', 'NegReg', (42, 51))	('L37', 'Gene', (18, 21))	('ectopic', 'Var', (10, 17))	('DNA damage', 'MPA', (56, 66))
71964	25058905	The ranking of the bases followed the order: G(N7) > C(N3) > C(O2) > G(O6) > A(N3)   A(N1) > A(N7) > G(N3) > T(O4) > T(O2), based on differential Pt(II) binding energies.	('N', 'Chemical', 'MESH:D009584', (55, 56))	('G(N7', 'Var', (45, 49))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('II', 'Chemical', '-', (149, 151))	('G(O6', 'Var', (69, 73))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('A(N7', 'Var', (93, 97))	('Pt', 'Chemical', 'MESH:D010984', (146, 148))	('C(N3', 'Var', (53, 57))
71972	25058905	The presence of the N1 proton diminishes the delocalization of electron density over the nitrogen lone pairs of the purine skeleton resulting in greater localization of electron density on the N3 and N7 atoms of guanine, compared to adenine where the electron density is delocalized over the N1, N3, and N7 atoms.	('adenine', 'Chemical', 'MESH:D000225', (233, 240))	('N', 'Chemical', 'MESH:D009584', (304, 305))	('N', 'Chemical', 'MESH:D009584', (193, 194))	('greater', 'PosReg', (145, 152))	('delocalization of electron density', 'MPA', (45, 79))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('purine', 'Chemical', 'MESH:C030985', (116, 122))	('N', 'Chemical', 'MESH:D009584', (292, 293))	('nitrogen', 'Chemical', 'MESH:D009584', (89, 97))	('localization', 'MPA', (153, 165))	('N', 'Chemical', 'MESH:D009584', (296, 297))	('presence', 'Var', (4, 12))	('diminishes', 'NegReg', (30, 40))	('guanine', 'Chemical', 'MESH:D006147', (212, 219))	('N', 'Chemical', 'MESH:D009584', (200, 201))
72002	25058905	However, cisplatin chemotherapy is also associated with substantial side effects that include hepatotoxic, nephrotoxic, cardiotoxic, neurotoxic and/or hematotoxic damage.	('cisplatin', 'Var', (9, 18))	('neurotoxic', 'Disease', 'MESH:D020258', (133, 143))	('hepatotoxic', 'Disease', (94, 105))	('hematotoxic damage', 'Disease', 'MESH:D004194', (151, 169))	('nephrotoxic', 'Disease', (107, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('cardiotoxic', 'Disease', (120, 131))	('neurotoxic', 'Disease', (133, 143))	('hematotoxic damage', 'Disease', (151, 169))	('hepatotoxic', 'Disease', 'MESH:D056486', (94, 105))	('cardiotoxic', 'Disease', 'MESH:D066126', (120, 131))	('nephrotoxic', 'Disease', 'MESH:D007674', (107, 118))
72013	21482409	Mutations in human STRA6 are associated with severe pathological phenotypes in many organs such as the eye, brain, heart, and lung.	('human', 'Species', '9606', (13, 18))	('STRA6', 'Gene', (19, 24))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (29, 39))	('heart', 'Disease', (115, 120))
72029	21482409	Consistent with the diverse functions of vitamin A, human STRA6 mutations cause severe pathological phenotypes including the absence of eyes (anophthalmia), mental retardation, congenital heart defects, lung hyperplasia, and intrauterine growth retardation.	('absence of eyes', 'Disease', (125, 140))	('intrauterine growth retardation', 'Disease', (225, 256))	('heart defects', 'Phenotype', 'HP:0030680', (188, 201))	('mental retardation', 'Phenotype', 'HP:0001249', (157, 175))	('STRA6', 'Gene', (58, 63))	('mental retardation', 'Disease', 'MESH:D008607', (157, 175))	('absence of eyes', 'Phenotype', 'HP:0000528', (125, 140))	('growth retardation', 'Phenotype', 'HP:0001510', (238, 256))	('mutations', 'Var', (64, 73))	('lung hyperplasia', 'Disease', (203, 219))	('mental retardation', 'Disease', (157, 175))	('congenital heart defects', 'Phenotype', 'HP:0001627', (177, 201))	('anophthalmia', 'Disease', 'MESH:D000853', (142, 154))	('lung hyperplasia', 'Disease', 'MESH:D006965', (203, 219))	('lung hyperplasia', 'Phenotype', 'HP:0002088', (203, 219))	('anophthalmia', 'Disease', (142, 154))	('congenital heart defects', 'Disease', 'MESH:D006330', (177, 201))	('anophthalmia', 'Phenotype', 'HP:0000528', (142, 154))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (225, 256))	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (225, 256))	('cause', 'Reg', (74, 79))	('absence of eyes', 'Disease', 'MESH:D005128', (125, 140))	('human', 'Species', '9606', (52, 57))	('vitamin A', 'Chemical', 'MESH:D014801', (41, 50))	('congenital heart defects', 'Disease', (177, 201))
72074	21482409	Vitamin A transport to different cell types needs to be precisely regulated because too little or too much vitamin A can be detrimental both to cellular survival and function.	('cellular survival', 'CPA', (144, 161))	('Vitamin A', 'Chemical', 'MESH:D014801', (0, 9))	('vitamin A', 'Chemical', 'MESH:D014801', (107, 116))	('too', 'Var', (98, 101))	('detrimental', 'NegReg', (124, 135))	('too much vitamin A', 'Phenotype', 'HP:0004905', (98, 116))
72089	21482409	The main conclusion from studies of RBP knockout mice is that loss of RBP makes mice extremely sensitive to vitamin A deficiency.	('loss', 'Var', (62, 66))	('sensitive', 'MPA', (95, 104))	('vitamin A', 'Chemical', 'MESH:D014801', (108, 117))	('A deficiency', 'Disease', 'MESH:D007153', (116, 128))	('mice', 'Species', '10090', (49, 53))	('vitamin A deficiency', 'Phenotype', 'HP:0004905', (108, 128))	('RBP', 'Gene', (70, 73))	('mice', 'Species', '10090', (80, 84))	('A deficiency', 'Disease', (116, 128))
72092	21482409	Given the role of vitamin A in immune regulation and the susceptibility of vitamin A deficient children to infection before visual symptoms, it is likely that the immune system is also sensitive to RBP defect under vitamin A sufficient conditions.	('deficient', 'Var', (85, 94))	('RBP defect', 'Disease', (198, 208))	('infection', 'Disease', (107, 116))	('children', 'Species', '9606', (95, 103))	('RBP defect', 'Disease', 'MESH:C566711', (198, 208))	('infection', 'Disease', 'MESH:D007239', (107, 116))	('vitamin A', 'Chemical', 'MESH:D014801', (18, 27))	('vitamin A deficient', 'Phenotype', 'HP:0004905', (75, 94))	('defect under vitamin A', 'Phenotype', 'HP:0004905', (202, 224))	('vitamin A', 'Chemical', 'MESH:D014801', (75, 84))	('vitamin A', 'Chemical', 'MESH:D014801', (215, 224))
72149	21482409	Circulating immunoglobulin level in RBP knockout mice is half that in wild-type mice, even under vitamin A sufficiency.	('vitamin A sufficiency', 'Phenotype', 'HP:0004905', (97, 118))	('knockout', 'Var', (40, 48))	('mice', 'Species', '10090', (49, 53))	('vitamin A', 'Chemical', 'MESH:D014801', (97, 106))	('Circulating immunoglobulin level', 'Phenotype', 'HP:0010702', (0, 32))	('A sufficiency', 'Disease', (105, 118))	('Circulating immunoglobulin level', 'MPA', (0, 32))	('mice', 'Species', '10090', (80, 84))	('RBP', 'Gene', (36, 39))	('A sufficiency', 'Disease', 'None', (105, 118))
72172	21482409	Mutations in any of three essential residues in this domain can abolish the binding of STRA6 to RBP and its vitamin A uptake activity without affecting its cell surface expression.	('vitamin A', 'Chemical', 'MESH:D014801', (108, 117))	('RBP', 'Protein', (96, 99))	('Mutations', 'Var', (0, 9))	('binding', 'Interaction', (76, 83))	('abolish', 'NegReg', (64, 71))	('vitamin A uptake activity', 'MPA', (108, 133))	('STRA6', 'Gene', (87, 92))
72173	21482409	Human genetic studies found that mutations in STRA6 are associated with severe pathological phenotypes such as mental retardation, anophthalmia, congenital heart defects, lung hyperplasia, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation.	('Human', 'Species', '9606', (0, 5))	('anophthalmia', 'Disease', 'MESH:D000853', (131, 143))	('mutations', 'Var', (33, 42))	('anophthalmia', 'Disease', (131, 143))	('associated', 'Reg', (56, 66))	('anophthalmia', 'Phenotype', 'HP:0000528', (131, 143))	('pancreatic malformations', 'Disease', (208, 232))	('pancreatic malformations', 'Disease', 'MESH:D000014', (208, 232))	('intrauterine growth retardation', 'Disease', (238, 269))	('heart defects', 'Phenotype', 'HP:0030680', (156, 169))	('lung hyperplasia', 'Disease', (171, 187))	('congenital heart defects', 'Phenotype', 'HP:0001627', (145, 169))	('lung hyperplasia', 'Disease', 'MESH:D006965', (171, 187))	('duodenal stenosis', 'Phenotype', 'HP:0100867', (189, 206))	('STRA6', 'Gene', (46, 51))	('congenital heart defects', 'Disease', 'MESH:D006330', (145, 169))	('lung hyperplasia', 'Phenotype', 'HP:0002088', (171, 187))	('pancreatic malformations', 'Phenotype', 'HP:0001732', (208, 232))	('growth retardation', 'Phenotype', 'HP:0001510', (251, 269))	('mental retardation', 'Phenotype', 'HP:0001249', (111, 129))	('mental retardation', 'Disease', 'MESH:D008607', (111, 129))	('duodenal stenosis', 'Disease', (189, 206))	('intrauterine growth retardation', 'Phenotype', 'HP:0001511', (238, 269))	('intrauterine growth retardation', 'Disease', 'MESH:D005317', (238, 269))	('congenital heart defects', 'Disease', (145, 169))	('mental retardation', 'Disease', (111, 129))
72174	21482409	More human genetic studies have further confirmed the role of STRA6 mutations in malformations in humans.	('malformations', 'Disease', 'MESH:D000014', (81, 94))	('humans', 'Species', '9606', (98, 104))	('human', 'Species', '9606', (98, 103))	('mutations', 'Var', (68, 77))	('human', 'Species', '9606', (5, 10))	('STRA6', 'Gene', (62, 67))	('malformations', 'Disease', (81, 94))
72176	21482409	Consistently, STRA6 knockdown also causes developmental defects in zebrafish.	('developmental defects', 'Disease', (42, 63))	('developmental defects', 'Disease', 'MESH:D003147', (42, 63))	('knockdown', 'Var', (20, 29))	('zebrafish', 'Species', '7955', (67, 76))	('STRA6', 'Gene', (14, 19))
72177	21482409	The loss of retinoid uptake in the eye due to loss of STRA6 has also been demonstrated in the zebrafish model.	('retinoid uptake in the', 'MPA', (12, 34))	('retinoid', 'Chemical', 'MESH:D012176', (12, 20))	('rat', 'Species', '10116', (81, 84))	('loss', 'Var', (46, 50))	('STRA6', 'Gene', (54, 59))	('zebrafish', 'Species', '7955', (94, 103))	('loss', 'NegReg', (4, 8))
72178	21482409	Functional assays showed that the pathogenic missense mutations identified in the human genetic study abolish the vitamin A uptake activity of STRA6, consistent with the severe clinical phenotypes.	('abolish', 'NegReg', (102, 109))	('missense mutations', 'Var', (45, 63))	('vitamin A', 'Chemical', 'MESH:D014801', (114, 123))	('vitamin A uptake activity', 'MPA', (114, 139))	('human', 'Species', '9606', (82, 87))
72179	21482409	As mentioned in a previous review, this is the first example of a retinoid signaling pathway mutation causing developmental abnormalities in humans.	('causing', 'Reg', (102, 109))	('retinoid', 'Chemical', 'MESH:D012176', (66, 74))	('developmental abnormalities', 'Disease', 'MESH:D006130', (110, 137))	('retinoid signaling pathway', 'Pathway', (66, 92))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (110, 137))	('developmental abnormalities', 'Disease', (110, 137))	('mutation', 'Var', (93, 101))	('humans', 'Species', '9606', (141, 147))
72218	21482409	Phenotypes associated with known human RBP mutations are different from phenotypes associated with known human STRA6 mutations.	('human', 'Species', '9606', (105, 110))	('mutations', 'Var', (43, 52))	('human', 'Species', '9606', (33, 38))	('RBP', 'Gene', (39, 42))
72219	21482409	Two natural RBP mutations have been identified in humans, and they cause vision defects such as dystrophy of the RPE.	('cause', 'Reg', (67, 72))	('vision defects', 'Disease', 'MESH:D014786', (73, 87))	('vision defect', 'Phenotype', 'HP:0000572', (73, 86))	('humans', 'Species', '9606', (50, 56))	('mutations', 'Var', (16, 25))	('dystrophy', 'Disease', (96, 105))	('dystrophy', 'Disease', 'MESH:D009136', (96, 105))	('RBP', 'Gene', (12, 15))	('vision defects', 'Disease', (73, 87))
72221	21482409	In contrast, known human STRA6 mutations cause severe and systemic phenotypes.	('STRA6', 'Gene', (25, 30))	('cause', 'Reg', (41, 46))	('mutations', 'Var', (31, 40))	('human', 'Species', '9606', (19, 24))
72222	21482409	First, biochemical analysis showed that the only two natural mutations found in human RBP cause only a partial loss of RBP function.	('loss', 'NegReg', (111, 115))	('RBP', 'Gene', (86, 89))	('mutations', 'Var', (61, 70))	('human', 'Species', '9606', (80, 85))	('RBP function', 'MPA', (119, 131))
72223	21482409	The human RBP mutants can still bind retinol.	('mutants', 'Var', (14, 21))	('human', 'Species', '9606', (4, 9))	('retinol', 'Chemical', 'MESH:D014801', (37, 44))	('RBP', 'Gene', (10, 13))	('bind', 'Interaction', (32, 36))
72224	21482409	In addition, holo-RBP formed by the mutant RBP can still bind TTR like the wild-type RBP.	('RBP', 'Gene', (43, 46))	('TTR', 'Gene', (62, 65))	('TTR', 'Gene', '7276', (62, 65))	('bind', 'Interaction', (57, 61))	('mutant', 'Var', (36, 42))
72226	21482409	The vision defect associated with human RBP mutations suggests that vision is most sensitive to the partial loss of RBP function.	('human', 'Species', '9606', (34, 39))	('vision defect', 'Disease', 'MESH:D014786', (4, 17))	('vision defect', 'Phenotype', 'HP:0000572', (4, 17))	('mutations', 'Var', (44, 53))	('vision defect', 'Disease', (4, 17))	('RBP', 'Gene', (40, 43))
72227	21482409	The fact that human RBP mutations are so rarely identified (only two so far) is consistent with its essential function.	('human', 'Species', '9606', (14, 19))	('mutations', 'Var', (24, 33))	('RBP', 'Gene', (20, 23))
72228	21482409	Moreover, the detection limit of serum retinol/RBP in patients with RBP mutations in the previous study is 200 nM, which is still much higher than the Kd of the RBP/STRA6 interaction.	('mutations', 'Var', (72, 81))	('RBP', 'Gene', (68, 71))	('retinol', 'Chemical', 'MESH:D014801', (39, 46))	('patients', 'Species', '9606', (54, 62))	('serum retinol/RBP', 'MPA', (33, 50))
72230	21482409	For example, placental delivery of vitamin A from maternal RBP to the human embryo is very different between RBP null embryos and RBP receptor null embryos.	('RBP', 'Gene', (109, 112))	('vitamin A', 'Chemical', 'MESH:D014801', (35, 44))	('human', 'Species', '9606', (70, 75))	('placental delivery', 'MPA', (13, 31))	('null', 'Var', (113, 117))	('different', 'Reg', (91, 100))
72234	21482409	Consistently, STRA6 mutations in human are associated with mental retardation.	('mental retardation', 'Disease', 'MESH:D008607', (59, 77))	('associated with', 'Reg', (43, 58))	('mental retardation', 'Phenotype', 'HP:0001249', (59, 77))	('human', 'Species', '9606', (33, 38))	('STRA6', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))	('mental retardation', 'Disease', (59, 77))
72235	21482409	Even human pathological phenotypes caused by STRA6 mutations are variable.	('STRA6', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('human', 'Species', '9606', (5, 10))
72303	21482409	Modulating vitamin A uptake is a known method to alleviate symptoms for some diseases such as Stargardt macular dystrophy.	('Modulating', 'Var', (0, 10))	('Stargardt macular dystrophy', 'Disease', (94, 121))	('vitamin A', 'Chemical', 'MESH:D014801', (11, 20))	('Stargardt macular dystrophy', 'Disease', 'MESH:C535805', (94, 121))	('macular dystrophy', 'Phenotype', 'HP:0007754', (104, 121))
72309	21482409	Retinoids have been used to treat many types of cancer, and targeting STRA6 is an alternative to systemic retinoid treatment.	('Retinoids', 'Chemical', 'MESH:D012176', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('targeting', 'Var', (60, 69))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('retinoid', 'Chemical', 'MESH:D012176', (106, 114))
72313	21482409	Given the role of STRA6 as the natural mechanism of vitamin A uptake, modulating STRA6 activity in the skin is an alternative and potentially less toxic method to regulating skin retinoid level.	('STRA6', 'Gene', (81, 86))	('vitamin A', 'Chemical', 'MESH:D014801', (52, 61))	('skin retinoid level', 'MPA', (174, 193))	('retinoid', 'Chemical', 'MESH:D012176', (179, 187))	('modulating', 'Var', (70, 80))
72315	21482409	Consistently, STRA6 mutations cause lung hypoplasia.	('lung hypoplasia', 'Disease', (36, 51))	('lung hypoplasia', 'Disease', 'MESH:D008171', (36, 51))	('cause', 'Reg', (30, 35))	('lung hypoplasia', 'Phenotype', 'HP:0002089', (36, 51))	('STRA6', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
72333	23413144	Retinoic acid receptors are present in both Sertoli cells and developing germ cells, and knockouts of any of the three main retinoic acid receptors results in infertility due to a breakdown in spermatogenesis.	('infertility', 'Disease', 'MESH:D007247', (159, 170))	('results in', 'Reg', (148, 158))	('Sertoli cells', 'Phenotype', 'HP:0100619', (44, 57))	('infertility', 'Phenotype', 'HP:0000789', (159, 170))	('breakdown', 'NegReg', (180, 189))	('infertility', 'Disease', (159, 170))	('Retinoic acid', 'Chemical', 'MESH:D014212', (0, 13))	('knockouts', 'Var', (89, 98))	('spermatogenesis', 'CPA', (193, 208))	('retinoic acid', 'Chemical', 'MESH:D014212', (124, 137))
72346	23413144	We hypothesized that intratesticular concentrations of retinoic acid would be lower in men with abnormal semen as compared to men with normal semen.	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (144, 147))	('abnormal', 'Var', (96, 104))	('men', 'Species', '9606', (87, 90))	('men', 'Species', '9606', (107, 110))	('lower', 'NegReg', (78, 83))	('intratesticular concentrations of retinoic acid', 'MPA', (21, 68))	('retinoic acid', 'Chemical', 'MESH:D014212', (55, 68))
72365	23413144	The sensitivity of the assay for FSH and LH are 0.016 IU/L and 0.019 IU/L, respectively with intraassay and interassay coefficients of variation of 3.0% and 5% for FSH and 5.6% and 13% for LH for mid-normal range values.	('FSH', 'Disease', (164, 167))	('FSH', 'Disease', 'MESH:D020391', (33, 36))	('0.019 IU/L', 'Var', (63, 73))	('LH', 'Chemical', 'MESH:D007986', (41, 43))	('FSH', 'Disease', 'MESH:D020391', (164, 167))	('FSH', 'Disease', (33, 36))	('LH', 'Chemical', 'MESH:D007986', (189, 191))
72413	23413144	Of the subjects with abnormal semen analyses, the subjects with concentrations of intratesticular 13-cis retinoic acid below 0.1 pmol/gram of tissue all had impaired sperm motility (18%, 28% and 33%), and the subject with the lowest intratesticular 13-cis retinoic acid concentration had both impaired motility (18%) and severe oligozoospermia with an average sperm concentration of 1.1 million sperm/ml of ejaculate.	('impaired sperm motility', 'Disease', 'MESH:D015835', (157, 180))	('impaired sperm motility', 'Disease', (157, 180))	('impaired motility', 'Disease', 'MESH:D015835', (293, 310))	('intratesticular', 'Var', (82, 97))	('13-cis retinoic acid', 'Chemical', 'MESH:D015474', (249, 269))	('oligozoospermia', 'Disease', 'MESH:D009845', (328, 343))	('13-cis retinoic acid', 'Chemical', 'MESH:D015474', (98, 118))	('men', 'Species', '9606', (32, 35))	('oligozoospermia', 'Disease', (328, 343))	('impaired motility', 'Disease', (293, 310))	('impaired sperm motility', 'Phenotype', 'HP:0012207', (157, 180))
72419	23413144	We observed that intratesticular 13-cis retinoic acid concentration were significantly lower in men with abnormal semen compared to men with normal semen, but intratesticular all-trans retinoic acid did not differ between these groups.	('men', 'Species', '9606', (96, 99))	('lower', 'NegReg', (87, 92))	('13-cis retinoic acid', 'Chemical', 'MESH:D015474', (33, 53))	('men', 'Species', '9606', (132, 135))	('intratesticular 13-cis retinoic acid concentration', 'MPA', (17, 67))	('abnormal', 'Var', (105, 113))	('men', 'Species', '9606', (150, 153))	('men', 'Species', '9606', (116, 119))	('all-trans retinoic acid', 'Chemical', 'MESH:D014212', (175, 198))
72452	23413144	In conclusion, we have observed that intratesticular 13-cis retinoic acid is significantly lower in men with abnormal semen analyses compared to men with normal semen analyses, but there is no significant difference in intratesticular all-trans retinoic acid between these groups.	('lower', 'NegReg', (91, 96))	('men', 'Species', '9606', (100, 103))	('men', 'Species', '9606', (145, 148))	('men', 'Species', '9606', (163, 166))	('13-cis retinoic acid', 'Chemical', 'MESH:D015474', (53, 73))	('intratesticular 13-cis retinoic acid', 'MPA', (37, 73))	('all-trans retinoic acid', 'Chemical', 'MESH:D014212', (235, 258))	('abnormal', 'Var', (109, 117))	('men', 'Species', '9606', (120, 123))
72454	10952776	Allelic losses in carcinoma in situ and testicular germ cell tumours of adolescents and adults: evidence suggestive of the linear progression model Testicular germ cell tumours (TGCTs) may arise through a process of multi-step carcinogenesis, and loss of heterozygosity (LOH) at specific loci is likely to be an important early event, although this has not been studied in detail.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('tumours', 'Disease', (169, 176))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('germ cell tumour', 'Phenotype', 'HP:0100728', (159, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', 'MESH:D009369', (169, 176))	('carcinoma in situ', 'Disease', (18, 35))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('multi-step carcinogenesis', 'Disease', 'MESH:D063646', (216, 241))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (18, 35))	('multi-step carcinogenesis', 'Disease', (216, 241))	('carcinoma in situ', 'Disease', 'MESH:D002278', (18, 35))	('Testicular germ cell tumours', 'Disease', 'MESH:C563236', (148, 176))	('loss of heterozygosity', 'Var', (247, 269))	('germ cell tumour', 'Phenotype', 'HP:0100728', (51, 67))	('tumours', 'Disease', (61, 68))	('Testicular germ cell tumours', 'Disease', (148, 176))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
72457	10952776	Evidence for allelic loss at 3q27-q28 was observed in all of the embryonal carcinoma samples analysed.	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (65, 84))	('embryonal carcinoma', 'Disease', (65, 84))	('allelic loss', 'Var', (13, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (65, 84))
72469	29534941	TCSs had higher median systolic blood pressure (126 vs. 119 mm Hg; P < .001), but fewer were smokers (8.4% vs. 28.2%; P < .001) than controls.	('TCSs', 'Var', (0, 4))	('higher median systolic blood pressure', 'Phenotype', 'HP:0004421', (9, 46))	('TCSs', 'Chemical', '-', (0, 4))	('systolic blood pressure', 'MPA', (23, 46))	('higher', 'PosReg', (9, 15))
72479	29534941	European studies have reported a 1.4-to 7-fold higher CVD risk among cisplatin-treated TCSs than in either the general population or in TCSs managed with surgery alone.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('TCSs', 'Chemical', '-', (136, 140))	('cisplatin-treated', 'Var', (69, 86))	('CVD', 'Phenotype', 'HP:0001626', (54, 57))	('TCSs', 'Chemical', '-', (87, 91))	('CVD risk', 'MPA', (54, 62))	('to 7', 'Species', '1214577', (37, 41))
72616	28038466	Drug-dependent functionalization of wild-type and mutant p53 in cisplatin-resistant human ovarian tum3or cells Cisplatin (cis-Pt) resistance in tumor cells from p53 dysfunction is a significant clinical problem.	('Cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('tumor', 'Disease', (144, 149))	('dysfunction', 'Var', (165, 176))	('cis-Pt', 'Chemical', 'MESH:D002945', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutant', 'Var', (50, 56))	('p53', 'Gene', (57, 60))	('human', 'Species', '9606', (84, 89))	('p53', 'Gene', (161, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', '7157', (161, 164))
72617	28038466	Although mutation can inhibit p53 function, >60% of p53 mutants retain normal function according to literature reports.	('mutation', 'Var', (9, 17))	('function', 'MPA', (34, 42))	('inhibit', 'NegReg', (22, 29))	('p53', 'Gene', (52, 55))	('mutants', 'Var', (56, 63))	('p53', 'Gene', '7157', (52, 55))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('normal function', 'MPA', (71, 86))
72620	28038466	Mutant p53 in 2780CP/Cl-16 (p53V172F) and OVCAR-10 (p53V172F and p53G266R) cells, predicted as non-functional in p53 database, displayed attenuated response to cis-Pt, as did the polymorphic p53P72R (functionally equivalent to wild-type p53) in HEY and OVCA-433 cell lines.	('p53', 'Gene', (28, 31))	('p53', 'Gene', '7157', (65, 68))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (191, 194))	('p53', 'Gene', (113, 116))	('cis-Pt', 'Chemical', 'MESH:D002945', (160, 166))	('p53', 'Gene', '7157', (7, 10))	('attenuated', 'NegReg', (137, 147))	('p53', 'Gene', '7157', (237, 240))	('p53', 'Gene', (65, 68))	('HEY', 'CellLine', 'CVCL:0297', (245, 248))	('p53', 'Gene', (191, 194))	('p53', 'Gene', (237, 240))	('p53', 'Gene', (7, 10))	('Mutant', 'Var', (0, 6))	('response', 'MPA', (148, 156))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', '7157', (52, 55))	('p53', 'Gene', '7157', (113, 116))
72621	28038466	However, p53 was robustly activated by oxali-Pt in all cell lines, with resultant drug potency confirmed as p53-dependent by p53 knockout using CRISPR/Cas9 system.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('knockout', 'Var', (129, 137))	('p53', 'Gene', '7157', (125, 128))	('p53', 'Gene', (125, 128))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (39, 47))
72624	28038466	In conclusion, cis-Pt resistance occurs in both wild-type and mutant p53 ovarian cancer cells, but is associated with loss of Ser20 phosphorylation.	('cis-Pt resistance', 'CPA', (15, 32))	('cis-Pt', 'Chemical', 'MESH:D002945', (15, 21))	('ovarian cancer', 'Disease', (73, 87))	('mutant', 'Var', (62, 68))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('Ser20', 'Chemical', '-', (126, 131))	('loss', 'NegReg', (118, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (73, 87))	('Ser20 phosphorylation', 'MPA', (126, 147))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ovarian cancer', 'Disease', 'MESH:D010051', (73, 87))
72625	28038466	However, these mutant p53, like polymorphic p53, are functional and activated by oxali-Pt-induced Ser20 phosphorylation.	('Ser20', 'Chemical', '-', (98, 103))	('p53', 'Gene', (22, 25))	('activated', 'PosReg', (68, 77))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('p53', 'Gene', '7157', (22, 25))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (81, 89))	('mutant', 'Var', (15, 21))
72626	28038466	Thus, the potential exists for repurposing oxali-Pt or similar drugs against refractory cancers harboring wild-type or specific mutant p53.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('mutant', 'Var', (128, 134))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('cancers', 'Disease', (88, 95))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('refractory', 'Disease', (77, 87))
72641	28038466	Normally, cis-Pt upregulates ATR, Chk1 and Chk2 kinases, which stabilize and activate p53 by phosphorylating Ser15 and Ser20, which are considered to be critical sites as they are located in the region of p53 that binds to Mdm2.	('ATR', 'Gene', '545', (29, 32))	('cis-Pt', 'Chemical', 'MESH:D002945', (10, 16))	('upregulates', 'PosReg', (17, 28))	('Mdm2', 'Gene', '4193', (223, 227))	('activate', 'PosReg', (77, 85))	('p53', 'Gene', '7157', (86, 89))	('Chk2', 'Gene', (43, 47))	('p53', 'Gene', '7157', (205, 208))	('p53', 'Gene', (86, 89))	('Ser15', 'Chemical', '-', (109, 114))	('ATR', 'Gene', (29, 32))	('p53', 'Gene', (205, 208))	('Chk1', 'Gene', (34, 38))	('Ser20', 'Chemical', '-', (119, 124))	('Ser20', 'Var', (119, 124))	('Chk1', 'Gene', '1111', (34, 38))	('Mdm2', 'Gene', (223, 227))	('Chk2', 'Gene', '11200', (43, 47))	('kinases', 'Enzyme', (48, 55))
72642	28038466	Of these kinases, contribution of Chk2 to cis-Pt resistance is possible as defects in this kinase and p53 are reported to be mutually exclusive and Chk2 dysfunction is known to exist in several cancers, including 23% of clinical ovarian cancer cases.	('Chk2', 'Gene', (148, 152))	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('p53', 'Gene', '7157', (102, 105))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cis-Pt', 'Chemical', 'MESH:D002945', (42, 48))	('defects', 'Var', (75, 82))	('Chk2', 'Gene', '11200', (34, 38))	('ovarian cancer', 'Disease', (229, 243))	('cancers', 'Disease', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Chk2', 'Gene', (34, 38))	('p53', 'Gene', (102, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('Chk2', 'Gene', '11200', (148, 152))
72643	28038466	Another major cause of p53 dysfunction is mutation in the p53 gene, and several clinical studies have attempted to correlate p53 gene status with chemotherapy response.	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('cause', 'Reg', (14, 19))	('mutation', 'Var', (42, 50))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('p53', 'Gene', (58, 61))	('p53', 'Gene', '7157', (58, 61))
72644	28038466	However, the results have been conflicting, since wild-type or mutant p53 can be associated with both antitumor therapeutic response and resistance.	('resistance', 'CPA', (137, 147))	('mutant', 'Var', (63, 69))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', (106, 111))
72645	28038466	Surprisingly, in high grade serous ovarian cancer (HGSOC), wild-type p53 is associated with a significantly inferior overall survival of patients.	('serous ovarian cancer', 'Disease', (28, 49))	('overall survival', 'MPA', (117, 133))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (28, 49))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('wild-type', 'Var', (59, 68))	('inferior', 'NegReg', (108, 116))
72646	28038466	These reports indicate that there is insufficient knowledge of how wild-type p53 is inactivated and whether all p53 mutations negatively impact p53 function and downstream cellular processes.	('p53', 'Gene', '7157', (144, 147))	('negatively impact', 'NegReg', (126, 143))	('p53', 'Gene', (77, 80))	('function', 'MPA', (148, 156))	('mutations', 'Var', (116, 125))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', (144, 147))
72647	28038466	However, one detailed study using the yeast functional assay (FASAY) for evaluating transcriptional activity of 2,314 p53 mutants revealed that only 9.6% exhibited no activity, 26.5% had partial activity and 63.9% expressed full activity relative to wild-type p53.	('mutants', 'Var', (122, 129))	('p53', 'Gene', (118, 121))	('activity', 'MPA', (229, 237))	('p53', 'Gene', '7157', (118, 121))	('yeast', 'Species', '4932', (38, 43))	('p53', 'Gene', (260, 263))	('p53', 'Gene', '7157', (260, 263))	('activity', 'MPA', (195, 203))
72649	28038466	More importantly, we have previously demonstrated that in a cis-Pt-resistant ovarian tumor model harboring mutant p53, ionizing radiation, but not cis-Pt, induced and activated p53.	('cis-Pt', 'Chemical', 'MESH:D002945', (60, 66))	('mutant', 'Var', (107, 113))	('p53', 'Gene', (114, 117))	('ovarian tumor', 'Disease', (77, 90))	('p53', 'Gene', '7157', (114, 117))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('activated', 'PosReg', (167, 176))	('cis-Pt', 'Chemical', 'MESH:D002945', (147, 153))	('ovarian tumor', 'Phenotype', 'HP:0100615', (77, 90))	('ovarian tumor', 'Disease', 'MESH:D010051', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
72650	28038466	In the present study, therefore, we have evaluated the response of wild-type or mutant p53 and its post-translational phosphorylation in well-studied models of cis-Pt resistance.	('p53', 'Gene', (87, 90))	('cis-Pt', 'Chemical', 'MESH:D002945', (160, 166))	('p53', 'Gene', '7157', (87, 90))	('mutant', 'Var', (80, 86))
72652	28038466	Our study indicates that Chk2 dysfunction is prevalent in cis-Pt-resistant cells, and the resultant loss in Ser20 phosphorylation is an important negative regulator of p53 function, both in wild-type and mutant p53 tumor cells.	('prevalent', 'Reg', (45, 54))	('Ser20 phosphorylation', 'MPA', (108, 129))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('p53', 'Gene', (211, 214))	('p53', 'Gene', '7157', (168, 171))	('cis-Pt', 'Chemical', 'MESH:D002945', (58, 64))	('Chk2', 'Gene', '11200', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mutant', 'Var', (204, 210))	('p53', 'Gene', '7157', (211, 214))	('Chk2', 'Gene', (25, 29))	('tumor', 'Disease', (215, 220))	('dysfunction', 'Var', (30, 41))	('p53', 'Gene', (168, 171))	('Ser20', 'Chemical', '-', (108, 113))	('loss', 'NegReg', (100, 104))
72655	28038466	Although the A2780 and 2780CP/Cl-16 cells are of ovarian origin, their histological sub-type is unknown, whereas OVCAR-10 is reported as being an adenocarcinoma and Hey and OVCA-433 as serous ovarian cancer.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('A2780', 'Var', (13, 18))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (185, 206))	('ovarian cancer', 'Phenotype', 'HP:0100615', (192, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('adenocarcinoma', 'Disease', (146, 160))	('serous ovarian cancer', 'Disease', (185, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
72658	28038466	However, the P72R polymorphism in Hey and OVCA-433 models, as expected from the literature, does not inhibit transcriptional activation of target gene promoters in the yeast FASAY system (http://p53.fr).	('p53', 'Gene', (195, 198))	('p53', 'Gene', '7157', (195, 198))	('inhibit', 'NegReg', (101, 108))	('P72R', 'Mutation', 'rs1042522', (13, 17))	('yeast', 'Species', '4932', (168, 173))	('P72R', 'Var', (13, 17))	('transcriptional activation', 'MPA', (109, 135))
72659	28038466	On the other hand, the V172F and G266R mutants appear to lack p53 function in this system.	('function', 'MPA', (66, 74))	('V172F', 'Var', (23, 28))	('V172F', 'Mutation', 'rs1131691043', (23, 28))	('G266R', 'Var', (33, 38))	('G266R', 'Mutation', 'rs1057519990', (33, 38))	('lack', 'NegReg', (57, 61))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
72666	28038466	The results with a larger population cohort confirm a previous report that overall survival (OS) tends toward being shorter in patients with cancers harboring wild-type p53 (median OS, 34 vs. 40 months; Figure 1C).	('shorter', 'NegReg', (116, 123))	('wild-type', 'Var', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('patients', 'Species', '9606', (127, 135))	('overall survival', 'MPA', (75, 91))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
72667	28038466	Since this may be due to either dysfunctional wild-type p53 or functional mutant p53, we correlated actual p53 mutations in HGSOC cancers to functionality as mined from the p53.fr database.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('p53', 'Gene', (56, 59))	('p53', 'Gene', (173, 176))	('p53', 'Gene', (107, 110))	('cancers', 'Disease', (130, 137))	('p53', 'Gene', '7157', (107, 110))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('p53', 'Gene', '7157', (173, 176))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('dysfunctional', 'Disease', (32, 45))	('dysfunctional', 'Disease', 'MESH:D006331', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('mutant', 'Var', (74, 80))
72668	28038466	Our findings demonstrate that of 175 missense p53 mutants in TCGA database, only one (0.6%) was fully active against all eight p53 target gene promoters in the FASAY system, with three (1.7%) inactive against 3-4 promoters, 19 (11%) inactive against 5-6 promoters, and 152 (87%) were inactive against 7-8 promoters (Figure 1D).	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('mutants', 'Var', (50, 57))	('missense', 'Var', (37, 45))	('p53', 'Gene', '7157', (127, 130))	('p53', 'Gene', (127, 130))
72669	28038466	These results indicate that the 2780CP/Cl-16 and OVCAR-10 tumor models with non-functionality of p53 mutants are consistent with majority (98%) of p53 mutants in HGSOC.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutants', 'Var', (151, 158))	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('mutants', 'Var', (101, 108))	('p53', 'Gene', '7157', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('p53', 'Gene', (147, 150))
72673	28038466	Thus, A2780 clones were exposed to 1 muM cis-Pt or 0.6 muM oxali-Pt, and clones from resistant cells were exposed to 5-fold higher concentrations in order to compensate in part for lower drug uptake in resistant cells.	('A2780', 'Var', (6, 11))	('muM', 'Gene', '56925', (55, 58))	('lower', 'NegReg', (181, 186))	('drug uptake', 'MPA', (187, 198))	('muM', 'Gene', (55, 58))	('cis-Pt', 'Chemical', 'MESH:D002945', (41, 47))	('muM', 'Gene', '56925', (37, 40))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (59, 67))	('muM', 'Gene', (37, 40))
72677	28038466	Significantly, it is readily evident from results with oxali-Pt that both wild-type and mutant p53 in resistant models can be consistently activated to upregulate p21.	('oxali-Pt', 'Chemical', 'MESH:D000077150', (55, 63))	('upregulate', 'PosReg', (152, 162))	('p21', 'Gene', (163, 166))	('p21', 'Gene', '644914', (163, 166))	('mutant', 'Var', (88, 94))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))
72679	28038466	A 2- to 3-fold increase in IC50 for cis-Pt was demonstrated in A2780 and 2780CP/Cl-16 p53-/- clones, but a surprisingly significant 1.4- to 2.1-fold decrease in cis-Pt IC50 in p53-/- clones derived from OVCAR-10 and HEY cells was noted (Figure 2B).	('cis-Pt', 'Chemical', 'MESH:D002945', (36, 42))	('A2780', 'Var', (63, 68))	('IC50', 'MPA', (27, 31))	('p53', 'Gene', '7157', (86, 89))	('p53', 'Gene', (176, 179))	('cis-Pt', 'Chemical', 'MESH:D002945', (161, 167))	('increase', 'PosReg', (15, 23))	('p53', 'Gene', '7157', (176, 179))	('HEY', 'CellLine', 'CVCL:0297', (216, 219))	('p53', 'Gene', (86, 89))
72681	28038466	However, in contrast, loss of p53 consistently increased IC50 of oxali-Pt in p53-/- clones from all cell lines by 2- to 11-fold.	('IC50 of oxali-Pt', 'MPA', (57, 73))	('p53', 'Gene', (77, 80))	('p53', 'Gene', (30, 33))	('increased', 'PosReg', (47, 56))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', '7157', (30, 33))	('loss', 'Var', (22, 26))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (65, 73))
72684	28038466	Specifically, we assessed phosphorylation of p53 at Ser15 and Ser20 sites that have been reported as most critical for its anti-proliferative and pro-apoptotic functions.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('Ser15', 'Chemical', '-', (52, 57))	('Ser20', 'Chemical', '-', (62, 67))	('Ser20', 'Var', (62, 67))	('phosphorylation', 'MPA', (26, 41))
72686	28038466	In resistant cell lines, inductions of p53 and p21 by cis-Pt were again attenuated in general, whereas oxali-Pt-mediated inductions were substantially greater.	('p21', 'Gene', '644914', (47, 50))	('cis-Pt', 'Chemical', 'MESH:D002945', (54, 60))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (103, 111))	('attenuated', 'NegReg', (72, 82))	('inductions', 'MPA', (25, 35))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('cis-Pt', 'Var', (54, 60))	('p21', 'Gene', (47, 50))
72688	28038466	In OVCAR-10 and HEY cells, however, Ser15 phosphorylation by cis-Pt was similar to or greater than that by oxali-Pt, whereas Ser20 phosphorylation by oxali-Pt was consistently greater than by cis-Pt.	('HEY', 'CellLine', 'CVCL:0297', (16, 19))	('Ser15 phosphorylation', 'MPA', (36, 57))	('cis-Pt', 'Chemical', 'MESH:D002945', (61, 67))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (107, 115))	('greater', 'PosReg', (86, 93))	('Ser20', 'MPA', (125, 130))	('cis-Pt', 'Chemical', 'MESH:D002945', (192, 198))	('Ser20', 'Chemical', '-', (125, 130))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (150, 158))	('cis-Pt', 'Var', (61, 67))	('Ser15', 'Chemical', '-', (36, 41))
72692	28038466	To validate p53-Ser20 phosphorylation as enhancing its transcriptional activity, we monitored p21 levels by immunoblot in A2780 p53-/- cells transfected with plasmids expressing wild-type p53, mutant p53-S20A (constitutively dephosphorylated mimic) or mutant p53-S20D (constitutively phosphorylated mimic).	('p53', 'Gene', '7157', (128, 131))	('enhancing', 'PosReg', (41, 50))	('p53', 'Gene', '7157', (200, 203))	('S20A', 'SUBSTITUTION', 'None', (204, 208))	('p53', 'Gene', (128, 131))	('p21', 'Gene', (94, 97))	('p53', 'Gene', (200, 203))	('p21', 'Gene', '644914', (94, 97))	('p53', 'Gene', '7157', (188, 191))	('S20A', 'Var', (204, 208))	('Ser20', 'Chemical', '-', (16, 21))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', '7157', (259, 262))	('p53', 'Gene', (188, 191))	('S20D', 'SUBSTITUTION', 'None', (263, 267))	('transcriptional activity', 'MPA', (55, 79))	('p53', 'Gene', (12, 15))	('p53', 'Gene', (259, 262))	('S20D', 'Var', (263, 267))
72693	28038466	The results in Figure 3C and 3D do indeed demonstrate that expression of p53-S20D, which as anticipated is detectable by Ser20-p53 antibody, increases p21 to significantly greater levels (~2 fold) as compared to wild-type p53 or mutant p53-S20A.	('p53', 'Gene', '7157', (127, 130))	('increases', 'PosReg', (141, 150))	('greater', 'PosReg', (172, 179))	('p53', 'Gene', (73, 76))	('p53', 'Gene', (236, 239))	('S20D', 'SUBSTITUTION', 'None', (77, 81))	('expression', 'Species', '29278', (59, 69))	('S20A', 'SUBSTITUTION', 'None', (240, 244))	('p53', 'Gene', '7157', (73, 76))	('p21', 'Gene', '644914', (151, 154))	('p53', 'Gene', '7157', (236, 239))	('S20A', 'Var', (240, 244))	('Ser20', 'Chemical', '-', (121, 126))	('p53', 'Gene', '7157', (222, 225))	('p53', 'Gene', (222, 225))	('S20D', 'Var', (77, 81))	('p53', 'Gene', (127, 130))	('p21', 'Gene', (151, 154))
72694	28038466	These results corroborate that Ser20 phosphorylation is an important potentiator of p53 transcriptional activity.	('transcriptional activity', 'MPA', (88, 112))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', (84, 87))	('Ser20', 'Chemical', '-', (31, 36))	('Ser20', 'Var', (31, 36))
72698	28038466	In addition, our lab has previously reported that knockdown of Chk2 in A2780 cells reduced the ability of cis-Pt to induce p53 and p21.	('induce', 'PosReg', (116, 122))	('reduced', 'NegReg', (83, 90))	('knockdown', 'Var', (50, 59))	('cis-Pt', 'Chemical', 'MESH:D002945', (106, 112))	('p21', 'Gene', (131, 134))	('Chk2', 'Gene', '11200', (63, 67))	('p53', 'Gene', (123, 126))	('p21', 'Gene', '644914', (131, 134))	('Chk2', 'Gene', (63, 67))	('p53', 'Gene', '7157', (123, 126))
72702	28038466	Cis-Pt or oxali-Pt treatment of A2780 control clone demonstrated that total Chk2 levels were unaffected and that induction of p53, phospho-p53 and p21 levels were consistent, and confirmed our previous report that Chk2 was activated via Thr68 phosphorylation by cis-Pt, and to a lesser extent by oxali-Pt (Figure 4B).	('oxali-Pt', 'Chemical', 'MESH:D000077150', (10, 18))	('p53', 'Gene', '7157', (126, 129))	('p21', 'Gene', (147, 150))	('Chk2', 'Gene', (76, 80))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (296, 304))	('Thr68', 'Chemical', '-', (237, 242))	('p21', 'Gene', '644914', (147, 150))	('Chk2', 'Gene', '11200', (214, 218))	('Cis-Pt', 'Chemical', 'MESH:D002945', (0, 6))	('Chk2', 'Gene', (214, 218))	('cis-Pt', 'Var', (262, 268))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('cis-Pt', 'Chemical', 'MESH:D002945', (262, 268))	('Thr68', 'Protein', (237, 242))	('activated', 'PosReg', (223, 232))	('p53', 'Gene', (126, 129))	('Chk2', 'Gene', '11200', (76, 80))
72703	28038466	Chk2 knockout, on the other hand, resulted in a dramatic decrease in p53-Ser20 phosphorylation and p21 levels with cis-Pt.	('Ser20', 'Chemical', '-', (73, 78))	('decrease', 'NegReg', (57, 65))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('knockout', 'Var', (5, 13))	('Chk2', 'Gene', '11200', (0, 4))	('Chk2', 'Gene', (0, 4))	('cis-Pt', 'Chemical', 'MESH:D002945', (115, 121))	('p21', 'Gene', (99, 102))	('p21', 'Gene', '644914', (99, 102))
72704	28038466	Remarkably, loss of Chk2 did not affect the ability of oxali-Pt to induce p53-Ser20 phosphorylation and p21 expression.	('oxali-Pt', 'Chemical', 'MESH:D000077150', (55, 63))	('Ser20', 'Chemical', '-', (78, 83))	('p21', 'Gene', (104, 107))	('Chk2', 'Gene', '11200', (20, 24))	('p53', 'Gene', (74, 77))	('loss', 'Var', (12, 16))	('p21', 'Gene', '644914', (104, 107))	('expression', 'Species', '29278', (108, 118))	('Chk2', 'Gene', (20, 24))	('p53', 'Gene', '7157', (74, 77))
72707	28038466	Loss of Chk2 led to a significant increase (~2- to 3-fold) in cis-Pt IC50 and, therefore, cis-Pt-resistance (Figure 4C).	('Chk2', 'Gene', '11200', (8, 12))	('Chk2', 'Gene', (8, 12))	('cis-Pt', 'Chemical', 'MESH:D002945', (62, 68))	('cis-Pt-resistance', 'MPA', (90, 107))	('cis-Pt IC50', 'MPA', (62, 73))	('cis-Pt', 'Chemical', 'MESH:D002945', (90, 96))	('increase', 'PosReg', (34, 42))	('Loss', 'Var', (0, 4))
72708	28038466	Conversely, ectopic re-expression of Chk2 in A2780 Chk2-/- clones restored cis-Pt-induced p53 transcriptional activity (Figure 4D) and cytotoxic sensitivity (IC50: control, 0.74 vs. Chk2-ki, 0.55 muM) (Figure 4E).	('p53', 'Gene', (90, 93))	('muM', 'Gene', '56925', (196, 199))	('cis-Pt-induced', 'MPA', (75, 89))	('Chk2', 'Gene', '11200', (37, 41))	('cis-Pt', 'Chemical', 'MESH:D002945', (75, 81))	('Chk2', 'Gene', (37, 41))	('p53', 'Gene', '7157', (90, 93))	('cytotoxic sensitivity', 'CPA', (135, 156))	('muM', 'Gene', (196, 199))	('A2780', 'Var', (45, 50))	('Chk2', 'Gene', '11200', (51, 55))	('restored', 'PosReg', (66, 74))	('Chk2', 'Gene', (51, 55))	('Chk2', 'Gene', '11200', (182, 186))	('expression', 'Species', '29278', (23, 33))	('Chk2', 'Gene', (182, 186))
72711	28038466	In either group, Pt-sensitive patients with relatively high levels of Chk2 were found to have significantly greater overall survival by 4-11 months (Figure 4F).	('Chk2', 'Gene', (70, 74))	('overall survival', 'CPA', (116, 132))	('greater', 'PosReg', (108, 115))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (55, 59))	('Chk2', 'Gene', '11200', (70, 74))
72717	28038466	Specifically, MAPK members ERK1/2 and MEK1/2 can transcriptionally activate p53 and MEK inhibitor U0126 is reported to induce cis-Pt resistance.	('p53', 'Gene', (76, 79))	('U0126', 'Var', (98, 103))	('induce', 'PosReg', (119, 125))	('p53', 'Gene', '7157', (76, 79))	('cis-Pt resistance', 'CPA', (126, 143))	('MEK', 'Gene', (38, 41))	('cis-Pt', 'Chemical', 'MESH:D002945', (126, 132))	('MEK', 'Gene', '5609', (38, 41))	('U0126', 'Chemical', 'MESH:C113580', (98, 103))	('MEK', 'Gene', '5609', (84, 87))	('MEK1/2', 'Gene', '5604;5605', (38, 44))	('MEK', 'Gene', (84, 87))	('activate', 'PosReg', (67, 75))	('MEK1/2', 'Gene', (38, 44))
72721	28038466	On the other hand, oxali-Pt-induced p53-Ser20 phosphorylation and p21 transactivation in 2780CP/Cl-16 cells were inhibited by the selective MEK1/2 inhibitors (MEKi) U0126 and PD98059 (Figures 5B and 5C).	('p21', 'Gene', (66, 69))	('MEK', 'Gene', (140, 143))	('Ser20', 'Chemical', '-', (40, 45))	('inhibited', 'NegReg', (113, 122))	('PD98059', 'Var', (175, 182))	('p53', 'Gene', (36, 39))	('p21', 'Gene', '644914', (66, 69))	('p53', 'Gene', '7157', (36, 39))	('MEK', 'Gene', (159, 162))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (19, 27))	('MEK', 'Gene', '5609', (159, 162))	('MEK', 'Gene', '5609', (140, 143))	('PD98059', 'Chemical', 'MESH:C093973', (175, 182))	('MEK1/2', 'Gene', '5604;5605', (140, 146))	('U0126', 'Chemical', 'MESH:C113580', (165, 170))	('MEK1/2', 'Gene', (140, 146))
72726	28038466	The p53 pathway when functionally activated through post-translational modifications plays a major role in mediating Pt chemotherapy response.	('p53', 'Gene', '7157', (4, 7))	('Pt chemotherapy', 'Disease', (117, 132))	('activated', 'PosReg', (34, 43))	('post-translational modifications', 'Var', (52, 84))	('p53', 'Gene', (4, 7))
72727	28038466	Therefore, it is not surprising that loss of p53 function through mutation has been identified as an important mechanism leading to cis-Pt resistance.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('leading', 'Reg', (121, 128))	('function', 'MPA', (49, 57))	('loss', 'NegReg', (37, 41))	('mutation', 'Var', (66, 74))	('cis-Pt', 'Chemical', 'MESH:D002945', (132, 138))	('cis-Pt resistance', 'MPA', (132, 149))
72728	28038466	In HGSOC, the high p53 mutation rate of 86%, based on TCGA data shown in Figure 1C, presents a major therapeutic barrier.	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('mutation', 'Var', (23, 31))
72735	28038466	Although Chk2 activated by cis-Pt has been reported to phosphorylate Ser20 and its knock-down in A2780 cells reduces the ability of cis-Pt to induce p21 in a p53-dependent manner, MEK1/2 has not been associated previously with phosphorylation at Ser20.	('Ser20', 'Chemical', '-', (246, 251))	('Chk2', 'Gene', '11200', (9, 13))	('p53', 'Gene', '7157', (158, 161))	('p21', 'Gene', (149, 152))	('MEK1/2', 'Gene', '5604;5605', (180, 186))	('Chk2', 'Gene', (9, 13))	('MEK1/2', 'Gene', (180, 186))	('cis-Pt', 'Chemical', 'MESH:D002945', (27, 33))	('knock-down', 'Var', (83, 93))	('p21', 'Gene', '644914', (149, 152))	('induce', 'PosReg', (142, 148))	('Ser20', 'Chemical', '-', (69, 74))	('p53', 'Gene', (158, 161))	('cis-Pt', 'Chemical', 'MESH:D002945', (132, 138))	('reduces', 'NegReg', (109, 116))
72739	28038466	These drug-dependent local distortions in damaged DNA are, therefore, recognized independently by specialized proteins, such as specific members of the high mobility group box (HMGB) and mismatch repair (MMR) families that bind only cis-Pt-DNA adducts, but not oxali-Pt adducts.	('oxali-Pt', 'Chemical', 'MESH:D000077150', (261, 269))	('cis-Pt', 'Chemical', 'MESH:D002945', (233, 239))	('bind', 'Interaction', (223, 227))	('adducts', 'Var', (244, 251))	('cis-Pt-DNA adducts', 'Var', (233, 251))
72744	28038466	Although several sites in p53 are amenable to phosphorylation following DNA damage, modifications at Ser15 and Ser20 are reported as most critical for its anti-proliferative and apoptotic functions.	('apoptotic functions', 'CPA', (178, 197))	('Ser20', 'Var', (111, 116))	('modifications', 'Var', (84, 97))	('p53', 'Gene', (26, 29))	('Ser15', 'Var', (101, 106))	('Ser15', 'Chemical', '-', (101, 106))	('p53', 'Gene', '7157', (26, 29))	('anti-proliferative', 'CPA', (155, 173))	('Ser20', 'Chemical', '-', (111, 116))
72747	28038466	This is in agreement with the report that Ser15 phosphorylation is more effective in stabilizing p53.	('p53', 'Gene', (97, 100))	('Ser15', 'Chemical', '-', (42, 47))	('Ser15 phosphorylation', 'Var', (42, 63))	('p53', 'Gene', '7157', (97, 100))	('stabilizing', 'MPA', (85, 96))
72748	28038466	An important discovery in our study was the substantial cis-Pt resistance in the four cell lines whether they harbored wild-type (polymorphic) or mutant p53.	('mutant', 'Var', (146, 152))	('p53', 'Gene', '7157', (153, 156))	('p53', 'Gene', (153, 156))	('cis-Pt', 'Chemical', 'MESH:D002945', (56, 62))	('cis-Pt resistance', 'MPA', (56, 73))
72749	28038466	The fact that both wild-type or mutant p53 in these resistant cells was functionally activated by oxali-Pt indicates that V172F and G266R mutations found in 2780CP/Cl-16 and/or OVCAR-10 cells were not inactivating, although the p53 functional FASAY database predicted these p53 mutants as inactive.	('V172F', 'Mutation', 'rs1131691043', (122, 127))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('p53', 'Gene', (274, 277))	('G266R', 'Var', (132, 137))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('G266R', 'Mutation', 'rs1057519990', (132, 137))	('p53', 'Gene', '7157', (274, 277))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (98, 106))	('V172F', 'Var', (122, 127))
72752	28038466	Our data nonetheless indicate that the specific mutations per se were not the inactivating event, but rather the loss of Ser20 phosphorylation due to downregulation of Chk2 in the four cell lines was the primary driver of resistance of the cell lines to cis-Pt.	('cis-Pt', 'Chemical', 'MESH:D002945', (254, 260))	('downregulation', 'NegReg', (150, 164))	('mutations', 'Var', (48, 57))	('loss', 'NegReg', (113, 117))	('Chk2', 'Gene', '11200', (168, 172))	('Ser20', 'Protein', (121, 126))	('Ser20', 'Chemical', '-', (121, 126))	('Chk2', 'Gene', (168, 172))
72754	28038466	The functional competency of the specific p53 mutants in our study is also consistent with a reported detailed analysis demonstrating that of 2,314 distinct missense p53 mutants, almost 64% retained p53 activity comparable to that of wild-type p53.	('p53', 'Gene', (42, 45))	('p53', 'Gene', (199, 202))	('p53', 'Gene', (244, 247))	('p53', 'Gene', '7157', (244, 247))	('p53', 'Gene', '7157', (199, 202))	('p53', 'Gene', '7157', (42, 45))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('mutants', 'Var', (170, 177))	('missense', 'Var', (157, 165))	('activity', 'MPA', (203, 211))
72755	28038466	This raises the intriguing possibility that some of the p53 mutants in HGSOC that were identified as functionally inactive from our FASAY databank mining may in fact be functional.	('HGSOC', 'Gene', (71, 76))	('mutants', 'Var', (60, 67))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (56, 59))
72756	28038466	In a similar manner, the data with HEY and OVCA-433 suggests that cis-Pt resistance in clinical tumors harboring polymorphic/wild-type p53 may also be at the level of a defect in post-translational phosphorylation at Ser20.	('polymorphic/wild-type', 'Var', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Ser20', 'Protein', (217, 222))	('defect', 'NegReg', (169, 175))	('p53', 'Gene', (135, 138))	('post-translational phosphorylation', 'MPA', (179, 213))	('p53', 'Gene', '7157', (135, 138))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('cis-Pt', 'Chemical', 'MESH:D002945', (66, 72))	('Ser20', 'Chemical', '-', (217, 222))	('cis-Pt resistance', 'MPA', (66, 83))	('HEY', 'CellLine', 'CVCL:0297', (35, 38))
72757	28038466	In summary, our present study demonstrates that Ser20 phosphorylation of p53 dictates cytotoxic response to cis-Pt and oxali-Pt, and loss of this post-translational phosphorylation in absence of Chk2 prevents p53 activation by cis-Pt and this leads to drug resistance.	('p53', 'Gene', '7157', (73, 76))	('Chk2', 'Gene', (195, 199))	('loss', 'Var', (133, 137))	('p53', 'Gene', (73, 76))	('Ser20', 'Chemical', '-', (48, 53))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (119, 127))	('dictates', 'Reg', (77, 85))	('Chk2', 'Gene', '11200', (195, 199))	('activation', 'PosReg', (213, 223))	('cytotoxic response to cis-Pt', 'MPA', (86, 114))	('cis-Pt', 'Chemical', 'MESH:D002945', (227, 233))	('cis-Pt', 'Chemical', 'MESH:D002945', (108, 114))	('p53', 'Gene', '7157', (209, 212))	('leads to', 'Reg', (243, 251))	('prevents', 'NegReg', (200, 208))	('Ser20 phosphorylation', 'MPA', (48, 69))	('drug resistance', 'MPA', (252, 267))	('drug resistance', 'Phenotype', 'HP:0020174', (252, 267))	('p53', 'Gene', (209, 212))
72759	28038466	More significantly, Ser20 phosphorylation of specific p53 mutants with oxali-Pt also activates p53 function, and this raises the likelihood that other p53 mutants in refractory human ovarian cancers could also be functionally activated with distinct drugs, such as oxali-Pt, to restore therapeutic sensitivity.	('ovarian cancers', 'Disease', (183, 198))	('ovarian cancers', 'Disease', 'MESH:D010051', (183, 198))	('mutants', 'Var', (155, 162))	('function', 'MPA', (99, 107))	('p53', 'Gene', '7157', (95, 98))	('human', 'Species', '9606', (177, 182))	('p53', 'Gene', '7157', (151, 154))	('mutants', 'Var', (58, 65))	('Ser20 phosphorylation', 'MPA', (20, 41))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('activates', 'PosReg', (85, 94))	('p53', 'Gene', (151, 154))	('ovarian cancers', 'Phenotype', 'HP:0100615', (183, 198))	('p53', 'Gene', (54, 57))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (71, 79))	('Ser20', 'Chemical', '-', (20, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('oxali-Pt', 'Chemical', 'MESH:D000077150', (265, 273))
72769	28038466	The ERK- and MEK-specific inhibitors, SCH772984 (S7101) and U0126 (S1102), respectively, were purchased from Selleckchem Chemicals.	('MEK', 'Gene', '5609', (13, 16))	('SCH772984 (S7101', 'Var', (38, 54))	('S7101', 'Var', (49, 54))	('S1102', 'Var', (67, 72))	('ERK', 'Gene', '5594', (4, 7))	('U0126', 'Chemical', 'MESH:C113580', (60, 65))	('SCH772984', 'Chemical', 'MESH:C587178', (38, 47))	('ERK', 'Gene', (4, 7))	('MEK', 'Gene', (13, 16))
72774	28038466	Ovarian cancer cells growing in tissue culture dishes were trypsinized, diluted to appropriate concentrations, and 100 muL/well aliquots plated in 96-well plates to achieve the following densities: A2780, 200 cells/well; 2780CP/Cl-16, 500 cells/well; OVCAR-10, 500 cells/well; HEY, 150 cells/well; and OVCA-433, 300 cells/well.	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('HEY', 'CellLine', 'CVCL:0297', (277, 280))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('2780CP/Cl-16', 'Var', (221, 233))	('ach', 'Chemical', 'MESH:D000109', (165, 168))	('Ovarian cancer', 'Disease', (0, 14))
72779	28038466	A 0.5 microg of p53, 1 microg of S20A or 0.5 microg of S20D plasmid aliquot was transfected into A2780-p53-/- cells in 6-well plates using Lipofectamine 2000 (Life Technologies) for 48 hr, following the manufacturer's recommended protocol.	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('S20D', 'Var', (55, 59))	('p53', 'Gene', (16, 19))	('p53', 'Gene', '7157', (16, 19))	('S20D', 'SUBSTITUTION', 'None', (55, 59))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (139, 157))	('S20A', 'Var', (33, 37))	('S20A', 'SUBSTITUTION', 'None', (33, 37))
72782	28038466	CRISPR plasmids TP53 (HS0000019748, NM_001126117), CHEK2 (HS0000041294, NM_001005735) and universal negative control (CRISPR08) were purchased from Sigma-Aldrich.	('NM_001005735', 'Var', (72, 84))	('NM_001126117', 'Var', (36, 48))	('CHEK2', 'Gene', '11200', (51, 56))	('CHEK2', 'Gene', (51, 56))	('TP53', 'Gene', '7157', (16, 20))	('HS0000041294', 'Var', (58, 70))	('HS0000019748', 'Var', (22, 34))	('TP53', 'Gene', (16, 20))
72786	28038466	2780CP/Cl-16 cells were seeded into 6-well plates and incubated overnight at 37 C. Cells were then treated for 1 hr with DMSO, 1.5 microM of ERK1/2 inhibitor SCH772984, 100 microM of MEK1/2 inhibitor PD98059 or 10 microM of the MEK1/2 inhibitor U0126.	('MEK1/2', 'Gene', '5604;5605', (228, 234))	('MEK1/2', 'Gene', (228, 234))	('MEK1/2', 'Gene', '5604;5605', (183, 189))	('SCH772984', 'Chemical', 'MESH:C587178', (158, 167))	('MEK1/2', 'Gene', (183, 189))	('U0126', 'Chemical', 'MESH:C113580', (245, 250))	('DMSO', 'Chemical', 'MESH:D004121', (121, 125))	('PD98059', 'Var', (200, 207))	('PD98059', 'Chemical', 'MESH:C093973', (200, 207))
72794	28038466	The Log-rank test assessed association between TP53 mutation status (wild-type vs. mutant) and overall survival, as depicted in Kaplan-Meyer curves.	('association', 'Interaction', (27, 38))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('mutant', 'Var', (83, 89))
72798	28038466	Mutations of p53 in tumors of HGSOC patients from the TCGA database and in ovarian cancer cell lines were evaluated for their effect on p53 function using the yeast FASAY data stored in a p53 database (http://p53.fr).	('ovarian cancer', 'Disease', 'MESH:D010051', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('yeast', 'Species', '4932', (159, 164))	('p53', 'Gene', '7157', (136, 139))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (36, 44))	('ovarian cancer', 'Disease', (75, 89))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('p53', 'Gene', '7157', (13, 16))	('p53', 'Gene', '7157', (188, 191))	('p53', 'Gene', (136, 139))	('tumors', 'Disease', (20, 26))	('p53', 'Gene', (188, 191))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (209, 212))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('p53', 'Gene', (209, 212))
72799	28038466	The mutation was assessed against eight gene promoters targeted by wild-type, and the number of promoters activated by each mutant p53 was quantified.	('mutant', 'Var', (124, 130))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('ach', 'Chemical', 'MESH:D000109', (120, 123))
72803	23372565	Dysregulation during migration of primordial germ cells has previously been suspected to be a part of TGCC development and this set of multiple rare variants may thereby have a minor contribution to an increased susceptibility of TGCCs.	('TGCCs', 'Disease', (230, 235))	('men', 'Species', '9606', (114, 117))	('variants', 'Var', (149, 157))
72814	23372565	The contribution of such rare, or even rarer, variants, to complex disease susceptibility is to a large extent unknown, but they seem to play an important role in psychiatric disorders (International Schizophrenia Consortium,; Pinto et al.,) and they have been indicated to influence childhood obesity (Glessner et al.,).	('psychiatric disorders', 'Disease', (163, 184))	('Schizophrenia', 'Phenotype', 'HP:0100753', (200, 213))	('childhood obesity', 'Phenotype', 'HP:0008915', (284, 301))	('role', 'Reg', (155, 159))	('obesity', 'Disease', 'MESH:D009765', (294, 301))	('influence', 'Reg', (274, 283))	('play', 'Reg', (137, 141))	('obesity', 'Disease', (294, 301))	('psychiatric disorders', 'Disease', 'MESH:D001523', (163, 184))	('variants', 'Var', (46, 54))	('Schizophrenia', 'Disease', (200, 213))	('Schizophrenia', 'Disease', 'MESH:D012559', (200, 213))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (163, 184))	('obesity', 'Phenotype', 'HP:0001513', (294, 301))
72815	23372565	Further, identification of de novo mutations is possible in studies of family-trios and recently three de novo CNVs were found in 3 out of 43 TGCC trios, a frequency higher than found in two other cancer types (Stadler et al.,), highlighting the paradigm of rare genetic events influencing susceptibility to TGCC.	('TGCC', 'Disease', (308, 312))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('TGCC', 'Disease', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mutations', 'Var', (35, 44))
72820	23372565	The CNV frequencies of the three clusters were in perfect agreement with those from the histogram analysis of the array-data, thereby corroborating that deletion of GSTM1 had no association to TGCC.	('men', 'Species', '9606', (63, 66))	('deletion', 'Var', (153, 161))	('association', 'Interaction', (178, 189))	('GSTM1', 'Gene', '2944', (165, 170))	('GSTM1', 'Gene', (165, 170))	('TGCC', 'Disease', (193, 197))
72824	23372565	The CNV at PTPN1 involved five cases, all found to have a heterozygous deletion at the same intronic region (Figure 2).	('PTPN1', 'Gene', '5770', (11, 16))	('PTPN1', 'Gene', (11, 16))	('deletion', 'Var', (71, 79))
72825	23372565	CNVs at KCNB2 were found at three different loci: four and one deletions at two different introns and one deletion and one duplication at the promoter (Figure 2).	('KCNB2', 'Gene', (8, 13))	('KCNB2', 'Gene', '9312', (8, 13))	('deletions', 'Var', (63, 72))
72827	23372565	We attempted to verify the CNV at PTPN1 by performing qPCR on the affected samples, but all five samples with an indication of a heterozygous deletion in the array-data were observed to have two copies in the qPCR.	('deletion', 'Var', (142, 150))	('PTPN1', 'Gene', '5770', (34, 39))	('PTPN1', 'Gene', (34, 39))
72838	23372565	Further, CNVs at the 20q13 chromosomal region have been observed in several other cancers (Nishizaki et al.,; Schaid,; Furukawa et al.,).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('observed', 'Reg', (56, 64))	('Schaid', 'Disease', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('CNVs', 'Var', (9, 13))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))
72839	23372565	Furthermore, all affected probands in this study presented a deletion, consistent with a tumor suppressing function of oncogenic kinases, and PTPN1 has been shown to be able to play both a pro- and anti-oncogenic role (Stuible et al.,).	('deletion', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PTPN1', 'Gene', '5770', (142, 147))	('PTPN1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
72841	23372565	However, despite the stringent QC the qPCR did not verify the heterozygous deletion of PTPN1 in any of the samples.	('PTPN1', 'Gene', '5770', (87, 92))	('deletion', 'Var', (75, 83))	('PTPN1', 'Gene', (87, 92))
72844	23372565	For instance, mutations of the KIT receptor, or the KIT ligand, in the mouse, blocks PGC migration, resulting in infertility (Matzuk and Lamb,).	('blocks', 'NegReg', (78, 84))	('resulting in', 'Reg', (100, 112))	('KIT ligand', 'Gene', (52, 62))	('PGC', 'Protein', (85, 88))	('KIT ligand', 'Gene', '17311', (52, 62))	('infertility', 'Phenotype', 'HP:0000789', (113, 124))	('infertility', 'Disease', 'MESH:D007247', (113, 124))	('mouse', 'Species', '10090', (71, 76))	('mutations', 'Var', (14, 23))	('infertility', 'Disease', (113, 124))
72845	23372565	In addition, a disturbance of the migration of PGCs during early fetal development may cause extragonadal germ cell cancers along the midline of the body (Oosterhuis and Looijenga,).	('PGCs', 'Protein', (47, 51))	('germ cell cancer', 'Phenotype', 'HP:0100728', (106, 122))	('cell cancers', 'Disease', (111, 123))	('cause', 'Reg', (87, 92))	('cell cancers', 'Disease', 'MESH:C538614', (111, 123))	('extragonadal', 'Disease', (93, 105))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('men', 'Species', '9606', (78, 81))	('disturbance', 'Var', (15, 26))	('migration', 'CPA', (34, 43))
72846	23372565	One of the afflicted genes in the "regulation of cell migration" gene set was PTPRK, at which two samples had a deletion.	('PTPRK', 'Gene', (78, 83))	('PTPRK', 'Gene', '5796', (78, 83))	('deletion', 'Var', (112, 120))
72854	23372565	Apart from such gene-environment interactions it is probable that part of the unexplained heritability can be explained by gene-gene interactions, where a combination of several genetic variations cause a greater effect on the phenotype than the sum of their individual effects (epistasis).	('phenotype', 'MPA', (227, 236))	('men', 'Species', '9606', (28, 31))	('variations', 'Var', (186, 196))	('effect', 'Reg', (213, 219))
72861	23372565	Finally, rare CNVs that had more than 50% overlap with segmental duplication regions (retrieved from UCSC hg18) were removed, since such regions have been shown to generate more false CNV calls (Pinto et al.,).	('false CNV calls', 'MPA', (178, 193))	('men', 'Species', '9606', (58, 61))	('regions', 'Var', (137, 144))
72864	23372565	Gene sets were retrieved from KEGG (Kyoto Encyclopedia of Genes and Genomes; Ogata et al.,), Reactome (D'Eustachio,), BioCarta1, NCI-Nature curated pathways (Pathway Interaction Database; Schaefer et al.,), GO (Gene Ontology; Ashburner et al.,), COSMIC (Catalog of Somatic Mutations In Cancer; Forbes et al.,), Cyclebase (Gauthier et al.,), protein-protein interaction complexes (Lage et al.,), OMIM (Online Mendelian Inheritance in Man2), MGI (Mouse Genome Informatics3) and a set of candidate infertility genes from a recent review (Matzuk and Lamb,).	('infertility', 'Disease', 'MESH:D007247', (495, 506))	('infertility', 'Phenotype', 'HP:0000789', (495, 506))	('infertility', 'Disease', (495, 506))	('Mutations', 'Var', (273, 282))	('Man2', 'Gene', '100036499', (433, 437))	('Mouse', 'Species', '10090', (445, 450))	('Man2', 'Gene', (433, 437))	('protein-protein', 'Protein', (341, 356))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))
72898	19491204	Similarly, exposure to either DBP or MBP results in a high incidence of cryptorchidism, while MBP exposure in rats also results in reduced fertility in some male offspring.	('cryptorchidism', 'Disease', 'MESH:D003456', (72, 86))	('MBP', 'Var', (94, 97))	('reduced fertility', 'Phenotype', 'HP:0000144', (131, 148))	('cryptorchidism', 'Phenotype', 'HP:0000028', (72, 86))	('reduced', 'NegReg', (131, 138))	('rats', 'Species', '10116', (110, 114))	('DBP', 'Chemical', 'MESH:D003993', (30, 33))	('fertility', 'CPA', (139, 148))	('MBP', 'Var', (37, 40))	('cryptorchidism', 'Disease', (72, 86))
72900	19491204	Furthermore, fetal testosterone production in mice is unaffected by DBP, MBP or monoethylhexyl phthalate (MEHP).	('MBP', 'Var', (73, 76))	('monoethylhexyl phthalate', 'Chemical', 'MESH:C016599', (80, 104))	('mice', 'Species', '10090', (46, 50))	('fetal', 'CPA', (13, 18))	('MEHP', 'Chemical', 'MESH:C016599', (106, 110))	('DBP', 'Chemical', 'MESH:D003993', (68, 71))	('DBP', 'Var', (68, 71))	('testosterone', 'Chemical', 'MESH:D013739', (19, 31))
72901	19491204	In contrast, phthalate effects on germ cell numbers and/or differentiation in the fetal testis have been shown in mice, rats and in vitro in the human.	('rats', 'Species', '10116', (120, 124))	('phthalate', 'Var', (13, 22))	('human', 'Species', '9606', (145, 150))	('germ cell numbers', 'CPA', (34, 51))	('differentiation in the fetal testis', 'CPA', (59, 94))	('phthalate', 'Chemical', 'MESH:C032279', (13, 22))	('effects', 'Reg', (23, 30))	('mice', 'Species', '10090', (114, 118))
72951	19491204	When killed, no gross abnormalities of the epididymis, vas deferens, prostate or seminal vesicles were apparent in MBP-exposed males or in controls (data not shown).	('abnormalities of the epididymis', 'Disease', (22, 53))	('MBP-exposed', 'Var', (115, 126))	('vas', 'Gene', (55, 58))	('abnormalities of the epididymis', 'Phenotype', 'HP:0009714', (22, 53))	('abnormalities of the epididymis', 'Disease', 'MESH:D000014', (22, 53))	('vas', 'Gene', '24221', (55, 58))
72961	19491204	2B), AP2gamma and C-KIT (not shown), indicating that they were undifferentiated gonocytes.	('C-KIT', 'Gene', '3815', (18, 23))	('AP2gamma', 'Var', (5, 13))	('C-KIT', 'Gene', (18, 23))
72966	19491204	Multinucleated gonocytes are induced by DBP treatment of rats, but none were found in MBP-exposed marmosets or controls.	('men', 'Species', '9606', (49, 52))	('induced', 'Reg', (29, 36))	('marmosets', 'Species', '38020', (98, 107))	('DBP', 'Var', (40, 43))	('DBP', 'Chemical', 'MESH:D003993', (40, 43))	('Multinucleated gonocytes', 'CPA', (0, 24))	('rats', 'Species', '10116', (57, 61))
72969	19491204	There was a non-significant trend towards an increase in the germ cell:Sertoli cell ratio in MBP-exposed animals (Fig.	('Sertoli cell', 'Phenotype', 'HP:0100619', (71, 83))	('rat', 'Species', '10116', (84, 87))	('MBP-exposed', 'Var', (93, 104))	('germ cell', 'CPA', (61, 70))	('increase', 'PosReg', (45, 53))
72972	19491204	Testis weights in MBP-treated co-twins were comparable to controls (Table III).	('MBP-treated', 'Var', (18, 29))	('Testis weight', 'Disease', 'MESH:D013736', (0, 13))	('Testis weight', 'Disease', (0, 13))
72983	19491204	One of the major effects of DBP/MBP exposure in rats is inhibition of testosterone production by the fetal testis which leads to downstream effects such as reduced anogenital distance, cryptorchidism and hypospadias in occasional animals and reduced Sertoli cell number at birth.	('inhibition', 'NegReg', (56, 66))	('cryptorchidism', 'Phenotype', 'HP:0000028', (185, 199))	('hypospadias', 'Disease', 'MESH:D007021', (204, 215))	('Sertoli cell number', 'CPA', (250, 269))	('DBP', 'Chemical', 'MESH:D003993', (28, 31))	('rats', 'Species', '10116', (48, 52))	('reduced', 'NegReg', (242, 249))	('hypospadias', 'Disease', (204, 215))	('DBP/MBP', 'Var', (28, 35))	('reduced', 'NegReg', (156, 163))	('testosterone production', 'MPA', (70, 93))	('testosterone', 'Chemical', 'MESH:D013739', (70, 82))	('anogenital distance', 'CPA', (164, 183))	('cryptorchidism', 'Disease', (185, 199))	('reduced anogenital distance', 'Phenotype', 'HP:0003241', (156, 183))	('cryptorchidism', 'Disease', 'MESH:D003456', (185, 199))	('hypospadias', 'Phenotype', 'HP:0000047', (204, 215))	('Sertoli cell', 'Phenotype', 'HP:0100619', (250, 262))
73022	32235691	The analysis of epigenetic modification and non-coding RNA microRNAs (miRNAs) are carrying most promising potential as tumor markers in future.	('epigenetic modification', 'Var', (16, 39))	('tumor', 'Disease', (119, 124))	('non-coding RNA', 'Var', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
73025	32235691	Studies showed that miR-371a-3p and miR-302/367 expression significantly differ between testicular tumors and healthy testicular tissue.	('miR-371a-3p', 'Chemical', '-', (20, 31))	('miR-371a-3p', 'Var', (20, 31))	('differ', 'Reg', (73, 79))	('testicular tumors', 'Disease', 'MESH:D013736', (88, 105))	('testicular tumors', 'Phenotype', 'HP:0010788', (88, 105))	('testicular tumor', 'Phenotype', 'HP:0010788', (88, 104))	('miR-302/367', 'Gene', '442912', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('testicular tumors', 'Disease', (88, 105))	('miR-302/367', 'Gene', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
73027	32235691	In addition, other miRNAs such as miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, and miR-214 will be discussed in this review.	('miR-449', 'Var', (46, 53))	('miR-223-3p', 'Chemical', '-', (34, 44))	('miR-383', 'Gene', '494332', (55, 62))	('miR-199a-3p', 'Gene', '406977', (77, 88))	('miR-514a-3p', 'Gene', '574518', (64, 75))	('miR-514a-3p', 'Gene', (64, 75))	('miR-214', 'Gene', '406996', (94, 101))	('miR-383', 'Gene', (55, 62))	('miR-223-3p', 'Var', (34, 44))	('miR-199a-3p', 'Gene', (77, 88))	('miR-214', 'Gene', (94, 101))
73045	32235691	Especially miRNAs of the miR-371-373 cluster (but also others, including miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, miR-214) are considered potential new tumor markers.	('miR-514a-3p', 'Gene', (103, 114))	('miR-449', 'Var', (85, 92))	('miR-371', 'Gene', (25, 32))	('miR-223-3p', 'Var', (73, 83))	('miR-383', 'Gene', (94, 101))	('miR-214', 'Gene', '406996', (129, 136))	('miR-199a-3p', 'Gene', '406977', (116, 127))	('miR-214', 'Gene', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('miR-383', 'Gene', '494332', (94, 101))	('miR-371', 'Gene', '442916', (25, 32))	('miR-223-3p', 'Chemical', '-', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('miR-514a-3p', 'Gene', '574518', (103, 114))	('tumor', 'Disease', (167, 172))	('miR-199a-3p', 'Gene', (116, 127))
73069	32235691	Cross-reactions of LH in beta-hCG assays can simulate elevated levels.	('beta-hCG', 'Chemical', '-', (25, 33))	('Cross-reactions', 'Var', (0, 15))	('beta-hCG', 'Protein', (25, 33))
73086	32235691	Genomic hypomethylation is generally found in tumors and hypermethylation at certain loci.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('found', 'Reg', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('hypomethylation', 'Var', (8, 23))	('tumors', 'Disease', (46, 52))	('hypermethylation', 'Var', (57, 73))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
73087	32235691	Hypomethylation increases with the dedifferentiation of testicular cancer.	('testicular cancer', 'Disease', 'MESH:D013736', (56, 73))	('testicular cancer', 'Disease', (56, 73))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increases', 'PosReg', (16, 25))	('testicular cancer', 'Phenotype', 'HP:0010788', (56, 73))
73092	32235691	Hypermethylation of APC, p16, and PTSG2 genes show high specificity and may be potential biomarkers.	('p16', 'Gene', (25, 28))	('Hypermethylation', 'Var', (0, 16))	('PTSG2', 'Gene', (34, 39))	('APC', 'Disease', 'MESH:D011125', (20, 23))	('APC', 'Disease', (20, 23))	('p16', 'Gene', '1029', (25, 28))
73102	32235691	miRNAs can prevent the transformation to cancer, but in the case of abnormal expression patterns, they may also promote it.	('expression', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('promote', 'PosReg', (112, 119))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('abnormal', 'Var', (68, 76))
73111	32235691	In their genome-wide analysis of the Cancer Genome data set, the authors identified six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) as strong predictors of survival in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (208, 225))	('miR-221', 'Gene', (120, 127))	('colorectal cancer', 'Disease', (208, 225))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('miR-188-3p', 'Chemical', '-', (108, 118))	('miR-221', 'Gene', '407006', (120, 127))	('miR-331', 'Gene', (132, 139))	('miR-425-3p', 'Gene', '100422914', (144, 154))	('miR-425-3p', 'Gene', (144, 154))	('miR-188-3p', 'Var', (108, 118))	('predictors', 'Reg', (182, 192))	('miR-331', 'Gene', '442903', (132, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (208, 225))	('miR-92b-3p', 'Var', (96, 106))	('Cancer', 'Disease', (37, 43))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('miR-497', 'Gene', (160, 167))	('miR-497', 'Gene', '574456', (160, 167))
73112	32235691	One of them, miR-188-3p increased the migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo.	('metastases', 'Disease', (97, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('miR-188-3p', 'Var', (13, 23))	('migratory behavior of', 'CPA', (38, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-188-3p', 'Chemical', '-', (13, 23))	('colorectal cancer', 'Disease', (60, 77))	('increased', 'PosReg', (24, 33))
73113	32235691	Furthermore, the authors could link miR-188-3p to MLLT4, a novel identified player involved in colorectal cancer cell.	('MLLT4', 'Gene', '4301', (50, 55))	('colorectal cancer', 'Disease', (95, 112))	('miR-188-3p', 'Var', (36, 46))	('MLLT4', 'Gene', (50, 55))	('miR-188-3p', 'Chemical', '-', (36, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('link', 'Reg', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
73122	32235691	miR-302 also inhibits the expression of other cell cycle inhibitors (CDK2, CDK4) and thus accelerates the transition from G1 phase to S phase.	('expression', 'MPA', (26, 36))	('transition', 'CPA', (106, 116))	('G1 phase', 'CPA', (122, 130))	('CDK4', 'Gene', (75, 79))	('CDK2', 'Gene', (69, 73))	('CDK4', 'Gene', '1019', (75, 79))	('accelerates', 'PosReg', (90, 101))	('CDK2', 'Gene', '1017', (69, 73))	('S phase', 'CPA', (134, 141))	('miR-302', 'Chemical', '-', (0, 7))	('inhibits', 'NegReg', (13, 21))	('miR-302', 'Var', (0, 7))
73128	32235691	Inhibition of miR-302 suppresses SPRY4, which subsequently decreases cell growth and invasion.	('SPRY4', 'Gene', '81848', (33, 38))	('suppresses', 'NegReg', (22, 32))	('decreases', 'NegReg', (59, 68))	('miR-302', 'Chemical', '-', (14, 21))	('miR-302', 'Gene', (14, 21))	('Inhibition', 'Var', (0, 10))	('SPRY4', 'Gene', (33, 38))	('cell growth', 'CPA', (69, 80))
73142	32235691	miR-367-3p was more elevated in seminomas than in non-seminomas.	('seminomas', 'Disease', 'MESH:D018239', (54, 63))	('miR-367-3p', 'Chemical', '-', (0, 10))	('miR-367-3p', 'Var', (0, 10))	('seminomas', 'Disease', (54, 63))	('seminomas', 'Disease', 'MESH:D018239', (32, 41))	('elevated', 'PosReg', (20, 28))	('seminomas', 'Disease', (32, 41))
73143	32235691	After performing orchiectomy, miR-367-3p decreased or was no longer detectable.	('decreased', 'NegReg', (41, 50))	('miR-367-3p', 'Var', (30, 40))	('miR-367-3p', 'Chemical', '-', (30, 40))	('orchiectomy', 'Disease', (17, 28))
73144	32235691	Another study in pediatric germ cell tumors analyzing cerebrospinal fluid and serum demonstrated that a four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) possesses high sensitivity/specificity for diagnosing pediatric extracranial malignant GCT, allows early detection of relapse of a testicular mixed malignant germ cell tumor, and distinguishes intracranial malignant germ cell tumors from intracranial non-germ cell tumours at diagnosis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('extracranial malignant GCT', 'Disease', (244, 270))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('germ cell tumor', 'Phenotype', 'HP:0100728', (27, 42))	('miR-372', 'Gene', (141, 148))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (406, 412))	('tumours', 'Disease', (445, 452))	('tumor', 'Disease', (406, 411))	('relapse', 'CPA', (298, 305))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('germ cell tumors', 'Phenotype', 'HP:0100728', (396, 412))	('tumors', 'Disease', (37, 43))	('miR-372', 'Gene', '442917', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('tumors', 'Disease', 'MESH:D009369', (406, 412))	('tumours', 'Phenotype', 'HP:0002664', (445, 452))	('tumours', 'Disease', 'MESH:D009369', (445, 452))	('miR-367-3p', 'Chemical', '-', (168, 178))	('miR-367-3p', 'Var', (168, 178))	('germ cell tumor', 'Phenotype', 'HP:0100728', (396, 411))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('miR-373', 'Gene', (153, 160))	('germ cell tumors', 'Phenotype', 'HP:0100728', (27, 43))	('miR-371a-3p', 'Chemical', '-', (128, 139))	('germ cell tumor', 'Phenotype', 'HP:0100728', (338, 353))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (348, 353))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('miR-373', 'Gene', '442918', (153, 160))
73149	32235691	Though some retrospective studies propose superiority of miR-371-3p to predict viable tumor tissue after chemotherapy and disease recurrence after curative treatment, others propose a value for miR-367-3p in indicating chemotherapy-refractory disease.	('miR-371-3p', 'Gene', '100500855', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('chemotherapy-refractory disease', 'Disease', (219, 250))	('miR-371-3p', 'Gene', (57, 67))	('miR-367-3p', 'Chemical', '-', (194, 204))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('miR-367-3p', 'Var', (194, 204))	('men', 'Species', '9606', (161, 164))
73154	32235691	MiR-371-373 and miR-302 clusters are universally overexpressed in malignant GCTs and coordinately down-regulate mRNAs involved in biologically significant pathways.	('down-regulate', 'NegReg', (98, 111))	('MiR-371', 'Gene', '442916', (0, 7))	('miR-302', 'Chemical', '-', (16, 23))	('overexpressed', 'PosReg', (49, 62))	('miR-302 clusters', 'Var', (16, 32))	('mRNAs', 'MPA', (112, 117))	('MiR-371', 'Gene', (0, 7))
73156	32235691	The substitution of mutant p53 and inhibition of Ras-induced senescence are functions of miR-371-373 up-regulation in TGCTs.	('miR-371', 'Gene', (89, 96))	('p53', 'Gene', '7157', (27, 30))	('up-regulation', 'PosReg', (101, 114))	('miR-371', 'Gene', '442916', (89, 96))	('Ras-induced', 'CPA', (49, 60))	('substitution', 'Var', (4, 16))	('inhibition', 'NegReg', (35, 45))	('mutant', 'Var', (20, 26))	('p53', 'Gene', (27, 30))
73158	32235691	Numerous studies described miR-371a-3p as a suitable tumor marker in TGCT patients in follow-up, recurrence detection, prognosis, diagnostics, and staging.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('patients', 'Species', '9606', (74, 82))	('miR-371a-3p', 'Var', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TGCT', 'Disease', (69, 73))	('tumor', 'Disease', (53, 58))	('miR-371a-3p', 'Chemical', '-', (27, 38))
73160	32235691	In this study, the authors reported much higher serum levels of miRNA-371-3p in TGCT patients than in healthy controls.	('miRNA-371-3p', 'Var', (64, 76))	('serum levels', 'MPA', (48, 60))	('patients', 'Species', '9606', (85, 93))	('higher', 'PosReg', (41, 47))	('TGCT', 'Disease', (80, 84))
73165	32235691	In tumors with germ cell neoplasia in situ (GCNIS) as precursor, as well as in non-GCNIS tumors, no association was found between the expression of miR-371a-3p and the level of serum markers, tumor stage and age of the patients.	('tumors', 'Disease', (89, 95))	('GCNIS', 'Chemical', '-', (44, 49))	('germ cell neoplasia', 'Phenotype', 'HP:0100728', (15, 34))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('neoplasia', 'Disease', 'MESH:D009369', (25, 34))	('neoplasia', 'Disease', (25, 34))	('tumor', 'Disease', (3, 8))	('miR-371a-3p', 'Chemical', '-', (148, 159))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', (192, 197))	('neoplasia', 'Phenotype', 'HP:0002664', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', (3, 9))	('GCNIS', 'Chemical', '-', (83, 88))	('miR-371a-3p', 'Var', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
73169	32235691	The expression level of miR-371a-3p was only slightly increased in teratomas.	('teratomas', 'Disease', (67, 76))	('teratomas', 'Disease', 'MESH:D013724', (67, 76))	('expression level', 'MPA', (4, 20))	('miR-371a-3p', 'Var', (24, 35))	('increased', 'PosReg', (54, 63))	('teratoma', 'Phenotype', 'HP:0009792', (67, 75))	('teratomas', 'Phenotype', 'HP:0009792', (67, 76))	('miR-371a-3p', 'Chemical', '-', (24, 35))
73171	32235691	Nonetheless, higher levels of miR-371a-3p expression were found in all tumor types than in healthy tissue.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('higher', 'PosReg', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('miR-371a-3p', 'Chemical', '-', (30, 41))	('tumor', 'Disease', (71, 76))	('miR-371a-3p', 'Var', (30, 41))
73175	32235691	Since only one in two patients with precursors of TGCTs had elevated serum levels and there were also contradictory results reported from other research groups, miR-371a-3p cannot replace a biopsy to differentiate between pre-cursor lesions and TGCT, but it may help with unclear histological results.	('miR-371a-3p', 'Var', (161, 172))	('serum levels', 'MPA', (69, 81))	('patients', 'Species', '9606', (22, 30))	('pre-cursor lesions', 'Disease', (222, 240))	('TGCT', 'Disease', (245, 249))	('miR-371a-3p', 'Chemical', '-', (161, 172))
73176	32235691	A recently published case report suggest a discriminative power of miR-371a-3p to differentiate between unspecific AFP elevations.	('miR-371a-3p', 'Var', (67, 78))	('miR-371a-3p', 'Chemical', '-', (67, 78))	('AFP', 'Gene', '174', (115, 118))	('AFP', 'Gene', (115, 118))
73186	32235691	Thus, miR-371a-3p not only plays a role in TGCT diagnostics, but could also serve as a biomarker for male infertility.	('TGCT', 'Disease', (43, 47))	('miR-371a-3p', 'Chemical', '-', (6, 17))	('miR-371a-3p', 'Var', (6, 17))	('infertility', 'Phenotype', 'HP:0000789', (106, 117))	('male infertility', 'Phenotype', 'HP:0003251', (101, 117))	('male infertility', 'Disease', (101, 117))	('male infertility', 'Disease', 'MESH:D007248', (101, 117))
73187	32235691	A prospective study investigated serum levels of miR-371a-3p, miR-372, and miR-373-3p in 24 patients with seminoma and non-seminomatous tumors.	('miR-373', 'Gene', '442918', (75, 82))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('miR-371a-3p', 'Chemical', '-', (49, 60))	('miR-373', 'Gene', (75, 82))	('seminoma', 'Disease', (123, 131))	('miR-371a-3p', 'Var', (49, 60))	('miR-372', 'Gene', (62, 69))	('patients', 'Species', '9606', (92, 100))	('seminoma', 'Disease', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('miR-372', 'Gene', '442917', (62, 69))	('seminoma', 'Disease', 'MESH:D018239', (123, 131))	('seminoma', 'Disease', 'MESH:D018239', (106, 114))	('non-seminomatous tumors', 'Disease', 'MESH:C537844', (119, 142))	('non-seminomatous tumors', 'Disease', (119, 142))
73188	32235691	All three miRNAs had significantly higher serum levels before orchiectomy than postoperatively, with miR-371a-3p decreasing most rapidly after surgery.	('serum levels', 'MPA', (42, 54))	('miR-371a-3p', 'Chemical', '-', (101, 112))	('higher', 'PosReg', (35, 41))	('miR-371a-3p', 'Var', (101, 112))
73191	32235691	In a large-scale prospective multicenter study, the serum levels of miR-371a-3p in a total of 616 patients with TGCT at different stages and 258 healthy men were recorded and compared with AFP, beta-hCG, and LDH.	('patients', 'Species', '9606', (98, 106))	('men', 'Species', '9606', (153, 156))	('miR-371a-3p', 'Var', (68, 79))	('AFP', 'Gene', (189, 192))	('miR-371a-3p', 'Chemical', '-', (68, 79))	('beta-hCG', 'Chemical', '-', (194, 202))	('AFP', 'Gene', '174', (189, 192))
73195	32235691	This can be attributed to metastases, which probably express miR-371a-3p.	('miR-371a-3p', 'Var', (61, 72))	('miR-371a-3p', 'Chemical', '-', (61, 72))	('metastases', 'Disease', 'MESH:D009362', (26, 36))	('metastases', 'Disease', (26, 36))
73206	32235691	described the influence of miR-371a-3p on progression-free-survival (PFS) and overall survival (OS) of TGCT patients.	('miR-371a-3p', 'Var', (27, 38))	('influence', 'Reg', (14, 23))	('TGCT', 'Disease', (103, 107))	('patients', 'Species', '9606', (108, 116))	('progression-free-survival', 'CPA', (42, 67))	('overall', 'MPA', (78, 85))	('miR-371a-3p', 'Chemical', '-', (27, 38))
73210	32235691	No association was found between miR-371a-3p and conventional tumor markers.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('miR-371a-3p', 'Chemical', '-', (33, 44))	('miR-371a-3p', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
73213	32235691	miR-20a-5p, miR-30b-5p, miR-93-5p and miR-191-5p were proposed as reference miRNAs and were commonly used in the analysis of miR-371a-3p and miR-372-3p.	('miR-93', 'Gene', '407051', (24, 30))	('miR-191', 'Gene', '406966', (38, 45))	('miR-93', 'Gene', (24, 30))	('miR-20a-5p', 'Var', (0, 10))	('miR-371a-3p', 'Chemical', '-', (125, 136))	('miR-30b', 'Gene', '407030', (12, 19))	('miR-30b', 'Gene', (12, 19))	('miR-372', 'Gene', (141, 148))	('miR-191', 'Gene', (38, 45))	('miR-371a-3p', 'Var', (125, 136))	('miR-372', 'Gene', '442917', (141, 148))
73216	32235691	As a further consequence, the determination of miR-371a-3p and miR-372-3p (which themselves are not affected by hemolysis) can be falsified, thus adversely affecting the diagnosis.	('affecting', 'Reg', (156, 165))	('miR-372', 'Gene', '442917', (63, 70))	('miR-372', 'Gene', (63, 70))	('hemolysis', 'Disease', (112, 121))	('miR-371a-3p', 'Chemical', '-', (47, 58))	('hemolysis', 'Disease', 'MESH:D006461', (112, 121))	('miR-371a-3p', 'Var', (47, 58))
73218	32235691	In summary, miR-371a-3p is currently considered a very suitable tumor marker for TGCTs, although further prospective studies have to follow in order to identify advantages and limitations.	('tumor', 'Disease', (64, 69))	('miR-371a-3p', 'Chemical', '-', (12, 23))	('TGCTs', 'Disease', (81, 86))	('miR-371a-3p', 'Var', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
73220	32235691	Although the expression of miR-372 and miR-373 differ in patients with healthy testes and those with TGCT, the diagnostic performance of miR-371a-3p is much better.	('miR-371a-3p', 'Var', (137, 148))	('expression', 'MPA', (13, 23))	('miR-373', 'Gene', '442918', (39, 46))	('patients', 'Species', '9606', (57, 65))	('miR-373', 'Gene', (39, 46))	('miR-372', 'Gene', (27, 34))	('differ', 'Reg', (47, 53))	('miR-371a-3p', 'Chemical', '-', (137, 148))	('miR-372', 'Gene', '442917', (27, 34))
73221	32235691	In a study of different serum miRNAs in TGCTs, the highest measurable levels were miR-371a-3p and these correlated most with the occurrence of testicular tumors (miR-371a-3p > miR-372a-3p > miR-373a-3p).	('miR-371a-3p', 'Var', (82, 93))	('miR-372', 'Gene', '442917', (176, 183))	('miR-373', 'Gene', '442918', (190, 197))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('miR-373', 'Gene', (190, 197))	('miR-371a-3p', 'Chemical', '-', (162, 173))	('testicular tumors', 'Disease', 'MESH:D013736', (143, 160))	('testicular tumors', 'Phenotype', 'HP:0010788', (143, 160))	('testicular tumor', 'Phenotype', 'HP:0010788', (143, 159))	('miR-371a-3p', 'Chemical', '-', (82, 93))	('miR-372', 'Gene', (176, 183))	('testicular tumors', 'Disease', (143, 160))
73224	32235691	miR-517a-3p, miR-519a-3p, and miR-519c-3p are three miRNAs that are part of the chromosome 19 miRNA cluster (C19MC), which is located near the miR-371-373 cluster.	('miR-371', 'Gene', (143, 150))	('miR-517a-3p', 'Var', (0, 11))	('miR-371', 'Gene', '442916', (143, 150))	('miR-519c-3p', 'Var', (30, 41))	('miR-519a-3p', 'Var', (13, 24))
73225	32235691	Overexpression of these miRNAs has already been found in various tumors and is associated with increased invasion, migration and poor overall survival.	('invasion', 'CPA', (105, 113))	('migration', 'CPA', (115, 124))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
73230	32235691	miR-223-3p is an important miRNA that plays a role in cell growth and apoptosis of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('miR-223-3p', 'Chemical', '-', (0, 10))	('cell growth', 'CPA', (54, 65))	('apoptosis', 'CPA', (70, 79))	('miR-223-3p', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
73232	32235691	F-box/WD repeat-containing protein 7 (FBXW7) is a tumor suppressor and one of the major targets of miR-223-3p.	('miR-223-3p', 'Chemical', '-', (99, 109))	('FBXW7', 'Gene', '55294', (38, 43))	('F-box/WD repeat-containing protein 7', 'Gene', (0, 36))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miR-223-3p', 'Var', (99, 109))	('FBXW7', 'Gene', (38, 43))	('F-box/WD repeat-containing protein 7', 'Gene', '55294', (0, 36))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
73233	32235691	Increased expression of miR-223-3p correlates with a decrease in FBWX7, which subsequently influences the progression of TGCTs.	('TGCTs', 'Disease', (121, 126))	('decrease', 'NegReg', (53, 61))	('miR-223-3p', 'Chemical', '-', (24, 34))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('miR-223-3p', 'Var', (24, 34))	('influences', 'Reg', (91, 101))	('FBWX7', 'Gene', (65, 70))
73234	32235691	In TGCTs, overexpression of miR-223-3p leads to the inhibition of apoptosis via FBWX7.	('miR-223-3p', 'Chemical', '-', (28, 38))	('FBWX7', 'Gene', (80, 85))	('apoptosis', 'CPA', (66, 75))	('overexpression', 'PosReg', (10, 24))	('miR-223-3p', 'Var', (28, 38))	('inhibition', 'NegReg', (52, 62))
73236	32235691	There are currently no studies on the use of miR-223-3p as a tumor marker, but it may be worth testing because of its role in tumorigenesis.	('miR-223-3p', 'Var', (45, 55))	('miR-223-3p', 'Chemical', '-', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (126, 131))
73241	32235691	This may be due to a mutation of retinoblastoma protein (pRB) that binds to E2F.	('due', 'Reg', (12, 15))	('pRB', 'Gene', (57, 60))	('retinoblastoma', 'Disease', 'MESH:D012175', (33, 47))	('retinoblastoma', 'Disease', (33, 47))	('mutation', 'Var', (21, 29))	('pRB', 'Gene', '5925', (57, 60))	('binds', 'Interaction', (67, 72))	('retinoblastoma', 'Phenotype', 'HP:0009919', (33, 47))
73268	32235691	In addition, epigenetic changes such as DNA methylation, histone modifications, or miRNAs carry great potential that can revolutionize the diagnosis of testicular tumors.	('testicular tumors', 'Phenotype', 'HP:0010788', (152, 169))	('testicular tumor', 'Phenotype', 'HP:0010788', (152, 168))	('epigenetic changes', 'Var', (13, 31))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('DNA methylation', 'Var', (40, 55))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('testicular tumors', 'Disease', (152, 169))	('testicular tumors', 'Disease', 'MESH:D013736', (152, 169))	('miRNAs', 'Var', (83, 89))	('histone modifications', 'Var', (57, 78))
73271	32235691	Many other miRNAs (miR-223-3p, miR-449, miR-383, miR-514a-3p, miR-199a-3p, miR-214) change their expression pattern during the transformation to malignant testicular tumors and may be considered as potential tumor markers or therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('miR-223-3p', 'Var', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('change', 'Reg', (84, 90))	('expression pattern', 'MPA', (97, 115))	('miR-214', 'Gene', (75, 82))	('miR-383', 'Gene', '494332', (40, 47))	('tumor', 'Disease', (208, 213))	('miR-383', 'Gene', (40, 47))	('testicular tumor', 'Phenotype', 'HP:0010788', (155, 171))	('miR-199a-3p', 'Gene', (62, 73))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('malignant testicular tumors', 'Disease', (145, 172))	('tumor', 'Disease', (166, 171))	('miR-199a-3p', 'Gene', '406977', (62, 73))	('miR-449', 'Var', (31, 38))	('miR-514a-3p', 'Gene', (49, 60))	('miR-223-3p', 'Chemical', '-', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('testicular tumors', 'Phenotype', 'HP:0010788', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('malignant testicular tumors', 'Disease', 'MESH:D013736', (145, 172))	('miR-214', 'Gene', '406996', (75, 82))	('miR-514a-3p', 'Gene', '574518', (49, 60))
73337	31355922	While a prior study noted TNM staging errors for GCT in SEER, this was largely driven by the S and N categories, which are avoided in the present analysis; the present cohort includes only M1a and M1b patients with identified sites of distant metastasis and excludes node-only disease.	('M1a', 'Var', (189, 192))	('TNM', 'Gene', '10178', (26, 29))	('patients', 'Species', '9606', (201, 209))	('TNM', 'Gene', (26, 29))
73367	30581773	Moreover, a previous epigenetic study showed that the promoter of some homeobox genes such as RASSF1A, SCGB3A1, and HOXA9 were hypermethylated in testicular cancer tumors, further supporting that deregulation of homeobox proteins may contribute to the development of TGCT.	('testicular cancer', 'Disease', (146, 163))	('homeobox genes', 'Gene', (71, 85))	('testicular cancer', 'Phenotype', 'HP:0010788', (146, 163))	('cancer tumors', 'Disease', (157, 170))	('deregulation', 'Var', (196, 208))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('contribute', 'Reg', (234, 244))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('SCGB3A1', 'Gene', '92304', (103, 110))	('HOXA9', 'Gene', (116, 121))	('hypermethylated', 'Var', (127, 142))	('RASSF1A', 'Gene', '11186', (94, 101))	('HOXA9', 'Gene', '3205', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('testicular cancer', 'Disease', 'MESH:D013736', (146, 163))	('SCGB3A1', 'Gene', (103, 110))	('cancer tumors', 'Disease', 'MESH:D009369', (157, 170))	('RASSF1A', 'Gene', (94, 101))	('men', 'Species', '9606', (259, 262))	('TGCT', 'Disease', (267, 271))
73368	30581773	Among the homeobox family genes, aberrant HOXA10 expressions have been implicated in numerous other types of cancers but not yet described in TGCT.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('implicated', 'Reg', (71, 81))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('expressions', 'MPA', (49, 60))	('HOXA10', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('aberrant', 'Var', (33, 41))
73371	30581773	In the setting of cancers, HOXA10 deregulation is known to play significant roles in mammary carcinoma, endometrial carcinoma, head and neck squamous cell carcinoma (HNSCC).	('HOXA10', 'Protein', (27, 33))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (104, 125))	('carcinoma', 'Disease', 'MESH:D002277', (116, 125))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('neck squamous cell carcinoma', 'Disease', (136, 164))	('cancers', 'Disease', (18, 25))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (136, 164))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (166, 171))	('carcinoma', 'Disease', (93, 102))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (127, 164))	('endometrial carcinoma', 'Disease', (104, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinoma', 'Disease', (116, 125))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (85, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('deregulation', 'Var', (34, 46))	('carcinoma', 'Disease', (155, 164))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (104, 125))	('roles', 'Reg', (76, 81))	('carcinoma', 'Disease', 'MESH:D002277', (93, 102))
73406	30581773	While highly expressed in spermatocytes of benign testes (HScore = 1.98 + 0.15), all cancerous testes had extremely low or no nuclear HOXA10 expression with HScores = 0.067 + 0.019 in seminoma, 0.207 + 0.06 in spermatocytic tumor, and 0 in non-seminoma.	('seminoma', 'Disease', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('non-seminoma', 'Disease', 'MESH:D018239', (240, 252))	('nuclear HOXA10', 'Protein', (126, 140))	('seminoma', 'Disease', 'MESH:D018239', (244, 252))	('spermatocytic tumor', 'Disease', 'MESH:C563236', (210, 229))	('non-seminoma', 'Disease', (240, 252))	('low', 'NegReg', (116, 119))	('seminoma', 'Disease', 'MESH:D018239', (184, 192))	('cancerous', 'Disease', (85, 94))	('expression', 'MPA', (141, 151))	('0.067 + 0.019', 'Var', (167, 180))	('seminoma', 'Disease', (244, 252))	('spermatocytic tumor', 'Disease', (210, 229))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancerous', 'Disease', 'MESH:D009369', (85, 94))
73416	30581773	These results suggest that aberrant HOXA10 expression may interrupt typical spermatocyte differentiations through altering cell cycles and cell proliferation, resulting in the development of TGCT.	('HOXA10', 'Gene', (36, 42))	('aberrant', 'Var', (27, 35))	('men', 'Species', '9606', (183, 186))	('cell cycles', 'CPA', (123, 134))	('interrupt', 'NegReg', (58, 67))	('expression', 'MPA', (43, 53))	('altering', 'Reg', (114, 122))	('cell proliferation', 'CPA', (139, 157))	('TGCT', 'Disease', (191, 195))	('typical spermatocyte differentiations', 'CPA', (68, 105))
73419	30581773	These results support that HOXA10 suppresses TGCT cell proliferation through the modulation of the TP53 signaling.	('TP53', 'Gene', (99, 103))	('HOXA10', 'Var', (27, 33))	('modulation', 'Reg', (81, 91))	('suppresses', 'NegReg', (34, 44))	('TGCT cell proliferation', 'CPA', (45, 68))	('TP53', 'Gene', '7157', (99, 103))
73420	30581773	Based on these results, we hypothesize that HOXA10 can enhance the functions of TP53 to suppress TGCT cell proliferation.	('enhance', 'PosReg', (55, 62))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('suppress', 'NegReg', (88, 96))	('functions', 'MPA', (67, 76))	('TGCT cell proliferation', 'CPA', (97, 120))	('HOXA10', 'Var', (44, 50))
73423	30581773	However, when cell cycling was synchronized at the G2/M phases by nocodazole and then released, HOXA10 caused significant delays of cell cycling passing through the G2/M phases into the G1 phase.	('delays', 'NegReg', (122, 128))	('cell cycling passing', 'CPA', (132, 152))	('nocodazole', 'Chemical', 'MESH:D015739', (66, 76))	('HOXA10', 'Var', (96, 102))
73424	30581773	First, we observed that HOXA10 transfection induced TP53 expression (Figure 5A).	('induced', 'Reg', (44, 51))	('HOXA10 transfection', 'Var', (24, 43))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
73426	30581773	Furthermore, upregulation of TP53 by HOXA10 was concurrent with the induction of cyclin-dependent kinase inhibitor p21, but not p27 (Figure 5A).	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('p27', 'Gene', (128, 131))	('upregulation', 'PosReg', (13, 25))	('HOXA10', 'Var', (37, 43))	('p21', 'Gene', (115, 118))	('p21', 'Gene', '644914', (115, 118))	('p27', 'Gene', '3429', (128, 131))
73428	30581773	Interestingly, cyclin D1 protein levels were reduced by HOXA10 in NT-2 and NCCIT but not the TCam2 cells, while cyclin E expression was suppressed by HOXA10 in TCam2 and NCCIT, but not the NT-2 cells.	('reduced', 'NegReg', (45, 52))	('suppressed', 'NegReg', (136, 146))	('cyclin D1', 'Gene', '595', (15, 24))	('HOXA10', 'Var', (56, 62))	('cyclin E expression', 'MPA', (112, 131))	('cyclin D1', 'Gene', (15, 24))
73429	30581773	Nevertheless, HOXA10 stimulates the TP53 and putatively the TP53-p21 axis, thereby exerting general inhibitory effects to all TGCT cell models regardless the inconsistent changes in cyclin D and cyclin E expressions.	('cyclin', 'MPA', (195, 201))	('p21', 'Gene', (65, 68))	('p21', 'Gene', '644914', (65, 68))	('cyclin', 'MPA', (182, 188))	('TP53', 'Gene', '7157', (36, 40))	('stimulates', 'PosReg', (21, 31))	('HOXA10', 'Var', (14, 20))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (36, 40))	('TP53', 'Gene', (60, 64))
73435	30581773	HOXA10 reduced pSTAT3 levels in the NCCIT cells, and abolished pSTAT3 expression in both TCam2 and NT-2 cells.	('reduced', 'NegReg', (7, 14))	('STAT3', 'Gene', '6774', (16, 21))	('HOXA10', 'Var', (0, 6))	('STAT3', 'Gene', (16, 21))	('STAT3', 'Gene', '6774', (64, 69))	('abolished', 'NegReg', (53, 62))	('STAT3', 'Gene', (64, 69))
73436	30581773	Furthermore, phosphorylated AKT and Erk kinases as the downstream effectors of the cKit and MAPK1 pathways were also inhibited by HOXA10.	('MAPK1', 'Gene', (92, 97))	('AKT', 'Gene', (28, 31))	('cKit', 'Gene', '3815', (83, 87))	('Erk', 'Gene', (36, 39))	('MAPK1', 'Gene', '5594', (92, 97))	('inhibited', 'NegReg', (117, 126))	('Erk', 'Gene', '5594', (36, 39))	('AKT', 'Gene', '207', (28, 31))	('cKit', 'Gene', (83, 87))	('HOXA10', 'Var', (130, 136))	('phosphorylated', 'MPA', (13, 27))
73437	30581773	These results indicate that HOXA10 not only stimulates the TP53-p21 axis, but also suppresses the cKit and STAT3 pathways to inhibit testicular cell proliferation (Figure 5D), supporting that loss of HOXA10 functions is associated with testicular cancers.	('cKit', 'Gene', '3815', (98, 102))	('stimulates', 'PosReg', (44, 54))	('testicular cancer', 'Phenotype', 'HP:0010788', (236, 253))	('cKit', 'Gene', (98, 102))	('testicular cell proliferation', 'CPA', (133, 162))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('suppresses', 'NegReg', (83, 93))	('p21', 'Gene', (64, 67))	('p21', 'Gene', '644914', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('TP53', 'Gene', (59, 63))	('testicular cancers', 'Disease', 'MESH:D013736', (236, 254))	('testicular cancers', 'Phenotype', 'HP:0010788', (236, 254))	('testicular cancers', 'Disease', (236, 254))	('inhibit', 'NegReg', (125, 132))	('STAT3', 'Gene', (107, 112))	('associated', 'Reg', (220, 230))	('STAT3', 'Gene', '6774', (107, 112))	('TP53', 'Gene', '7157', (59, 63))	('loss', 'Var', (192, 196))
73443	30581773	In addition, since HOXA10 tyrosine phosphorylation was reported to have reduced its DNA-binding activities, disruptions in HOXA10 phosphorylation regulators such as JAK2 and phosphatases SHP1/SHP2 may contribute to the cytoplasmic localization.	('contribute', 'Reg', (201, 211))	('disruptions', 'Var', (108, 119))	('reduced', 'NegReg', (72, 79))	('SHP1', 'Gene', '5777', (187, 191))	('tyrosine', 'Var', (26, 34))	('HOXA10', 'Gene', (19, 25))	('JAK2', 'Gene', '3717', (165, 169))	('cytoplasmic', 'MPA', (219, 230))	('DNA-binding', 'Interaction', (84, 95))	('SHP1', 'Gene', (187, 191))	('JAK2', 'Gene', (165, 169))	('SHP2', 'Gene', '5781', (192, 196))	('SHP2', 'Gene', (192, 196))	('tyrosine', 'Chemical', 'MESH:D014443', (26, 34))
73449	30581773	The latter mechanisms are more likely to be true at least in NCCIT cells, which have mutated TP53 in contrast to that of TCam2 and NT-2 cells.	('TP53', 'Gene', '7157', (93, 97))	('mutated', 'Var', (85, 92))	('TP53', 'Gene', (93, 97))
73459	30581773	However, TCam2 cells have mutated BRAF genes uncommonly seen in TGCT tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TGCT tumors', 'Disease', 'MESH:C563236', (64, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('BRAF', 'Gene', '673', (34, 38))	('mutated', 'Var', (26, 33))	('BRAF', 'Gene', (34, 38))	('TGCT tumors', 'Disease', (64, 75))
73463	30581773	Although our study is the first to report clinical and functional significances of HOXA10 in testicular cancer, it is interesting that HOXA10 mutations were reported to be linked to higher incidence of inguino-scrotal cryptorchidism and that cryptorchidism is one of the strongest risk factors for testicular cancer.	('mutations', 'Var', (142, 151))	('HOXA10', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('testicular cancer', 'Disease', (93, 110))	('cryptorchidism', 'Disease', (242, 256))	('testicular cancer', 'Disease', 'MESH:D013736', (298, 315))	('testicular cancer', 'Phenotype', 'HP:0010788', (298, 315))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('inguino-scrotal cryptorchidism', 'Disease', (202, 232))	('inguino-scrotal cryptorchidism', 'Disease', 'MESH:D003456', (202, 232))	('cryptorchidism', 'Phenotype', 'HP:0000028', (242, 256))	('cryptorchidism', 'Phenotype', 'HP:0000028', (218, 232))	('testicular cancer', 'Phenotype', 'HP:0010788', (93, 110))	('testicular cancer', 'Disease', 'MESH:D013736', (93, 110))	('testicular cancer', 'Disease', (298, 315))
73464	30581773	These finding, together, suggest that TGCT tumorigenesis likely happens both in utero and after birth, and that dysfunctional HOXA10 may aid the tumorigenic process throughout development.	('TGCT', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('dysfunctional', 'Var', (112, 125))	('men', 'Species', '9606', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('aid', 'PosReg', (137, 140))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('HOXA10', 'Protein', (126, 132))
73467	30581773	In summary, we report that altered HOXA10 localization is associated with TGCT and that loss of nuclear HOXA10 canonical function results in attenuated TP53 signaling and increased cell cycling through regulating the G2/M checkpoint.	('altered', 'Var', (27, 34))	('G2/M checkpoint', 'MPA', (217, 232))	('associated', 'Reg', (58, 68))	('attenuated', 'NegReg', (141, 151))	('HOXA10', 'Protein', (35, 41))	('localization', 'MPA', (42, 54))	('TP53', 'Gene', '7157', (152, 156))	('loss', 'NegReg', (88, 92))	('regulating', 'Reg', (202, 212))	('HOXA10', 'Gene', (104, 110))	('TP53', 'Gene', (152, 156))	('cell cycling', 'CPA', (181, 193))	('TGCT', 'Disease', (74, 78))	('increased', 'PosReg', (171, 180))
73545	26893743	However, the results of the single-factor analysis in the present study indicated that HCG level variations did not affect the prognosis of testicular seminoma (P=0.055) while LDH and AFP levels were statistically significant with regard to prognosis (P=0.022; P=0.029).	('AFP', 'Gene', (184, 187))	('AFP', 'Gene', '174', (184, 187))	('testicular seminoma', 'Phenotype', 'HP:0100617', (140, 159))	('HCG', 'Gene', '93659', (87, 90))	('testicular seminoma', 'Disease', (140, 159))	('HCG', 'Gene', (87, 90))	('testicular seminoma', 'Disease', 'MESH:D018239', (140, 159))	('variations', 'Var', (97, 107))
73600	22068818	MGMT, VGF, ER-beta and FKBP4 were predominately methylated in NSEs compared with SEs.	('MGMT', 'Gene', (0, 4))	('VGF', 'Gene', (6, 9))	('VGF', 'Gene', '7425', (6, 9))	('SE', 'Disease', 'None', (63, 65))	('methylated', 'Var', (48, 58))	('NSEs', 'Chemical', '-', (62, 66))	('ER-beta', 'Gene', '2100', (11, 18))	('FKBP4', 'Gene', (23, 28))	('SE', 'Disease', 'None', (81, 83))	('FKBP4', 'Gene', '2288', (23, 28))	('ER-beta', 'Gene', (11, 18))	('MGMT', 'Gene', '4255', (0, 4))
73614	22068818	The importance of epigenetic alterations has long been demonstrated in carcinogenesis.	('epigenetic alterations', 'Var', (18, 40))	('carcinogenesis', 'Disease', (71, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
73615	22068818	Several studies have shown that methylation-associated silencing inactivates certain tumour suppressor genes (TSGs) as effectively as mutations and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('TSG', 'Gene', (110, 113))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (162, 168))	('tumour', 'Disease', (85, 91))	('TSG', 'Gene', '57045', (110, 113))	('silencing inactivates', 'NegReg', (55, 76))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('methylation-associated', 'Var', (32, 54))
73616	22068818	In normal cells, CpG methylation is an important mechanism for regulating gene expression, whereas in cancer cells, aberrant promoter methylation (hypermethylation) can lead to abnormal gene silencing, including repression of TSGs.	('lead', 'Reg', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gene', 'MPA', (186, 190))	('TSG', 'Gene', '57045', (226, 229))	('promoter methylation', 'MPA', (125, 145))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('repression', 'NegReg', (212, 222))	('TSG', 'Gene', (226, 229))	('aberrant', 'Var', (116, 124))
73671	22068818	hMLH1 was significantly methylated in TGCT (39% (22 out of 57)) in comparison with normal (4% (1 out of 23)); P=0.002, by Fisher's exact test).	('TGCT', 'Disease', (38, 42))	('hMLH1', 'Gene', (0, 5))	('methylated', 'Var', (24, 34))	('hMLH1', 'Gene', '4292', (0, 5))
73674	22068818	At least one TSG locus was methylated in 37 out of 43 SE cases (86%), and a total of 11 out of 43 (25.6%) tumour samples showed methylation at three or more of the loci.	('TSG', 'Gene', '57045', (13, 16))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('methylated', 'Var', (27, 37))	('SE', 'Disease', 'None', (54, 56))	('tumour', 'Disease', (106, 112))	('TSG', 'Gene', (13, 16))	('methylation', 'Var', (128, 139))
73688	22068818	Results indicated that association of hMLH1 hypermethylation with tumour remained positive (OR=8.29; 95% CI=0.66-103.5), albeit no statistical significance (P=0.100).	('association', 'Interaction', (23, 34))	('hMLH1', 'Gene', (38, 43))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('hMLH1', 'Gene', '4292', (38, 43))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('hypermethylation', 'Var', (44, 60))	('tumour', 'Disease', (66, 72))
73708	22068818	Remarkably, both SE and NSE were methylated for APC and hMLH1.	('SE', 'Disease', 'None', (25, 27))	('SE', 'Disease', 'None', (17, 19))	('APC', 'Gene', (48, 51))	('hMLH1', 'Gene', (56, 61))	('APC', 'Gene', '324', (48, 51))	('hMLH1', 'Gene', '4292', (56, 61))	('methylated', 'Var', (33, 43))
73711	22068818	), using conventional MSP, analysed a panel of 21 genes and observed a near absence of methylation in SEs and a higher percentage in NSEs, suggesting a role for different panel of methylation-induced inactivation of TSGs in two common types of TGCT.	('absence', 'NegReg', (76, 83))	('NSEs', 'Chemical', '-', (133, 137))	('TSG', 'Gene', '57045', (216, 219))	('SE', 'Disease', 'None', (134, 136))	('methylation', 'MPA', (87, 98))	('inactivation', 'NegReg', (200, 212))	('TSG', 'Gene', (216, 219))	('SE', 'Disease', 'None', (102, 104))	('methylation-induced', 'Var', (180, 199))
73715	22068818	In breast cancer,) observed that the presence of promoter methylation in DAPK was frequent in invasive lobular cancer (53%) and not frequent in another histological subtype (9% invasive ductal carcinoma).	('promoter methylation', 'Var', (49, 69))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (186, 202))	('lobular cancer', 'Phenotype', 'HP:0030076', (103, 117))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (177, 202))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('invasive lobular cancer', 'Disease', (94, 117))	('frequent', 'Reg', (82, 90))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('DAPK', 'Gene', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('invasive lobular cancer', 'Disease', 'MESH:D013274', (94, 117))	('invasive ductal carcinoma', 'Disease', (177, 202))
73716	22068818	Other reports that include different epigenetic alterations in histological subtypes of the same cancer type include: presence of methylator phenotype in low-grade gliomas when compared with de novo glioblastomas, high frequency of SFN methylation in small cell lung cancer, whereas a rare frequency in non-small cell lung cancer.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (307, 329))	('glioblastomas', 'Disease', 'MESH:D005909', (199, 212))	('gliomas', 'Disease', 'MESH:D005910', (164, 171))	('SFN', 'Gene', (232, 235))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (303, 329))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('methylation', 'Var', (236, 247))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('small cell lung cancer', 'Disease', 'MESH:D055752', (251, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (318, 329))	('cancer', 'Disease', (267, 273))	('non-small cell lung cancer', 'Disease', (303, 329))	('small cell lung cancer', 'Disease', 'MESH:D055752', (307, 329))	('small cell lung cancer', 'Disease', (251, 273))	('glioblastomas', 'Phenotype', 'HP:0012174', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (323, 329))	('SFN', 'Gene', '25996', (232, 235))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (303, 329))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('gliomas', 'Disease', (164, 171))	('glioblastomas', 'Disease', (199, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (251, 273))
73718	22068818	reported that Kit mutations are predominant in SEs and very rarely observed in NSEs.	('Kit', 'Gene', (14, 17))	('SE', 'Disease', 'None', (80, 82))	('NSEs', 'Chemical', '-', (79, 83))	('predominant', 'Reg', (32, 43))	('SE', 'Disease', 'None', (47, 49))	('mutations', 'Var', (18, 27))
73719	22068818	Previous studies did indicate a role for hypermethylation of TSG promoters in the pathogenesis of SE.	('TSG', 'Gene', (61, 64))	('hypermethylation', 'Var', (41, 57))	('TSG', 'Gene', '57045', (61, 64))	('SE', 'Disease', 'None', (98, 100))
73720	22068818	In our data, when comparing SEs versus NT samples, the genes that showed higher frequency of methylation in SE were PGP9.5, hMLH1 and ER-beta, when compared with the observed frequency in normal samples.	('ER-beta', 'Gene', '2100', (134, 141))	('PGP9.5', 'Gene', (116, 122))	('SE', 'Disease', 'None', (28, 30))	('ER-beta', 'Gene', (134, 141))	('hMLH1', 'Gene', (124, 129))	('PGP9.5', 'Gene', '7345', (116, 122))	('methylation', 'Var', (93, 104))	('hMLH1', 'Gene', '4292', (124, 129))	('SE', 'Disease', 'None', (108, 110))
73727	22068818	APC was previously observed with 10% of methylation in tumours and 0% in NT, but both positive tumours were NSE, and no APC methylation has been reported in Ses; it is important to emphasise that this study was performed using conventional MSP, a less sensitive technique than QMSP used in the present study, which may explain the different percentages observed.	('methylation', 'Var', (40, 51))	('tumours', 'Disease', (55, 62))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('APC', 'Gene', (0, 3))	('APC', 'Gene', (120, 123))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('APC', 'Gene', '324', (120, 123))	('SE', 'Disease', 'None', (109, 111))	('tumours', 'Disease', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('APC', 'Gene', '324', (0, 3))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
73732	22068818	In 2004,) showed methylation in MGMT in 20% of NSEs analysed by conventional MSP, a less sensitive technique as mentioned earlier.	('NSEs', 'Disease', (47, 51))	('NSEs', 'Chemical', '-', (47, 51))	('methylation', 'Var', (17, 28))	('MGMT', 'Gene', '4255', (32, 36))	('MGMT', 'Gene', (32, 36))	('men', 'Species', '9606', (112, 115))
73733	22068818	Using empiric cutoffs, at least one of the three genes (hMLH1, APC and ER-beta) was methylated in 13 out of 14 (93%) of NSE cases and 10 out of 23 (43%) of the NT samples.	('ER-beta', 'Gene', (71, 78))	('SE', 'Disease', 'None', (121, 123))	('APC', 'Gene', (63, 66))	('hMLH1', 'Gene', (56, 61))	('hMLH1', 'Gene', '4292', (56, 61))	('methylated', 'Var', (84, 94))	('APC', 'Gene', '324', (63, 66))	('ER-beta', 'Gene', '2100', (71, 78))
73737	22068818	Epigenetic inactivation of hMLH1 is found in a wide range of cancers.	('hMLH1', 'Gene', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('found', 'Reg', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('hMLH1', 'Gene', '4292', (27, 32))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Epigenetic inactivation', 'Var', (0, 23))
73738	22068818	hMLH1 is a DNA mismatch repair (MMR) gene and is an essential component of the DNA MMR pathway, and is frequently mutated in hereditary non-polyposis colon cancer also known as Lynch syndrome.	('hMLH1', 'Gene', (0, 5))	('hereditary non-polyposis colon cancer', 'Disease', 'MESH:D015179', (125, 162))	('mutated', 'Var', (114, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (150, 162))	('hereditary non-polyposis colon cancer', 'Disease', (125, 162))	('hMLH1', 'Gene', '4292', (0, 5))	('Lynch syndrome', 'Disease', (177, 191))	('Lynch syndrome', 'Disease', 'MESH:D003123', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('hereditary non-polyposis colon cancer', 'Phenotype', 'HP:0006716', (125, 162))
73739	22068818	hMLH1 is the most prominent target of epigenetic silencing in the MMR pathway in sporadic tumours, comprising ovarian, head and neck, breast and colorectal cancer.	('hMLH1', 'Gene', (0, 5))	('sporadic tumours', 'Disease', 'MESH:D009369', (81, 97))	('epigenetic silencing', 'Var', (38, 58))	('MMR pathway', 'Pathway', (66, 77))	('ovarian', 'Disease', (110, 117))	('hMLH1', 'Gene', '4292', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('ovarian', 'Disease', 'MESH:D010051', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('sporadic tumours', 'Disease', (81, 97))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (134, 162))
73740	22068818	However, hypermethylation of hMLH1 is often associated with other hypermethylated genes, which complicates mechanistic interpretation of associations with response to therapy in patients.	('associated', 'Reg', (44, 54))	('hMLH1', 'Gene', '4292', (29, 34))	('patients', 'Species', '9606', (178, 186))	('hypermethylation', 'Var', (9, 25))	('hMLH1', 'Gene', (29, 34))
73742	22068818	Promoter methylation of hMLH1 has been associated with chemoresistance to cisplatin-based therapies in ovarian cancer more than a decade ago.	('associated with', 'Reg', (39, 54))	('hMLH1', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('hMLH1', 'Gene', '4292', (24, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('Promoter methylation', 'Var', (0, 20))	('chemoresistance to cisplatin-based therapies', 'MPA', (55, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('ovarian cancer', 'Disease', (103, 117))
73745	22068818	hypothesised that this epigenetic alteration could be linked to the chemoresistance in a small group of testicular tumours, but could not observe any association.	('epigenetic alteration', 'Var', (23, 44))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('testicular tumours', 'Disease', 'MESH:D013736', (104, 122))	('testicular tumours', 'Disease', (104, 122))	('chemoresistance', 'CPA', (68, 83))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('linked', 'Reg', (54, 60))
73748	22068818	It is widely accepted that hMLH1 dysfunction induces microsatellite instability (MSI) in various cancers, and loss of hMLH1 expression was related to its promoter methylation.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('loss', 'NegReg', (110, 114))	('hMLH1', 'Gene', '4292', (118, 123))	('MSI', 'Disease', (81, 84))	('cancers', 'Disease', (97, 104))	('hMLH1', 'Gene', (27, 32))	('microsatellite instability', 'MPA', (53, 79))	('induces', 'Reg', (45, 52))	('hMLH1', 'Gene', '4292', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('expression', 'MPA', (124, 134))	('MSI', 'Disease', 'None', (81, 84))	('hMLH1', 'Gene', (118, 123))	('dysfunction', 'Var', (33, 44))
73750	22068818	In our study, hMLH1 methylation was detected in 22 out of 57 (39%) of TGCTs.	('TGCTs', 'Disease', (70, 75))	('hMLH1', 'Gene', (14, 19))	('detected', 'Reg', (36, 44))	('hMLH1', 'Gene', '4292', (14, 19))	('methylation', 'Var', (20, 31))
73752	22068818	reported that promoter methylation of MGMT results in enhanced sensitivity to alkylating agents in gliomas.	('MGMT', 'Gene', '4255', (38, 42))	('promoter methylation', 'Var', (14, 34))	('sensitivity to alkylating agents', 'MPA', (63, 95))	('gliomas', 'Disease', (99, 106))	('gliomas', 'Disease', 'MESH:D005910', (99, 106))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('enhanced', 'PosReg', (54, 62))	('MGMT', 'Gene', (38, 42))
73753	22068818	In the present study, MGMT was highly methylated in NSEs, which could indicate that the epigenetic silencing of this gene may be also linked to the cisplatin-based chemotherapy response, but this data needs to be further explored in a well-defined cohort consisting of cisplatin responsive group and non-responsive group.	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (269, 278))	('methylated', 'Var', (38, 48))	('NSEs', 'Chemical', '-', (52, 56))	('MGMT', 'Gene', (22, 26))	('NSEs', 'Disease', (52, 56))	('MGMT', 'Gene', '4255', (22, 26))	('linked', 'Reg', (134, 140))	('epigenetic silencing', 'Var', (88, 108))
73765	29141149	Complexation with PtII significantly degrades colloidal stability of the conjugate; however, PEGylation provides substantial improvement of stability in conjunction with an insignificant trade-off in drug loading capacity compared with the non-PEGylated control (< 20 % decrease in loading capacity).	('stability', 'MPA', (140, 149))	('PEG', 'Chemical', 'MESH:D011092', (244, 247))	('degrades', 'NegReg', (37, 45))	('PEGylation', 'Var', (93, 103))	('PtII', 'Chemical', '-', (18, 22))	('improvement', 'PosReg', (125, 136))	('PEG', 'Chemical', 'MESH:D011092', (93, 96))	('colloidal stability of the conjugate', 'MPA', (46, 82))
73771	29141149	The relative molar mass of PEG had no significant influence on PtII uptake or release performance, while PEGylation substantially improved the colloidal stability of the conjugate.	('PEGylation', 'Var', (105, 115))	('PEG', 'Chemical', 'MESH:D011092', (105, 108))	('colloidal stability', 'MPA', (143, 162))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))	('improved', 'PosReg', (130, 138))	('PtII', 'Chemical', '-', (63, 67))
73772	29141149	Notably, the PtII release over 10 days (examined at 0.5 PtII/nm2 drug loading) remained constant for non-PEGylated, 1K-PEGylated and 5K-PEGylated conjugates.	('non-PEGylated', 'Var', (101, 114))	('PtII', 'Chemical', '-', (56, 60))	('1K-PEGylated', 'Var', (116, 128))	('PEG', 'Chemical', 'MESH:D011092', (105, 108))	('PtII release', 'MPA', (13, 25))	('5K-PEGylated', 'Var', (133, 145))	('PEG', 'Chemical', 'MESH:D011092', (119, 122))	('PEG', 'Chemical', 'MESH:D011092', (136, 139))	('PtII', 'Chemical', '-', (13, 17))
73775	29141149	The synergistic combination of PtII and ionizing radiation induces additional damage to DNA, and degrades cell viability through formation of toxic Pt intermediates and inhibition of the DNA repair process .	('DNA repair process', 'CPA', (187, 205))	('PtII', 'Chemical', '-', (31, 35))	('inhibition', 'NegReg', (169, 179))	('damage', 'MPA', (78, 84))	('Pt', 'Chemical', 'MESH:D010984', (31, 33))	('PtII', 'Var', (31, 35))	('DNA', 'Protein', (88, 91))	('Pt', 'Chemical', 'MESH:D010984', (148, 150))	('formation', 'MPA', (129, 138))	('degrades', 'NegReg', (97, 105))	('cell viability', 'CPA', (106, 120))
73787	29141149	In addition, PEGylation has been shown to enhance biocompatibility and delay clearance,  though quantifying these effects was beyond the scope of this study.	('clearance', 'MPA', (77, 86))	('enhance', 'PosReg', (42, 49))	('biocompatibility', 'MPA', (50, 66))	('PEGylation', 'Var', (13, 23))	('PEG', 'Chemical', 'MESH:D011092', (13, 16))	('delay', 'NegReg', (71, 76))
73800	29141149	Among the different structural forms of dendrons, we selected SH-G1-COOH because it yielded the highest loading capacity for cisplatin (PtII).	('COOH', 'Chemical', 'MESH:D002255', (68, 72))	('SH-G1-COOH', 'Var', (62, 72))	('loading capacity', 'MPA', (104, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))	('PtII', 'Chemical', '-', (136, 140))	('dendrons', 'Chemical', 'MESH:D050091', (40, 48))
73832	29141149	The ratio can be measured quantitatively by ICP-MS as:  where IPt(cps) and IAu(cps) represents the signal intensity of 195Pt and 197Au detected by ICP-MS in counts per second (cps); SAuNP and VAuNP are the surface area and volume of a single AuNP (in this case, these parameters are obtained from the DMA diameter dp and assuming spherical geometry); Mm,Au and rhoAu are the molar mass and density of Au, and Nav is Avogadro's number; alphaAu-Pt is a calibration factor taking into account the relative sensitivity of ICP-MS for 197Au and 195Pt (see SI Figure S2 (a)-(b)).	('Au', 'Chemical', 'MESH:D006046', (242, 244))	('AuNP', 'Chemical', '-', (193, 197))	('AuNP', 'Chemical', '-', (242, 246))	('Pt', 'Chemical', 'MESH:D010984', (443, 445))	('Pt', 'Chemical', 'MESH:D010984', (63, 65))	('DMA', 'Chemical', 'MESH:C405765', (301, 304))	('Au', 'Chemical', 'MESH:D006046', (401, 403))	('cps', 'Chemical', '-', (176, 179))	('Au', 'Chemical', 'MESH:D006046', (440, 442))	('AuNP', 'Chemical', '-', (183, 187))	('dp', 'Chemical', '-', (314, 316))	('Au', 'Chemical', 'MESH:D006046', (193, 195))	('SI Figure S2', 'Disease', 'None', (550, 562))	('cps', 'Chemical', '-', (79, 82))	('Au', 'Chemical', 'MESH:D006046', (183, 185))	('Pt', 'Chemical', 'MESH:D010984', (122, 124))	('Au', 'Chemical', 'MESH:D006046', (132, 134))	('Au', 'Chemical', 'MESH:D006046', (532, 534))	('IPt', 'Chemical', '-', (62, 65))	('Pt', 'Chemical', 'MESH:D010984', (542, 544))	('IAu', 'Chemical', '-', (75, 78))	('197Au', 'Var', (529, 534))	('SI Figure S2', 'Disease', (550, 562))	('cps', 'Chemical', '-', (66, 69))	('Au', 'Chemical', 'MESH:D006046', (364, 366))	('Au', 'Chemical', 'MESH:D006046', (354, 356))	('Au', 'Chemical', 'MESH:D006046', (76, 78))
73864	29141149	The plateau surface density, when dendron is pre-attached to the surface, is 0.003 molecules/nm2, 0.008 molecules/nm2 and 0.003 molecules/nm2, for SH-PEG1K, SH-PEG5K and SH-PEG10K, respectively (Conversion to molecules per AuNP in SI, Table S2).	('SH-PEG1', 'Chemical', '-', (147, 154))	('SH-PEG1K', 'Var', (147, 155))	('SH-PEG5', 'Chemical', '-', (157, 164))	('PEG5K', 'Chemical', '-', (160, 165))	('dendron', 'Chemical', 'MESH:C501244', (34, 41))	('SH-PEG1', 'Chemical', '-', (170, 177))	('SH-PEG5K', 'Var', (157, 165))	('SI', 'Disease', 'None', (231, 233))	('AuNP', 'Chemical', '-', (223, 227))	('SH-PEG10K', 'Var', (170, 179))
73869	29141149	In comparison, the saturated molecular packing density of SH-PEG accounted for <= 0.2 % relative to the dendrons, (0.08 %, 0.2 % and 0.08 % for SH-PEG1K, SH-PEG5K and SH-PEG10K, respectively, in ratio to dendron).	('SH-PEG1', 'Chemical', '-', (167, 174))	('SH-PEG1K', 'Var', (144, 152))	('SH-PEG', 'Chemical', '-', (167, 173))	('SH-PEG1', 'Chemical', '-', (144, 151))	('dendron', 'Chemical', 'MESH:C501244', (204, 211))	('saturated molecular packing density', 'MPA', (19, 54))	('SH-PEG10K', 'Var', (167, 176))	('SH-PEG', 'Chemical', '-', (154, 160))	('SH-PEG', 'Chemical', '-', (144, 150))	('SH-PEG5', 'Chemical', '-', (154, 161))	('dendrons', 'Chemical', 'MESH:D050091', (104, 112))	('SH-PEG', 'Chemical', '-', (58, 64))	('PEG5K', 'Chemical', '-', (157, 162))	('SH-PEG5K', 'Var', (154, 162))	('SH-PEG', 'Var', (58, 64))	('dendron', 'Chemical', 'MESH:C501244', (104, 111))
73874	29141149	By comparison, in terms of molar mass, the saturated packing density of PEG-1K, 5K, and 10K is 0.2 %, 3 % and 2.3 %, respectively, relative to that of dendron.	('PEG-1K', 'Var', (72, 78))	('PEG', 'Chemical', 'MESH:D011092', (72, 75))	('saturated packing density', 'MPA', (43, 68))	('dendron', 'Chemical', 'MESH:C501244', (151, 158))	('10K', 'Var', (88, 91))
73877	29141149	By contrast, the resulting SH-PEG packing density on citrate-stabilized AuNPs, as shown in Figure 4(c), is   0.12 molecules/nm2, 0.08 molecules/nm2 and 0.02 molecules/nm2, for SH-PEG1K, SH-PEG5K and SH-PEG10K, respectively.	('AuNP', 'Chemical', '-', (72, 76))	('SH-PEG5', 'Chemical', '-', (186, 193))	('SH-PEG5K', 'Var', (186, 194))	('SH-PEG1', 'Chemical', '-', (199, 206))	('citrate', 'Chemical', 'MESH:D019343', (53, 60))	('SH-PEG', 'Chemical', '-', (199, 205))	('SH-PEG', 'Chemical', '-', (27, 33))	('SH-PEG1', 'Chemical', '-', (176, 183))	('SH-PEG10K', 'Var', (199, 208))	('SH-PEG1K', 'Var', (176, 184))	('SH-PEG', 'Chemical', '-', (176, 182))	('PEG5K', 'Chemical', '-', (189, 194))	('SH-PEG', 'Chemical', '-', (186, 192))
73880	29141149	Note that the higher relative molar mass of SH-PEG10K yields a higher occupied area per molecule on the AuNP surface, and therefore a lower molecular packing density.	('lower', 'NegReg', (134, 139))	('SH-PEG1', 'Chemical', '-', (44, 51))	('occupied area per molecule', 'MPA', (70, 96))	('SH-PEG10K', 'Var', (44, 53))	('molecular packing density', 'MPA', (140, 165))	('AuNP', 'Chemical', '-', (104, 108))	('higher', 'PosReg', (63, 69))	('higher', 'PosReg', (14, 20))
73885	29141149	Note that the signal intensity for 197Au is significantly higher than that for195Pt, however the two curves are clearly superimposed and indicate sufficient signal-to-noise for characterizing size classified particles.	('Pt', 'Chemical', 'MESH:D010984', (81, 83))	('197Au', 'Var', (35, 40))	('signal intensity', 'MPA', (14, 30))	('Au', 'Chemical', 'MESH:D006046', (38, 40))	('higher', 'PosReg', (58, 64))
73895	29141149	With PEGylation, the loading capacity decreased by less than 20 %.	('PEG', 'Chemical', 'MESH:D011092', (5, 8))	('decreased', 'NegReg', (38, 47))	('PEGylation', 'Var', (5, 15))	('loading capacity', 'MPA', (21, 37))
73905	29141149	Previous work has shown that complexation of PtII itself leads to colloidal destabilization of the conjugate due to electrostatic interactions between the anionic carboxylates and the positively charged PtII.	('PtII', 'Chemical', '-', (203, 207))	('colloidal destabilization', 'MPA', (66, 91))	('complexation', 'Var', (29, 41))	('carboxylates', 'Chemical', '-', (163, 175))	('PtII', 'Chemical', '-', (45, 49))	('electrostatic interactions', 'MPA', (116, 142))
73929	29141149	However PEGylated samples exhibited visibly improved stability with a DA less than   1.5 over a period of two days.	('stability', 'MPA', (53, 62))	('improved', 'PosReg', (44, 52))	('PEGylated', 'Var', (8, 17))	('PEG', 'Chemical', 'MESH:D011092', (8, 11))
73938	29141149	The absolute amount of PtII release was about 6x greater for high PtII loading compared with that of low PtII loading.	('greater', 'PosReg', (49, 56))	('PtII', 'Chemical', '-', (66, 70))	('PtII release', 'MPA', (23, 35))	('PtII', 'Chemical', '-', (105, 109))	('PtII', 'Chemical', '-', (23, 27))	('high PtII loading', 'Var', (61, 78))
73965	27474852	We identified potentially eligible cases from the Cancer Surveillance System, a part of the Surveillance, Epidemiology and End Results Program of the National Cancer Institute, based on International Classification of Diseases for Oncology topography C62.0 to 62.9 and histology codes 9060 to 9091.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Oncology', 'Phenotype', 'HP:0002664', (231, 239))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('C62.0', 'Var', (251, 256))	('Cancer', 'Disease', (159, 165))	('Cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Cancer', 'Disease', 'MESH:D009369', (159, 165))
73986	27474852	Finally, we used polytomous logistic regression to calculate odds ratio estimates separately for seminoma (ICD-O histologies 9060-9064) and nonseminoma (ICD-O histologies 9070, 9071, 9080, 9082-9084, 9065, 9085, 9081, 9101) tumors.	('seminoma', 'Disease', 'MESH:D018239', (143, 151))	('nonseminoma', 'Disease', 'None', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('seminoma', 'Disease', (143, 151))	('seminoma', 'Disease', 'MESH:D018239', (97, 105))	('tumors', 'Disease', (224, 230))	('9070', 'Var', (171, 175))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('9060-9064', 'Var', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('nonseminoma', 'Disease', (140, 151))	('seminoma', 'Disease', (97, 105))	('9080', 'Var', (183, 187))
74049	21529158	The CYP26 family:CYP26A1, CYP26B1, and CYP26C1:is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns.	('CYP26A1', 'Var', (17, 24))	('CYP26B1', 'Var', (26, 33))	('at', 'Chemical', 'MESH:D001246', (123, 125))	('at', 'Chemical', 'MESH:D001246', (182, 184))	('at-RA', 'Chemical', '-', (123, 128))	('at', 'Chemical', 'MESH:D001246', (83, 85))	('active', 'MPA', (95, 101))	('RA', 'Chemical', 'MESH:D014212', (126, 128))	('CYP26C1', 'Var', (39, 46))	('RA', 'Chemical', 'MESH:D014212', (119, 121))
74051	21529158	CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development.	('at', 'Chemical', 'MESH:D001246', (86, 88))	('CYP26B1', 'Var', (56, 63))	('CYP26A1', 'Var', (0, 7))
74053	21529158	Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future.	('activity', 'MPA', (49, 57))	('RA', 'Chemical', 'MESH:D014212', (103, 105))	('half-life', 'MPA', (90, 99))	('limiting', 'NegReg', (36, 44))	('CYP26 enzymes', 'Var', (61, 74))	('extend', 'PosReg', (79, 85))
74062	21529158	This review focuses on mechanisms that regulate RA through the process of oxidative metabolism, and particularly on the gene family cytochrome P450 (CYP)26, for which at-RA is often a strong inducer at the level of gene transcription as well as the substrate for the gene product at the level of enzyme activity.	('at', 'Chemical', 'MESH:D001246', (280, 282))	('at', 'Chemical', 'MESH:D001246', (44, 46))	('at', 'Chemical', 'MESH:D001246', (36, 38))	('at', 'Chemical', 'MESH:D001246', (167, 169))	('at-RA', 'Var', (167, 172))	('at-RA', 'Chemical', '-', (167, 172))	('at', 'Chemical', 'MESH:D001246', (78, 80))	('RA', 'Chemical', 'MESH:D014212', (48, 50))	('inducer', 'PosReg', (191, 198))	('at', 'Chemical', 'MESH:D001246', (199, 201))	('at', 'Chemical', 'MESH:D001246', (255, 257))	('cytochrome P450 (CYP)26', 'Gene', '1592', (132, 155))	('RA', 'Chemical', 'MESH:D014212', (170, 172))	('cytochrome P450 (CYP)26', 'Gene', (132, 155))	('rat', 'Species', '10116', (254, 257))
74090	21529158	On the basis of available sequence information in the Genbank database for human, mouse, and rat CYP26 family genes, it appears likely that the CYP26A1, CYP26B1, and CYP26C genes complete the CYP26 gene family, although additional protein variants may exist through either alternative RNA splicing or alternative usage of promoters.	('CYP26C', 'Var', (166, 172))	('mouse', 'Species', '10090', (82, 87))	('CYP26A1', 'Gene', (144, 151))	('at', 'Chemical', 'MESH:D001246', (279, 281))	('at', 'Chemical', 'MESH:D001246', (137, 139))	('at', 'Chemical', 'MESH:D001246', (41, 43))	('at', 'Chemical', 'MESH:D001246', (63, 65))	('at', 'Chemical', 'MESH:D001246', (94, 96))	('human', 'Species', '9606', (75, 80))	('at', 'Chemical', 'MESH:D001246', (307, 309))	('CYP26B1', 'Var', (153, 160))	('rat', 'Species', '10116', (93, 96))
74092	21529158	Upon alignment of all three human CYP26 proteins, less than 55% of the amino acids are identical: CYP26A1 and CYP26B1 share only 43% amino acid identity, CYP26A1 and CYP26C1 45%, and CYP26B1 and CYP26C1 51%.	('CYP26A1', 'Var', (98, 105))	('CYP26A1', 'Var', (154, 161))	('human', 'Species', '9606', (28, 33))	('CYP26C1', 'Var', (166, 173))	('CYP26B1', 'Var', (110, 117))	('CYP26B1', 'Var', (183, 190))
74101	21529158	The other group expresses the CYP26A1 gene at a higher basal level but is less regulated by vitamin A or RA; this includes HEK293T and SK-LC6.	('at', 'Chemical', 'MESH:D001246', (84, 86))	('at', 'Chemical', 'MESH:D001246', (43, 45))	('RA', 'Chemical', 'MESH:D014212', (105, 107))	('HEK293T', 'CellLine', 'CVCL:0063', (123, 130))	('SK-LC6', 'Chemical', '-', (135, 141))	('HEK293T', 'Var', (123, 130))	('vitamin A', 'Chemical', 'MESH:D014801', (92, 101))	('CYP26A1', 'Gene', (30, 37))
74105	21529158	CYP26B1 is expressed in T-cells in the gut, apparently to control RA signaling by regulating the concentrations of RA originated from the synthesis in the dendritic cells of the gut-related organs.	('at', 'Chemical', 'MESH:D001246', (105, 107))	('RA', 'Chemical', 'MESH:D014212', (66, 68))	('regulating', 'Reg', (82, 92))	('concentrations', 'MPA', (97, 111))	('CYP26B1', 'Var', (0, 7))	('RA signaling', 'MPA', (66, 78))	('control', 'Reg', (58, 65))	('at', 'Chemical', 'MESH:D001246', (185, 187))	('at', 'Chemical', 'MESH:D001246', (124, 126))	('RA', 'Chemical', 'MESH:D014212', (115, 117))	('at', 'Chemical', 'MESH:D001246', (87, 89))	('rat', 'Species', '10116', (104, 107))
74112	21529158	For CYPA1 member, two mutant alleles that result in coding changes (F186L and C358R) were found to have 40% to 80% lower activity toward RA metabolism as compared with the wild-type proteins.	('at', 'Chemical', 'MESH:D001246', (39, 41))	('RA', 'Chemical', 'MESH:D014212', (137, 139))	('activity', 'MPA', (121, 129))	('C358R', 'Mutation', 'rs146619916', (78, 83))	('lower', 'NegReg', (115, 120))	('RA metabolism', 'MPA', (137, 150))	('CYP', 'Gene', (4, 7))	('C358R', 'Var', (78, 83))	('F186L', 'Mutation', 'rs1376885914', (68, 73))	('F186L', 'Var', (68, 73))	('CYP', 'Gene', '4051', (4, 7))
74114	21529158	That at-RA is not only the specific substrate for CYP26A1 and CYP26B1 isozymes but also a potent inducer of these genes is particularly evident for CYP26A1 in liver (see also Figure 3) and for CYP26B1 in lung tissue.	('at-RA', 'Chemical', '-', (5, 10))	('at', 'Chemical', 'MESH:D001246', (5, 7))	('at', 'Chemical', 'MESH:D001246', (2, 4))	('inducer', 'PosReg', (97, 104))	('at', 'Chemical', 'MESH:D001246', (42, 44))	('CYP26A1', 'Var', (148, 155))	('rat', 'Species', '10116', (41, 44))	('CYP26B1', 'Var', (193, 200))
74129	21529158	In the lungs of neonatal rats treated with vitamin A, RA, or a combination of both, CYP26B1 mRNA increased rapidly and, relative to CYP26A1, to a higher level, and the increase was also more persistent.	('at', 'Chemical', 'MESH:D001246', (26, 28))	('CYP26B1', 'Var', (84, 91))	('increased', 'PosReg', (97, 106))	('rats', 'Species', '10116', (25, 29))	('at', 'Chemical', 'MESH:D001246', (20, 22))	('at', 'Chemical', 'MESH:D001246', (123, 125))	('RA', 'Chemical', 'MESH:D014212', (54, 56))	('at', 'Chemical', 'MESH:D001246', (69, 71))	('vitamin A', 'Chemical', 'MESH:D014801', (43, 52))	('at', 'Chemical', 'MESH:D001246', (33, 35))
74130	21529158	In T cells from gut-related lymphoid organs, CYP26B1 has been shown to be upor down-regulated by at-RA and transforming growth factor-beta (TGF-beta), respectively.	('at', 'Chemical', 'MESH:D001246', (89, 91))	('at', 'Chemical', 'MESH:D001246', (23, 25))	('upor', 'PosReg', (74, 78))	('down-regulated', 'NegReg', (79, 93))	('CYP26B1', 'Var', (45, 52))	('at-RA', 'Chemical', '-', (97, 102))	('at', 'Chemical', 'MESH:D001246', (97, 99))
74131	21529158	Additionally, CYP26B1 is expressed in the postnatal mouse ovary, where it is down-regulated by activin, a member of the TGF-beta family.	('down-regulated', 'NegReg', (77, 91))	('activin', 'Gene', (95, 102))	('mouse', 'Species', '10090', (52, 57))	('at', 'Chemical', 'MESH:D001246', (47, 49))	('CYP26B1', 'Var', (14, 21))	('activin', 'Gene', '83729', (95, 102))	('at', 'Chemical', 'MESH:D001246', (87, 89))
74134	21529158	At present, CYP26C1 stands apart as an atypical member of this gene family due to its relatively low expression in adult tissues, wider substrate utilization, and preference for 9-cis-RA, and down-regulation as well as up-regulation of its mRNA in response to retinoid treatment.	('at', 'Chemical', 'MESH:D001246', (39, 41))	('rat', 'Species', '10116', (141, 144))	('9-cis-RA', 'Chemical', 'MESH:D000077556', (178, 186))	('mRNA', 'MPA', (240, 244))	('at', 'Chemical', 'MESH:D001246', (89, 91))	('at', 'Chemical', 'MESH:D001246', (202, 204))	('at', 'Chemical', 'MESH:D001246', (272, 274))	('down-regulation', 'NegReg', (192, 207))	('CYP26C1', 'Var', (12, 19))	('retinoid', 'Chemical', 'MESH:D012176', (260, 268))	('at', 'Chemical', 'MESH:D001246', (227, 229))	('at', 'Chemical', 'MESH:D001246', (142, 144))	('expression', 'MPA', (101, 111))	('up-regulation', 'PosReg', (219, 232))	('at', 'Chemical', 'MESH:D001246', (152, 154))
74152	21529158	Each of the four individual elements in both the distal and proximal regions is essential for full activity of the promoter in response to RA in HepG2 cells because deletion or mutation of any one of these elements significantly blunted or abrogated the promoter response to at-RA (Figure 3B).	('mutation', 'Var', (177, 185))	('HepG2', 'CellLine', 'CVCL:0027', (145, 150))	('blunted', 'NegReg', (229, 236))	('promoter response to at-RA', 'MPA', (254, 280))	('at', 'Chemical', 'MESH:D001246', (245, 247))	('RA', 'Chemical', 'MESH:D014212', (278, 280))	('at', 'Chemical', 'MESH:D001246', (275, 277))	('deletion', 'Var', (165, 173))	('RA', 'Chemical', 'MESH:D014212', (139, 141))	('at', 'Chemical', 'MESH:D001246', (180, 182))	('at-RA', 'Chemical', '-', (275, 280))	('abrogated', 'NegReg', (240, 249))
74166	21529158	The substrate specificity of both CYP26A1 and CYP26B1 appears to be similar based on studies in transfected COS-1 cells.	('CYP26A1', 'Var', (34, 41))	('COS-1', 'CellLine', 'CVCL:0223', (108, 113))	('rat', 'Species', '10116', (9, 12))	('CYP26B1', 'Var', (46, 53))
74174	21529158	These activities include the induction of differentiation and subsequent proliferation of growth-arrested A spermatogonia in vitamin A-deficient mice testis, modulation of positional specification in early embryo in Xenopus, good growth response in vitamin A-deficient rats as compared to retinyl acetate, and epithelial differentiation.	('at', 'Chemical', 'MESH:D001246', (81, 83))	('at', 'Chemical', 'MESH:D001246', (113, 115))	('vitamin A', 'Chemical', 'MESH:D014801', (125, 134))	('growth response', 'CPA', (230, 245))	('Xenopus', 'Species', '8355', (216, 223))	('rat', 'Species', '10116', (269, 272))	('good growth', 'Phenotype', 'HP:0001510', (225, 236))	('at', 'Chemical', 'MESH:D001246', (191, 193))	('at', 'Chemical', 'MESH:D001246', (301, 303))	('retinyl acetate', 'Chemical', 'MESH:C009166', (289, 304))	('differentiation', 'CPA', (42, 57))	('at', 'Chemical', 'MESH:D001246', (270, 272))	('rat', 'Species', '10116', (80, 83))	('vitamin A-deficient', 'Phenotype', 'HP:0004905', (249, 268))	('vitamin A', 'Chemical', 'MESH:D014801', (249, 258))	('epithelial differentiation', 'CPA', (310, 336))	('at', 'Chemical', 'MESH:D001246', (52, 54))	('mice', 'Species', '10090', (145, 149))	('modulation', 'Var', (158, 168))	('at', 'Chemical', 'MESH:D001246', (163, 165))	('at', 'Chemical', 'MESH:D001246', (331, 333))	('proliferation', 'CPA', (73, 86))	('vitamin A-deficient', 'Phenotype', 'HP:0004905', (125, 144))	('positional specification', 'CPA', (172, 196))	('rats', 'Species', '10116', (269, 273))
74179	21529158	Vitamin A deficiency at the time of mating and during pregnancy results in a collection of defects and malformations in the fetus, referred to as vitamin A-deficiency syndrome.	('at', 'Chemical', 'MESH:D001246', (37, 39))	('Vitamin A', 'Chemical', 'MESH:D014801', (0, 9))	('vitamin A-deficiency', 'Phenotype', 'HP:0004905', (146, 166))	('A-deficiency syndrome', 'Disease', (154, 175))	('malformations', 'Disease', 'MESH:D000014', (103, 116))	('malformations', 'Disease', (103, 116))	('collection of', 'MPA', (77, 90))	('Vitamin A deficiency', 'Phenotype', 'HP:0004905', (0, 20))	('vitamin A', 'Chemical', 'MESH:D014801', (146, 155))	('results in', 'Reg', (64, 74))	('at', 'Chemical', 'MESH:D001246', (21, 23))	('A-deficiency syndrome', 'Disease', 'MESH:D013577', (154, 175))	('at', 'Chemical', 'MESH:D001246', (110, 112))	('deficiency', 'Var', (10, 20))	('Vitamin A', 'Gene', (0, 9))
74188	21529158	Whereas RA, which is known to stimulate meiosis, is produced in the mesonephros adjacent to the developing gonads of both sexes, as demonstrated by expression of an RA-sensitive reporter gene, by 13.5 dpc only the male gonad expresses CYP26B1, apparently in Sertoli cells, and the relative amount of RA in the male gonad is reduced to 25% of that in the female gonad.	('CYP26B1', 'Var', (235, 242))	('at', 'Chemical', 'MESH:D001246', (36, 38))	('at', 'Chemical', 'MESH:D001246', (284, 286))	('at', 'Chemical', 'MESH:D001246', (140, 142))	('rat', 'Species', '10116', (139, 142))	('RA', 'Chemical', 'MESH:D014212', (165, 167))	('RA', 'Chemical', 'MESH:D014212', (300, 302))	('meiosis', 'CPA', (40, 47))	('Sertoli cells', 'Phenotype', 'HP:0100619', (258, 271))	('RA', 'Chemical', 'MESH:D014212', (8, 10))	('at', 'Chemical', 'MESH:D001246', (344, 346))
74190	21529158	However, conversely, in CYP26B1-null mouse embryos, the levels of Stra8 and Scp3, considered markers of female germ cells, were up-regulated in XY gonads, and meiosis progressed earlier than normal.	('at', 'Chemical', 'MESH:D001246', (136, 138))	('CYP26B1-null', 'Var', (24, 36))	('up-regulated', 'PosReg', (128, 140))	('Stra8', 'Gene', (66, 71))	('mouse', 'Species', '10090', (37, 42))	('meiosis progressed', 'CPA', (159, 177))	('Stra8', 'Gene', '20899', (66, 71))	('Scp3', 'Gene', (76, 80))
74192	21529158	concluded that CYP26B1 in Sertoli cells, acting as a meiosis-inhibiting factor in males, holds the key to the appropriate timing of male germ cell maturation by retarding meiosis in the male fetal testis.	('Sertoli cells', 'Phenotype', 'HP:0100619', (26, 39))	('CYP26B1', 'Var', (15, 22))	('retarding meiosis', 'Disease', (161, 178))	('rat', 'Species', '10116', (151, 154))	('at', 'Chemical', 'MESH:D001246', (148, 150))	('at', 'Chemical', 'MESH:D001246', (12, 14))	('at', 'Chemical', 'MESH:D001246', (118, 120))	('at', 'Chemical', 'MESH:D001246', (152, 154))	('retarding meiosis', 'Disease', 'MESH:C536875', (161, 178))
74197	21529158	Whereas CYP26A1 is expressed as early as embryonic day (E)6.0 in extraembryonic and embryonic endoderm, just before gastrulation stage and presumably to protect the embryo from excess maternal vitamin A or RA, the expression of CYP26B1 is initiated at E8.0 in the hindbrain, in distinctive rhombomeric regions that differ from those that express either CYP26A1 or CYP26C1 at the same stage of development.	('at', 'Chemical', 'MESH:D001246', (249, 251))	('RA', 'Chemical', 'MESH:D014212', (206, 208))	('at', 'Chemical', 'MESH:D001246', (335, 337))	('CYP26C1', 'Var', (364, 371))	('at', 'Chemical', 'MESH:D001246', (312, 314))	('at', 'Chemical', 'MESH:D001246', (123, 125))	('at', 'Chemical', 'MESH:D001246', (185, 187))	('at', 'Chemical', 'MESH:D001246', (244, 246))	('vitamin A', 'Chemical', 'MESH:D014801', (193, 202))	('CYP26B1', 'Var', (228, 235))	('at', 'Chemical', 'MESH:D001246', (372, 374))
74198	21529158	During human prenatal development, CYP26B1 mRNA expression is much higher in cephalic tissues than hepatic tissues, and in the early gestation period, CYP26B1 expression in cephalic tissue is about ten times higher than at later gestational stages.	('early gestation period', 'Phenotype', 'HP:0001622', (127, 149))	('higher', 'PosReg', (208, 214))	('higher', 'PosReg', (67, 73))	('mRNA expression', 'MPA', (43, 58))	('human', 'Species', '9606', (7, 12))	('at', 'Chemical', 'MESH:D001246', (17, 19))	('at', 'Chemical', 'MESH:D001246', (137, 139))	('expression', 'MPA', (159, 169))	('CYP26B1', 'Var', (151, 158))	('CYP26B1', 'Gene', (35, 42))	('at', 'Chemical', 'MESH:D001246', (102, 104))	('at', 'Chemical', 'MESH:D001246', (233, 235))	('at', 'Chemical', 'MESH:D001246', (220, 222))	('at', 'Chemical', 'MESH:D001246', (224, 226))
74200	21529158	As CYP26 isozymes function to catalyze the oxidation of RA to less active metabolites, any ablation of these enzymes may result in abnormalities similar to those observed in RA or vitamin A toxicity.	('ablation', 'Var', (91, 99))	('RA', 'Chemical', 'MESH:D014212', (56, 58))	('vitamin A toxicity', 'Phenotype', 'HP:0004905', (180, 198))	('at', 'Chemical', 'MESH:D001246', (47, 49))	('CYP26 isozymes', 'Enzyme', (3, 17))	('abnormalities', 'MPA', (131, 144))	('at', 'Chemical', 'MESH:D001246', (31, 33))	('vitamin A', 'Chemical', 'MESH:D014801', (180, 189))	('toxicity', 'Disease', 'MESH:D064420', (190, 198))	('at', 'Chemical', 'MESH:D001246', (94, 96))	('toxicity', 'Disease', (190, 198))	('oxidation', 'MPA', (43, 52))	('RA', 'Chemical', 'MESH:D014212', (174, 176))	('result in', 'Reg', (121, 130))
74201	21529158	Whereas null mutations of the genes for CYP26A1 and CYP26B1 are lethal, the CYP26C1 gene seems to be nonessential because CYP26C1-null mice lack any particular phenotype and appear to behave like wild-type mice.	('lack', 'NegReg', (140, 144))	('at', 'Chemical', 'MESH:D001246', (16, 18))	('mice', 'Species', '10090', (206, 210))	('CYP26C1', 'Var', (76, 83))	('mice', 'Species', '10090', (135, 139))	('CYP26A1', 'Gene', (40, 47))	('CYP26C1-null', 'Var', (122, 134))
74204	21529158	CYP26B1-null mice that are born alive die right after birth due to respiratory defects.	('mice', 'Species', '10090', (13, 17))	('respiratory defects', 'Disease', (67, 86))	('CYP26B1-null', 'Var', (0, 12))	('respiratory defects', 'Disease', 'MESH:D012131', (67, 86))	('at', 'Chemical', 'MESH:D001246', (20, 22))	('at', 'Chemical', 'MESH:D001246', (73, 75))
74205	21529158	Consistent with a critical role of CYP26B1 in normal male germ cell development, CYP26B1-null mice have smaller testes and lack any germ cells, indicating that CYP26B1 not only acts as a meiotic inhibiting factor but also is essential for germ cell survival, apparently by preventing premature exposure to RA.	('testes', 'CPA', (112, 118))	('meiotic', 'CPA', (187, 194))	('at', 'Chemical', 'MESH:D001246', (288, 290))	('RA', 'Chemical', 'MESH:D014212', (306, 308))	('smaller', 'NegReg', (104, 111))	('at', 'Chemical', 'MESH:D001246', (157, 159))	('smaller testes', 'Phenotype', 'HP:0008734', (104, 118))	('mice', 'Species', '10090', (94, 98))	('at', 'Chemical', 'MESH:D001246', (149, 151))	('CYP26B1-null', 'Var', (81, 93))	('CYP26B1', 'Var', (160, 167))
74206	21529158	Despite CYP26C1-null mouse mutants not showing a particular phenotype, the loss of this gene in combination with the other two members of CYP26 family exacerbated the teratogenic effects of RA on embryonic development.	('at', 'Chemical', 'MESH:D001246', (170, 172))	('rat', 'Species', '10116', (169, 172))	('mouse', 'Species', '10090', (21, 26))	('at', 'Chemical', 'MESH:D001246', (158, 160))	('teratogenic effects', 'CPA', (167, 186))	('RA', 'Chemical', 'MESH:D014212', (190, 192))	('at', 'Chemical', 'MESH:D001246', (102, 104))	('loss', 'Var', (75, 79))	('exacerbated', 'PosReg', (151, 162))
74207	21529158	Overall, the differences among CYP26A1, CYP26B1, and CYP26C1 in their expression patterns, timing of expression, and consequences of gene deletion, together with the conservation of all three genes in all vertebrates studied, imply that CYP26A1 and CYP26B1 are essential for survival, but in different ways, while CYP26C1 confers a protective advantage against excessive RA signaling that may be tissue specific.	('at', 'Chemical', 'MESH:D001246', (173, 175))	('RA', 'Chemical', 'MESH:D014212', (371, 373))	('at', 'Chemical', 'MESH:D001246', (386, 388))	('rat', 'Species', '10116', (211, 214))	('at', 'Chemical', 'MESH:D001246', (82, 84))	('at', 'Chemical', 'MESH:D001246', (212, 214))	('at', 'Chemical', 'MESH:D001246', (234, 236))	('CYP26C1', 'Var', (314, 321))	('CYP26C1', 'Var', (53, 60))	('deletion', 'Var', (138, 146))
74209	21529158	In undifferentiated ES cells, removal of leukemia inhibitory factor (LIF), which functions to prevent differentiation, resulted in increased CYP26A1 expression and increased conversion of all-trans-retinol to 4-oxo-retinol; however, neither RA nor 4-oxo-RA were detected.	('at', 'Chemical', 'MESH:D001246', (112, 114))	('RA', 'Chemical', 'MESH:D014212', (254, 256))	('4-oxo-RA', 'Chemical', 'MESH:C002202', (248, 256))	('LIF', 'Gene', (69, 72))	('increased', 'PosReg', (164, 173))	('increased', 'PosReg', (131, 140))	('at', 'Chemical', 'MESH:D001246', (15, 17))	('RA', 'Chemical', 'MESH:D014212', (241, 243))	('leukemia inhibitory factor', 'Gene', '3976', (41, 67))	('conversion', 'MPA', (174, 184))	('expression', 'MPA', (149, 159))	('all-trans-retinol to 4-oxo-retinol', 'MPA', (188, 222))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('leukemia inhibitory factor', 'Gene', (41, 67))	('4-oxo-retinol', 'Chemical', 'MESH:C041819', (209, 222))	('CYP26A1', 'Gene', (141, 148))	('LIF', 'Gene', '3976', (69, 72))	('all-trans-retinol', 'Chemical', 'MESH:D014801', (188, 205))	('removal', 'Var', (30, 37))
74210	21529158	In another study using AB1 ES cells, the disruption of both alleles of the CYP26A1 gene by homologous recombination resulted in an 11-fold higher concentration of intracellular RA in cells treated 48 hours earlier with RA together with reduced expression of RA-responsive genes involved in cell differentiation.	('at', 'Chemical', 'MESH:D001246', (305, 307))	('RA', 'Chemical', 'MESH:D014212', (219, 221))	('at', 'Chemical', 'MESH:D001246', (154, 156))	('rat', 'Species', '10116', (153, 156))	('RA', 'Chemical', 'MESH:D014212', (258, 260))	('at', 'Chemical', 'MESH:D001246', (192, 194))	('disruption', 'Var', (41, 51))	('at', 'Chemical', 'MESH:D001246', (110, 112))	('RA', 'Chemical', 'MESH:D014212', (177, 179))	('CYP26A1', 'Gene', (75, 82))	('concentration of intracellular RA', 'MPA', (146, 179))	('higher', 'PosReg', (139, 145))
74211	21529158	Thus, the expression of CYP26A1, through regulation of retinoid concentrations in undifferentiated pluripotent ES cells, is important for their differentiation, which may involve CYP26-produced metabolites of retinol as well as of RA.	('at', 'Chemical', 'MESH:D001246', (46, 48))	('rat', 'Species', '10116', (71, 74))	('at', 'Chemical', 'MESH:D001246', (154, 156))	('CYP26A1', 'Gene', (24, 31))	('retinol', 'Chemical', 'MESH:D014801', (209, 216))	('CYP26-produced', 'Var', (179, 193))	('at', 'Chemical', 'MESH:D001246', (72, 74))	('at', 'Chemical', 'MESH:D001246', (94, 96))	('RA', 'Chemical', 'MESH:D014212', (231, 233))	('retinoid', 'Chemical', 'MESH:D012176', (55, 63))
74241	21529158	Kinetically, CYP26A1, CYP26B1, and CYP2C22 mRNAs all increased rapidly in the liver in response to treatment with RA, as early as 30 minutes after RA administration, and reached a maximum at about 6-10 hours.	('CYP26B1', 'Var', (22, 29))	('CYP26A1', 'Var', (13, 20))	('RA', 'Chemical', 'MESH:D014212', (147, 149))	('at', 'Chemical', 'MESH:D001246', (188, 190))	('CYP2C22', 'Gene', '171518', (35, 42))	('at', 'Chemical', 'MESH:D001246', (102, 104))	('increased', 'PosReg', (53, 62))	('RA', 'Chemical', 'MESH:D014212', (114, 116))	('rat', 'Species', '10116', (158, 161))	('at', 'Chemical', 'MESH:D001246', (159, 161))	('CYP2C22', 'Gene', (35, 42))
74252	21529158	However, no significant change was observed in the mRNA levels of either CYP26A1 or CYP26B1 in the liver of control rats treated only with LPS.	('mRNA levels', 'MPA', (51, 62))	('CYP26B1', 'Var', (84, 91))	('rats', 'Species', '10116', (116, 120))	('CYP26A1', 'Var', (73, 80))	('at', 'Chemical', 'MESH:D001246', (117, 119))	('at', 'Chemical', 'MESH:D001246', (124, 126))
74255	21529158	RA-4-hydroxylation activity in hepatic microsomes was inhibited by more than 75% by parathion, a potent insecticide; by 50% by quinidine, a heart antiarrhythmic drug; and by 30% by ketoconazole, a general inhibitor of cytochrome P450 enzymes.	('inhibited', 'NegReg', (54, 63))	('RA-4', 'Gene', '474224', (0, 4))	('quinidine', 'Chemical', 'MESH:D011802', (127, 136))	('at', 'Chemical', 'MESH:D001246', (13, 15))	('at', 'Chemical', 'MESH:D001246', (34, 36))	('quinidine', 'Var', (127, 136))	('ketoconazole', 'Chemical', 'MESH:D007654', (181, 193))	('RA-4', 'Gene', (0, 4))	('at', 'Chemical', 'MESH:D001246', (87, 89))	('parathion', 'Chemical', 'MESH:D010278', (84, 93))
74264	21529158	Recently, clofibrate, a specific PPARalpha agonist, was shown to suppress the mRNA expression of both CYP26A1 and CYP26B1 in HepG2 cells incubated with low concentration of at-RA.	('rat', 'Species', '10116', (163, 166))	('at', 'Chemical', 'MESH:D001246', (173, 175))	('HepG2', 'CellLine', 'CVCL:0027', (125, 130))	('CYP26A1', 'Gene', (102, 109))	('at-RA', 'Chemical', '-', (173, 178))	('rat', 'Species', '10116', (16, 19))	('mRNA expression', 'MPA', (78, 93))	('PPARalpha', 'Gene', (33, 42))	('at', 'Chemical', 'MESH:D001246', (164, 166))	('at', 'Chemical', 'MESH:D001246', (17, 19))	('clofibrate', 'Chemical', 'MESH:D002994', (10, 20))	('PPARalpha', 'Gene', '5465', (33, 42))	('at', 'Chemical', 'MESH:D001246', (142, 144))	('suppress', 'NegReg', (65, 73))	('CYP26B1', 'Var', (114, 121))
74265	21529158	In the same report, however, ligands for both PPARgamma (rosiglitazone and pioglitazone) and PPARbeta/delta (L-165,041) dramatically and dose-dependently increased CYP26B1 mRNA in HepG2 cells incubated with at-RA.	('HepG2', 'CellLine', 'CVCL:0027', (180, 185))	('PPARgamma', 'Gene', (46, 55))	('at', 'Chemical', 'MESH:D001246', (207, 209))	('at-RA', 'Chemical', '-', (207, 212))	('PPARgamma', 'Gene', '5468', (46, 55))	('CYP26B1 mRNA', 'MPA', (164, 176))	('PPARbeta/delta', 'Gene', '5467', (93, 107))	('pioglitazone', 'Chemical', 'MESH:D000077205', (75, 87))	('at', 'Chemical', 'MESH:D001246', (197, 199))	('at', 'Chemical', 'MESH:D001246', (124, 126))	('L-165,041', 'Var', (109, 118))	('increased', 'PosReg', (154, 163))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (57, 70))	('PPARbeta/delta', 'Gene', (93, 107))
74266	21529158	In parallel to these results, the CYP26B1, but not CYP26A1, transcript was higher in individual donors positive for fatty liver than in donors negative for fatty liver.	('fatty liver', 'Phenotype', 'HP:0001397', (156, 167))	('fatty liver', 'Disease', 'MESH:D005234', (156, 167))	('fatty liver', 'Disease', (156, 167))	('transcript', 'MPA', (60, 70))	('higher', 'PosReg', (75, 81))	('fatty liver', 'Phenotype', 'HP:0001397', (116, 127))	('fatty liver', 'Disease', 'MESH:D005234', (116, 127))	('at', 'Chemical', 'MESH:D001246', (157, 159))	('CYP26B1', 'Var', (34, 41))	('positive', 'Reg', (103, 111))	('fatty liver', 'Disease', (116, 127))	('at', 'Chemical', 'MESH:D001246', (117, 119))	('at', 'Chemical', 'MESH:D001246', (146, 148))
74268	21529158	Ischemia, as another factor, may also affect the expression of CYP26A1 but not CYP26B1.	('Ischemia', 'Disease', 'MESH:D007511', (0, 8))	('CYP26A1', 'Var', (63, 70))	('expression', 'MPA', (49, 59))	('Ischemia', 'Disease', (0, 8))	('affect', 'Reg', (38, 44))
74272	21529158	CYP26A1 mRNA was elevated in 42% of primary breast cancer specimens.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('CYP26A1', 'Var', (0, 7))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('at', 'Chemical', 'MESH:D001246', (21, 23))	('elevated', 'PosReg', (17, 25))
74279	21529158	R116010 enhances the biological activity of at-RA and exhibited antitumor activity in a mouse mammary carcinoma model, whereas a single oral dose of R115866 in intact rats resulted in increases in endogenous tissue RA levels in plasma, skin, fat, kidney, and testis, and as a result R115866 exerted retinoidal activities.	('at-RA', 'Chemical', '-', (44, 49))	('at', 'Chemical', 'MESH:D001246', (168, 170))	('enhances', 'PosReg', (8, 16))	('retinoid', 'Chemical', 'MESH:D012176', (299, 307))	('RA', 'Chemical', 'MESH:D014212', (47, 49))	('R115866', 'Var', (149, 156))	('increases', 'PosReg', (184, 193))	('R115866', 'Var', (283, 290))	('endogenous tissue RA levels', 'MPA', (197, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('retinoidal activities', 'MPA', (299, 320))	('carcinoma', 'Disease', (102, 111))	('rats', 'Species', '10116', (167, 171))	('R116010', 'Var', (0, 7))	('biological activity', 'MPA', (21, 40))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (94, 111))	('at', 'Chemical', 'MESH:D001246', (44, 46))	('at-RA', 'Protein', (44, 49))	('at', 'Chemical', 'MESH:D001246', (243, 245))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))	('antitumor activity', 'CPA', (64, 82))	('mouse', 'Species', '10090', (88, 93))	('RA', 'Chemical', 'MESH:D014212', (215, 217))
74280	21529158	Compound R115866 has also been shown to be effective in treating skin disorders, to potentially increase the endogenous level of RA in the keratinocytes and epidermis, and to increase retinoid signaling in intimal smooth muscle cells, which is postulated to offer potential new therapeutic ways to treat vascular proliferative disorders.	('endogenous level of RA', 'MPA', (109, 131))	('R115866', 'Var', (9, 16))	('skin disorders', 'Disease', (65, 79))	('retinoid signaling', 'MPA', (184, 202))	('rat', 'Species', '10116', (141, 144))	('at', 'Chemical', 'MESH:D001246', (301, 303))	('vascular proliferative disorders', 'Disease', 'MESH:D000783', (304, 336))	('at', 'Chemical', 'MESH:D001246', (142, 144))	('increase', 'PosReg', (96, 104))	('RA', 'Chemical', 'MESH:D014212', (129, 131))	('rat', 'Species', '10116', (320, 323))	('vascular proliferative disorders', 'Disease', (304, 336))	('at', 'Chemical', 'MESH:D001246', (250, 252))	('at', 'Chemical', 'MESH:D001246', (321, 323))	('retinoid', 'Chemical', 'MESH:D012176', (184, 192))	('at', 'Chemical', 'MESH:D001246', (59, 61))	('skin disorders', 'Disease', 'MESH:D012871', (65, 79))	('increase', 'PosReg', (175, 183))	('skin disorders', 'Phenotype', 'HP:0000951', (65, 79))
74294	21529158	CYP26A1 and CYP26B1 exhibit nutritional regulation according to vitamin A status.	('vitamin A', 'Chemical', 'MESH:D014801', (64, 73))	('CYP26A1', 'Var', (0, 7))	('at', 'Chemical', 'MESH:D001246', (45, 47))	('at', 'Chemical', 'MESH:D001246', (76, 78))	('CYP26B1', 'Var', (12, 19))
74296	21529158	Studies in knockout mice have demonstrated that CYP26A1 is essential for the development of the embryo, CYP26B1 is essential for postnatal survival, and CYP26C1 can be eliminated without causing a major phenotype, but it still appears to contribute positively by reducing the sensitivity of the embryo to excessive RA.	('RA', 'Chemical', 'MESH:D014212', (315, 317))	('at', 'Chemical', 'MESH:D001246', (134, 136))	('at', 'Chemical', 'MESH:D001246', (174, 176))	('at', 'Chemical', 'MESH:D001246', (38, 40))	('rat', 'Species', '10116', (37, 40))	('mice', 'Species', '10090', (20, 24))	('CYP26C1', 'Var', (153, 160))	('at', 'Chemical', 'MESH:D001246', (45, 47))	('CYP26B1', 'Var', (104, 111))	('sensitivity', 'MPA', (276, 287))	('reducing', 'NegReg', (263, 271))
74297	21529158	CYP26B1 also plays a unique role in male germ cell development, serving to restrain RA signaling in embryonic testis and thus to prevent premature meiosis.	('embryonic testis', 'Disease', 'MESH:D013736', (100, 116))	('premature meiosis', 'CPA', (137, 154))	('prevent', 'NegReg', (129, 136))	('CYP26B1', 'Var', (0, 7))	('embryonic testis', 'Disease', (100, 116))	('RA', 'Chemical', 'MESH:D014212', (84, 86))	('at', 'Chemical', 'MESH:D001246', (141, 143))	('restrain', 'NegReg', (75, 83))	('RA signaling', 'MPA', (84, 96))
74304	21529158	Given the very strong regulation of this gene by at-RA, CYP26A1 appears to be an ideal model for future studies at the chromatin level.	('at', 'Chemical', 'MESH:D001246', (112, 114))	('regulation', 'MPA', (22, 32))	('CYP26A1', 'Var', (56, 63))	('at', 'Chemical', 'MESH:D001246', (27, 29))	('at', 'Chemical', 'MESH:D001246', (124, 126))	('at', 'Chemical', 'MESH:D001246', (49, 51))	('at-RA', 'Chemical', '-', (49, 54))
74305	21529158	Evidence suggests that CYP26A1, CYP26B1, and CYP26C1 fulfill different functions, based on developmental studies and on nonidentical tissue distributions in the adult vertebrate, but their specific functions are not well defined.	('rat', 'Species', '10116', (173, 176))	('at', 'Chemical', 'MESH:D001246', (174, 176))	('CYP26C1', 'Var', (45, 52))	('at', 'Chemical', 'MESH:D001246', (20, 22))	('CYP26A1', 'Var', (23, 30))	('CYP26B1', 'Var', (32, 39))
74316	21529158	Thus, additional studies with patient samples and/or in vitro studies to investigate retinoid-drug interactions and the effects of CYP26 gene polymorphisms are likely to yield important new information.	('patient', 'Species', '9606', (30, 37))	('at', 'Chemical', 'MESH:D001246', (81, 83))	('at', 'Chemical', 'MESH:D001246', (196, 198))	('polymorphisms', 'Var', (142, 155))	('at', 'Chemical', 'MESH:D001246', (31, 33))	('CYP26', 'Gene', (131, 136))	('retinoid', 'Chemical', 'MESH:D012176', (85, 93))
74325	31143362	Testicular descent is a mechanism for improved sperm quality through the imposition of relative hypoxia within the scrotal sac, causing stress-induced enhanced oxidative metabolism that could result in increased gametic aerobic fitness.	('oxidative metabolism', 'MPA', (160, 180))	('increased', 'PosReg', (202, 211))	('Testicular descent', 'CPA', (0, 18))	('imposition', 'Var', (73, 83))	('improved', 'PosReg', (38, 46))	('enhanced', 'PosReg', (151, 159))	('enhanced oxidative metabolism', 'Phenotype', 'HP:0025464', (151, 180))	('hypoxia within the scrotal', 'Disease', 'MESH:D001929', (96, 122))	('gametic aerobic fitness', 'CPA', (212, 235))	('hypoxia within the scrotal', 'Disease', (96, 122))	('improved sperm quality', 'Phenotype', 'HP:0012207', (38, 60))	('sperm quality', 'CPA', (47, 60))
74352	31143362	The duplication/amplification of the betaAdrenergic Receptor during the transition from water to land facilitated local control of lung blood pressure, rendering it independent of systemic blood pressure control.	('duplication/amplification', 'Var', (4, 29))	('water', 'Chemical', 'MESH:D014867', (88, 93))	('lung blood pressure', 'MPA', (131, 150))	('facilitated', 'PosReg', (102, 113))	('local control', 'MPA', (114, 127))	('betaAdrenergic Receptor', 'Protein', (37, 60))
74368	31143362	During the Phanerozoic period, much larger fluctuations in atmospheric oxygen, ranging between 12% and 35% are now widely recognized to have caused dramatic increases in animal body size.	('increases', 'PosReg', (157, 166))	('fluctuations', 'Var', (43, 55))	('animal body size', 'CPA', (170, 186))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))
74371	31143362	This physiologic mechanism is of evolutionary significance because catecholamines cause surfactant secretion from the lung alveoli.	('catecholamines', 'Var', (67, 81))	('catecholamines', 'Chemical', 'MESH:D002395', (67, 81))	('surfactant secretion from the', 'MPA', (88, 117))	('cause', 'Reg', (82, 87))
74456	31143362	It has been advanced that the water-land transition was finally accomplished through known gene duplications for the Parathyroid Hormone-related Protein (PTHrP) Receptor, the Glucocorticoid Receptor and the betaAdrenergic Receptor.	('Glucocorticoid Receptor', 'Gene', (175, 198))	('Parathyroid Hormone-related Protein', 'Gene', (117, 152))	('gene duplications', 'Var', (91, 108))	('water', 'Chemical', 'MESH:D014867', (30, 35))	('PTHrP', 'Gene', '5744', (154, 159))	('Parathyroid Hormone-related Protein', 'Gene', '19227', (117, 152))	('Glucocorticoid Receptor', 'Gene', '2908', (175, 198))	('PTHrP', 'Gene', (154, 159))
74457	31143362	Amplification of the PTHrP pathway played a pivotal role in the evolution of the skeletal system, lung, and kidney.	('PTHrP', 'Gene', '5744', (21, 26))	('Amplification', 'Var', (0, 13))	('PTHrP', 'Gene', (21, 26))
74479	31143362	Recent research has provided some indication of a genetic cause, including mutations in the genes for Insl3 and its receptor.	('Insl3', 'Gene', '3640', (102, 107))	('Insl3', 'Gene', (102, 107))	('mutations', 'Var', (75, 84))
74482	31143362	It is well established that cryptochidism is associated with relative or complete impairment of fertility which can persist even after correction.	('fertility', 'CPA', (96, 105))	('men', 'Species', '9606', (88, 91))	('impairment of fertility', 'Phenotype', 'HP:0000144', (82, 105))	('cryptochidism', 'Var', (28, 41))	('impairment', 'NegReg', (82, 92))
74490	31143362	Others have found a high rate of polymorphisms in receptor (ESR) genes and steroid hormone metabolism genes that might be associated with TGCT.	('associated', 'Reg', (122, 132))	('polymorphisms', 'Var', (33, 46))	('TGCT', 'Disease', (138, 142))	('ESR) genes', 'Gene', (60, 70))	('steroid hormone metabolism genes', 'Gene', (75, 107))	('steroid hormone', 'Chemical', 'MESH:D013256', (75, 90))
74505	31143362	Although it had been previously thought that the great majority of cancers are due to genetic mutations, increasing numbers of cancers are now known to be caused by infectious disease.	('infectious disease', 'Disease', 'MESH:D003141', (165, 183))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('infectious disease', 'Disease', (165, 183))	('cancers', 'Disease', (127, 134))	('due', 'Reg', (79, 82))	('genetic mutations', 'Var', (86, 103))
74517	31143362	Therefore, both infertility and increased teratogenic potential manifested in cryptochidism are reflections of testicular tissue ecological disruption, either primarily at the metabolic level or through disruption of its associated microbiome.	('cryptochidism', 'Var', (78, 91))	('infertility', 'Disease', 'MESH:D007247', (16, 27))	('teratogenic potential', 'CPA', (42, 63))	('infertility', 'Phenotype', 'HP:0000789', (16, 27))	('infertility', 'Disease', (16, 27))	('disruption', 'Reg', (203, 213))
74532	30442178	The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('predict', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('response to therapy', 'MPA', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('genetic alterations', 'Var', (62, 81))
74533	30442178	The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
74535	30442178	To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutation', 'Var', (181, 189))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
74541	30442178	Next-generation sequencing has facilitated comprehensive mutational profiling of all major cancers and has led to the discovery of oncogenic driver mutations, many of which can be targeted therapeutically.	('mutations', 'Var', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
74543	30442178	However, sequencing data has shown that actionable mutations, albeit with different frequencies, occur across cancers, which has raised the question about histotype-independent therapies and novel ways of tumor classifications no longer relying on histology but on genetic profiles.	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
74546	30442178	That targeted therapies against the same single molecular alteration can be effective across cancers, as shown, for instance, by the efficacy of anti-Her2 therapy in both gastric and breast cancers or the clinical benefit from inhibition of mutated cKIT in gastrointestinal stromal tumors (GIST) and melanoma or mastocytosis.	('gastric and breast cancers', 'Disease', 'MESH:D013274', (171, 197))	('melanoma or mastocytosis', 'Disease', (300, 324))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Her2', 'Gene', '2064', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('GIST', 'Phenotype', 'HP:0100723', (290, 294))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('Her2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutated', 'Var', (241, 248))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cKIT', 'Gene', '3815', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancers', 'Disease', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('melanoma or mastocytosis', 'Disease', 'MESH:D008415', (300, 324))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('inhibition', 'Var', (227, 237))	('mastocytosis', 'Phenotype', 'HP:0100495', (312, 324))	('cKIT', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
74547	30442178	However, the fact that inhibition of BRAF mutated at V600 is effective in melanoma but not in colorectal cancer is a prominent example against the general transferability of knowledge on a single actionable mutation from one histological tumor type to another.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('BRAF', 'Gene', (37, 41))	('mutated at V600', 'Var', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('ran', 'Gene', (156, 159))	('ran', 'Gene', '5901', (156, 159))
74549	30442178	Using mutational profiles or just single genetic aberrations, as is the case in the current basket trials, is unlikely to cover the full scope of (tissue-specific) molecular effects including epigenetic mechanisms and downstream regulation such as post-translational modifications.	('mutational', 'Var', (6, 16))	('ran', 'Gene', (254, 257))	('ran', 'Gene', '5901', (254, 257))
74564	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational differences', 'Var', (31, 53))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
74579	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('mutations', 'Var', (279, 288))	('ran', 'Gene', '5901', (129, 132))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
74593	30442178	In the proposal by Ciriello et al., tumors are classified by the presence of somatic mutations and copy number alterations in cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
74605	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', (147, 150))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
74624	30442178	With CES = 2%, the overall classification effectivity score of this classification is the lowest among all tested classifications indicating that global comparisons based on somatic mutations only are not effective in classifying tumors in a meaningful way if the available protein profiles are considered relevant.	('CES', 'Chemical', '-', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Disease', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('CES', 'Var', (5, 8))	('lowest', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
74627	30442178	For this classification, class discriminability sdis is highest between class toLGG (cases that are most similar to low-grade glioma cases by their mutation profile) and class toPRAD for low-grade glioma (LGG) (sdis = - 3.26; p = 0.0; srand = - 6.1e-5; characteristic protein profiles increased in toLGG: p70S6K_pT389; increased in ToPRAD: YAP_pS127, HER2_pY1248, HER2, EGFR_pY1068, EGFR_pY1173, Src_pY416, and Cyclin_D1).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('EGFR', 'Gene', (370, 374))	('HER2', 'Gene', '2064', (351, 355))	('increased', 'PosReg', (285, 294))	('sdis', 'Chemical', '-', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('p70S6K', 'Gene', '6198', (305, 311))	('Cyclin_D1', 'Gene', (411, 420))	('EGFR', 'Gene', (383, 387))	('sdis', 'Chemical', '-', (211, 215))	('EGFR', 'Gene', '1956', (370, 374))	('HER2', 'Gene', '2064', (364, 368))	('HER2', 'Gene', (351, 355))	('ran', 'Gene', (236, 239))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', '5901', (236, 239))	('increased', 'PosReg', (319, 328))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('p70S6K', 'Gene', (305, 311))	('EGFR', 'Gene', '1956', (383, 387))	('glioma', 'Disease', (197, 203))	('Src_pY416', 'Var', (396, 405))	('HER2', 'Gene', (364, 368))	('Cyclin_D1', 'Gene', '595', (411, 420))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
74650	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('mutations', 'Var', (96, 105))
74655	30442178	Overall, our analysis showed for all analyzed 12 actionable genes (OncoKB evidence levels 1-3) that the mutational status is associated with significant differences in protein profiles in histotypes for which the respective targeted drugs are approved or currently being clinically tested and showed additional mutation-associated protein profiles in 9 histological tumor types.	('tumor', 'Disease', (366, 371))	('mutational', 'Var', (104, 114))	('associated', 'Reg', (125, 135))	('protein profiles', 'MPA', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('differences', 'Reg', (153, 164))
74657	30442178	Only KRAS/NRAS mutations in colorectal cancer do not result in discriminable protein profiles comparing wild-type and mutated cases, whereas an effect can be observed for thyroid cancer and melanoma.	('result', 'Reg', (53, 59))	('NRAS', 'Gene', '4893', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (15, 24))	('colorectal cancer', 'Disease', (28, 45))	('KRAS', 'Gene', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('KRAS', 'Gene', '3845', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('thyroid cancer', 'Disease', (171, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('NRAS', 'Gene', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))
74660	30442178	Our results demonstrate that in addition to confirming known druggable genes in the available cell line data, protein profile discriminability in between presence or absence of oncogenic mutations is predictive of drug response in cell line data across cancers (p = 0.048, Table 2).	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (187, 196))	('protein profile', 'MPA', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
74661	30442178	BRAF mutations are actionable in melanomas (OncoKB level 1).	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (33, 42))
74662	30442178	Mutations of BRAF are frequent enough in our data for melanoma (46% cases with mutation) and thyroid carcinoma (not yet reported by OncoKB, 56% cases with mutation) for further analysis.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('thyroid carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', (13, 17))	('melanoma', 'Disease', (54, 62))	('Mutations', 'Var', (0, 9))	('mutation', 'Var', (79, 87))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (93, 110))
74663	30442178	The actionable mutations create discriminable groups of cases for thyroid carcinoma (sdis = - 2.07; p = 0.0; srand = - 1.0e-4) and melanoma (sdis = - 0.10; p = 4.7e-3; srand = - 1.1e-4).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma', 'Disease', (131, 139))	('thyroid carcinoma', 'Disease', (66, 83))	('sdis', 'Chemical', '-', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('sdis', 'Chemical', '-', (141, 145))	('ran', 'Gene', (169, 172))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (66, 83))	('ran', 'Gene', '5901', (169, 172))
74667	30442178	CDK4 amplification is actionable for differentiated sarcomas (OncoKB level 2).	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('amplification', 'Var', (5, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Disease', (52, 60))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
74669	30442178	For sarcoma, 36% of the cases show CDK4 amplification and protein profiles are discriminable (sdis = - 0.34; p = 0.0; srand = - 6.0e-5) with E-Cadherin, Caveolin-1, Akt_pS473, Cyclin_B1, ER-alpha, Akt_pT308, YAP_pS127, S6_pS240_S244, and Cyclin_E1 decreased and HSP70, Syk, Lck, Src_pY416, and Src_pY527 increased in CDK4 amplified cases.	('CDK4', 'Gene', '1019', (317, 321))	('Cyclin_B1', 'Gene', (176, 185))	('decreased', 'NegReg', (248, 257))	('Lck', 'Gene', (274, 277))	('ER-alpha', 'Gene', (187, 195))	('E-Cadherin', 'Gene', '999', (141, 151))	('ER-alpha', 'Gene', '2099', (187, 195))	('increased', 'PosReg', (304, 313))	('sdis', 'Chemical', '-', (94, 98))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('Cyclin_B1', 'Gene', '891', (176, 185))	('Syk', 'Gene', '6850', (269, 272))	('CDK4', 'Gene', (35, 39))	('HSP70', 'Gene', (262, 267))	('ran', 'Gene', (119, 122))	('sarcoma', 'Disease', (4, 11))	('ran', 'Gene', '5901', (119, 122))	('Syk', 'Gene', (269, 272))	('Cyclin_E1', 'Gene', '898', (238, 247))	('E-Cadherin', 'Gene', (141, 151))	('Caveolin-1', 'Gene', (153, 163))	('CDK4', 'Gene', (317, 321))	('CDK4', 'Gene', '1019', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Src_pY416', 'Var', (279, 288))	('Caveolin-1', 'Gene', '857', (153, 163))	('Src_pY527', 'Var', (294, 303))	('Cyclin_E1', 'Gene', (238, 247))	('HSP70', 'Gene', '3308', (262, 267))	('Lck', 'Gene', '3932', (274, 277))
74671	30442178	EGFR mutations are actionable in non-small cell lung cancer (OncoKB level 1).	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('EGFR', 'Gene', '1956', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
74673	30442178	Lung adenocarcinoma (LUAD) cases with actionable mutation of EGFR are discriminable from those without by protein profile (sdis = - 0.44; p = 5.9e-4; srand = 3.1e-5).	('sdis', 'Chemical', '-', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('ran', 'Gene', (151, 154))	('ran', 'Gene', '5901', (151, 154))	('mutation', 'Var', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
74674	30442178	EGFR_pY1068 levels are increased for cases with the respective mutations, and Claudin-7 levels are decreased among those cases.	('mutations', 'Var', (63, 72))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', (0, 4))	('Claudin-7', 'Gene', '1366', (78, 87))	('increased', 'PosReg', (23, 32))	('EGFR', 'Gene', '1956', (0, 4))	('Claudin-7', 'Gene', (78, 87))
74675	30442178	ERBB2/HER2 amplification is actionable in breast cancer and gastric cancer (level 1 evidence, FDA-approved).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ERBB2', 'Gene', (0, 5))	('gastric cancer', 'Disease', (60, 74))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('breast cancer', 'Disease', (42, 55))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('amplification', 'Var', (11, 24))
74685	30442178	Two histological tumor types in which ERBB2 amplification has a similar impact on proteins are breast (BRCA) and gastric (STAD) cancers (p = 2.3e-3).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (17, 22))	('BRCA', 'Gene', '672', (103, 107))	('BRCA', 'Gene', (103, 107))	('gastric (STAD) cancers', 'Disease', 'MESH:D013274', (113, 135))	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('proteins', 'MPA', (82, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('impact', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
74690	30442178	For FGFR1 amplification, clinical evidence (OncoKB level 3) exists on its actionability in lung squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('FGFR1', 'Gene', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('lung squamous cell carcinomas', 'Disease', (91, 120))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (96, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
74691	30442178	Our analysis shows that besides lung squamous cell carcinoma, protein expression of amplified cases is discriminable from non-amplified cases in renal clear cell carcinoma, testicular germ cell tumors, lung adenocarcinoma, endometrial carcinoma, breast cancer, and thymoma (all currently not reported by OncoKB).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (145, 171))	('renal clear cell carcinoma', 'Disease', (145, 171))	('thymoma', 'Disease', (265, 272))	('thymoma', 'Phenotype', 'HP:0100522', (265, 272))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('lung adenocarcinoma', 'Disease', (202, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('protein expression', 'MPA', (62, 80))	('thymoma', 'Disease', 'MESH:D013945', (265, 272))	('testicular', 'Disease', (173, 183))	('amplified', 'Var', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
74694	30442178	A cross-cancer effect is found between breast cancer and lung adenocarcinoma with HER2, HER2_pY1248, and EGFR_pY1068 levels decrease and 4E-BP1 levels increase associated with FGFR1 amplification for both histological tumor types.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('A cross-cancer', 'Disease', 'MESH:C537866', (0, 14))	('increase', 'PosReg', (151, 159))	('HER2', 'Gene', '2064', (88, 92))	('4E-BP1', 'Gene', (137, 143))	('EGFR', 'Gene', (105, 109))	('decrease', 'NegReg', (124, 132))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (39, 52))	('levels', 'MPA', (117, 123))	('A cross-cancer', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('lung adenocarcinoma', 'Disease', (57, 76))	('HER2', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR1', 'Gene', '2260', (176, 181))	('HER2', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('4E-BP1', 'Gene', '1978', (137, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FGFR1', 'Gene', (176, 181))	('HER2', 'Gene', '2064', (82, 86))	('levels', 'MPA', (144, 150))	('amplification', 'Var', (182, 195))
74695	30442178	Certain FGFR3 mutations are actionable in bladder cancer (OncoKB level 3).	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FGFR3', 'Gene', '2261', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('actionable', 'Reg', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
74696	30442178	Targetable FGFR3 mutations are only frequent enough in urothelial and bladder carcinoma for our analysis.	('frequent', 'Reg', (36, 44))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (70, 87))	('FGFR3', 'Gene', '2261', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('bladder carcinoma', 'Disease', 'MESH:D001749', (70, 87))	('FGFR3', 'Gene', (11, 16))	('bladder carcinoma', 'Disease', (70, 87))	('urothelial', 'Disease', (55, 65))	('mutations', 'Var', (17, 26))
74697	30442178	The protein profiles of cases with at least one of these mutations are discriminable from the profiles of those without (sdis = - 0.76; p = 2.7e-3; srand = - 1.3e-5).	('ran', 'Gene', '5901', (149, 152))	('mutations', 'Var', (57, 66))	('sdis', 'Chemical', '-', (121, 125))	('ran', 'Gene', (149, 152))
74698	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('PTEN', 'Gene', '5728', (38, 42))	('FGF3', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('Ku80', 'Gene', '7520', (32, 36))	('beta-Catenin', 'Gene', '1499', (12, 24))	('beta-Catenin', 'Gene', (12, 24))	('53BP1', 'Gene', '7158', (54, 59))	('Ku80', 'Gene', (32, 36))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('HER2', 'Gene', '2064', (26, 30))	('FGF3', 'Gene', '2248', (114, 118))	('IRS1', 'Gene', (44, 48))	('IRS1', 'Gene', '3667', (44, 48))	('increased', 'PosReg', (64, 73))	('E-Cadherin', 'Gene', '999', (0, 10))	('PTEN', 'Gene', (38, 42))	('53BP1', 'Gene', (54, 59))
74699	30442178	IDH1 mutations are actionable in acute myeloid leukemia, cholangiocarcinoma, and glioma (OncoKB level 3).	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('acute myeloid leukemia', 'Disease', (33, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', (81, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('IDH1', 'Gene', '3417', (0, 4))
74700	30442178	Specific IDH1 mutations lead to discriminable protein profiles for low-grade glioma (sdis = - 0.47; p = 0.0; srand = - 3.1e-6) and glioblastoma (sdis = - 1.59; p = 5.0e-4; srand = - 1.0e-5).	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('sdis', 'Chemical', '-', (85, 89))	('IDH1', 'Gene', '3417', (9, 13))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('glioma', 'Disease', (77, 83))	('ran', 'Gene', (173, 176))	('protein profiles', 'MPA', (46, 62))	('ran', 'Gene', '5901', (173, 176))	('sdis', 'Chemical', '-', (145, 149))	('mutations', 'Var', (14, 23))	('glioblastoma', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
74702	30442178	For glioblastoma IGFBP2, EGFR_pY1068, HER2_pY1248, Caveolin-1, Akt_pT308, Fibronectin, Collagen_VI, and EGFR_pY1173 are decreased in the group of mutated cases.	('decreased', 'NegReg', (120, 129))	('Fibronectin', 'Gene', (74, 85))	('HER2', 'Gene', (38, 42))	('EGFR', 'Gene', (25, 29))	('mutated', 'Var', (146, 153))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (104, 108))	('Caveolin-1', 'Gene', '857', (51, 61))	('glioblastoma', 'Disease', (4, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('Caveolin-1', 'Gene', (51, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('IGFBP2', 'Gene', '3485', (17, 23))	('IGFBP2', 'Gene', (17, 23))	('EGFR', 'Gene', '1956', (25, 29))	('HER2', 'Gene', '2064', (38, 42))	('Fibronectin', 'Gene', '2335', (74, 85))
74703	30442178	Therefore, IGFBP2, EGFR_pY1068, HER2_pY1248, and EGFR_pY1173 are affected in the same way by IDH1 mutations in low-grade glioma and glioblastoma, and we report a cross-cancer effect for those groups.	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', (19, 23))	('glioblastoma', 'Disease', (132, 144))	('glioma', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cross-cancer', 'Disease', 'MESH:C537866', (162, 174))	('IDH1', 'Gene', (93, 97))	('HER2', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cross-cancer', 'Disease', (162, 174))	('IGFBP2', 'Gene', '3485', (11, 17))	('EGFR', 'Gene', '1956', (49, 53))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (98, 107))	('affected', 'Reg', (65, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('IGFBP2', 'Gene', (11, 17))
74704	30442178	KIT mutations are actionable in gastrointestinal stromal tumors (OncoKB level 1).	('gastrointestinal stromal tumors', 'Disease', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (32, 63))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (32, 63))
74705	30442178	For the tested KIT mutations, only testicular germ cell tumors (TGCT) had enough mutated cases sufficient for our analysis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KIT', 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
74706	30442178	The protein profiles of the mutated and wild-type cases are discriminable (sdis = - 0.90; p = 4.5e-3; srand = - 2.6e-4) with decreased E-Cadherin and Fibronectin expression in wildtype cases and increased c-Kit, STAT5-alpha, and Syk expression levels.	('Fibronectin', 'Gene', '2335', (150, 161))	('mutated', 'Var', (28, 35))	('c-Kit', 'Gene', (205, 210))	('Fibronectin', 'Gene', (150, 161))	('E-Cadherin', 'Gene', '999', (135, 145))	('expression levels', 'MPA', (233, 250))	('c-Kit', 'Gene', '3815', (205, 210))	('Syk', 'Gene', '6850', (229, 232))	('decreased', 'NegReg', (125, 134))	('sdis', 'Chemical', '-', (75, 79))	('STAT5-alpha', 'Gene', '6776', (212, 223))	('ran', 'Gene', (103, 106))	('expression', 'MPA', (162, 172))	('ran', 'Gene', '5901', (103, 106))	('Syk', 'Gene', (229, 232))	('STAT5-alpha', 'Gene', (212, 223))	('increased', 'PosReg', (195, 204))	('E-Cadherin', 'Gene', (135, 145))
74708	30442178	KRAS/NRAS mutations are therapeutically relevant for melanomas, colorectal cancer, and thyroid cancer (OncoKB level 3).	('melanomas', 'Disease', (53, 62))	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', (64, 81))	('NRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
74709	30442178	Specific KRAS/NRAS mutations are correlated with differences in protein profiles for melanomas and thyroid cancer and also for testicular germ cell tumors, endometrial carcinoma, and lung adenocarcinoma (in conformity with OncoKB level 4 data).	('melanomas', 'Disease', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('thyroid cancer', 'Disease', (99, 113))	('differences', 'Reg', (49, 60))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NRAS', 'Gene', '4893', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('KRAS', 'Gene', '3845', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('protein profiles', 'MPA', (64, 80))	('lung adenocarcinoma', 'Disease', (183, 202))	('KRAS', 'Gene', (9, 13))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumors', 'Disease', (148, 154))	('NRAS', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('endometrial carcinoma', 'Disease', (156, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
74712	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('Caveolin-1', 'Gene', (67, 77))	('mutated', 'Var', (125, 132))	('MAPK_pT202_Y204', 'Var', (144, 159))	('decreased', 'NegReg', (111, 120))	('sdis', 'Chemical', '-', (14, 18))	('Caveolin-1', 'Gene', '857', (67, 77))	('c-Kit', 'Gene', (83, 88))	('c-Kit', 'Gene', '3815', (83, 88))	('E-Cadherin', 'Gene', (55, 65))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('expression levels', 'MPA', (89, 106))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
74713	30442178	For thyroid carcinoma (sdis = - 1.53; p = 0.0; srand = - 3.0e-4), the level of Fibronectin is decreased in mutated cases.	('sdis', 'Chemical', '-', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('ran', 'Gene', (48, 51))	('mutated', 'Var', (107, 114))	('ran', 'Gene', '5901', (48, 51))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('decreased', 'NegReg', (94, 103))	('Fibronectin', 'Gene', '2335', (79, 90))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
74714	30442178	For lung adenocarcinoma and endometrial carcinoma, we observed a cross-cancer effect for KRAS/NRAS-mutated cases as ATM levels are decreased, and MAPK_pT202_Y204, Claudin-7, S6_pS235_S236, and MEK1_pS217_S221 are increased in both histological tumor types consistently.	('S6_pS235_S236', 'Var', (174, 187))	('endometrial carcinoma', 'Disease', (28, 49))	('Claudin-7', 'Gene', '1366', (163, 172))	('lung adenocarcinoma', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (28, 49))	('NRAS', 'Gene', '4893', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Gene', '5609', (193, 196))	('ATM', 'Gene', '472', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('KRAS', 'Gene', '3845', (89, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (28, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('cross-cancer', 'Disease', 'MESH:C537866', (65, 77))	('MEK', 'Gene', (193, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('MAPK_pT202_Y204', 'Var', (146, 161))	('KRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (94, 98))	('tumor', 'Disease', (244, 249))	('cross-cancer', 'Disease', (65, 77))	('decreased', 'NegReg', (131, 140))	('ATM', 'Gene', (116, 119))	('Claudin-7', 'Gene', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('increased', 'PosReg', (213, 222))
74715	30442178	MDM2 amplification is actionable in liposarcoma (OncoKB level 3).	('liposarcoma', 'Disease', (36, 47))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
74716	30442178	Besides sarcoma, the protein profiles of cases with MDM2 amplification are discriminable from those with normal copy numbers for renal clear cell carcinoma, lung adenocarcinoma, thyroid carcinoma, breast cancer, ovarian carcinoma, and low-grade glioma (all currently not reported by OncoKB).	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('MDM2', 'Gene', (52, 56))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (129, 155))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('renal clear cell carcinoma', 'Disease', (129, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (178, 195))	('MDM2', 'Gene', '4193', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('thyroid carcinoma', 'Disease', (178, 195))	('breast cancer', 'Disease', (197, 210))	('amplification', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (212, 229))	('ovarian carcinoma', 'Disease', (212, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (178, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('sarcoma', 'Disease', (8, 15))	('glioma', 'Disease', (245, 251))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('lung adenocarcinoma', 'Disease', (157, 176))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
74717	30442178	Protein levels of sarcoma cases with MDM2 amplifications are discriminable from those without, with a dissimilarity score of sdis = - 0.41 (p = 0.0; srand = - 8.9e-5).	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', (18, 25))	('Protein levels', 'MPA', (0, 14))	('MDM2', 'Gene', '4193', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('amplifications', 'Var', (42, 56))	('MDM2', 'Gene', (37, 41))	('sdis', 'Chemical', '-', (125, 129))	('ran', 'Gene', (150, 153))
74718	30442178	Amplified cases show decreased levels of E-Cadherin, Akt_pS473, Akt_pT308, ER-alpha, Caveolin-1, S6_pS240_S244, S6_pS235_S236, and Cyclin_B1 and increased levels of HSP70, Syk, and Lck.	('Lck', 'Gene', (181, 184))	('Akt_pT308', 'Gene', (64, 73))	('HSP70', 'Gene', '3308', (165, 170))	('Cyclin_B1', 'Gene', '891', (131, 140))	('Caveolin-1', 'Gene', (85, 95))	('E-Cadherin', 'Gene', (41, 51))	('Caveolin-1', 'Gene', '857', (85, 95))	('S6_pS240_S244', 'Var', (97, 110))	('levels', 'MPA', (155, 161))	('ER-alpha', 'Gene', (75, 83))	('increased', 'PosReg', (145, 154))	('ER-alpha', 'Gene', '2099', (75, 83))	('Syk', 'Gene', '6850', (172, 175))	('HSP70', 'Gene', (165, 170))	('S6_pS235_S236', 'Var', (112, 125))	('Syk', 'Gene', (172, 175))	('decreased', 'NegReg', (21, 30))	('Cyclin_B1', 'Gene', (131, 140))	('Lck', 'Gene', '3932', (181, 184))	('Akt_pS473', 'Protein', (53, 62))	('E-Cadherin', 'Gene', '999', (41, 51))
74721	30442178	In addition to these histotypes, we found 11 other histological tumor types (renal clear cell carcinoma, low-grade glioma, renal papillary cell carcinoma, colon carcinoma, thyroid carcinoma, thymoma, sarcoma, lung adenocarcinoma, testicular germ cell tumors, prostate adenocarcinoma, glioblastoma, breast and ovarian carcinoma) where MET amplification is associated with a significant change in protein expression.	('tumor', 'Disease', (251, 256))	('glioma', 'Disease', (115, 121))	('breast and ovarian carcinoma', 'Disease', 'MESH:D001943', (298, 326))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('protein expression', 'MPA', (395, 413))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MET amplification', 'Var', (334, 351))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lung adenocarcinoma', 'Disease', (209, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (172, 189))	('thymoma', 'Disease', 'MESH:D013945', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('thyroid carcinoma', 'Disease', (172, 189))	('renal papillary cell carcinoma', 'Disease', (123, 153))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('thymoma', 'Disease', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (172, 189))	('thymoma', 'Phenotype', 'HP:0100522', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('prostate adenocarcinoma', 'Disease', (259, 282))	('tumors', 'Disease', (251, 257))	('colon carcinoma', 'Disease', (155, 170))	('change', 'Reg', (385, 391))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (309, 326))	('renal clear cell carcinoma', 'Disease', (77, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Disease', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('colon carcinoma', 'Disease', 'MESH:D015179', (155, 170))	('sarcoma', 'Disease', (200, 207))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (259, 282))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('glioblastoma', 'Disease', (284, 296))
74724	30442178	MET amplification is present in renal clear cell carcinoma cases, and protein profiles of amplified and non-amplified cases can be discriminated (sdis = - 0.18; p = 0.0; srand = - 2.0e-5; Src_pY527, Bcl-2, beta-Catenin, PTEN, MAPK_pT202_Y204 are decreased in amplified cases and ACC1, Cyclin_B1, ASNS, ACC_pS79, and Transglutaminase are increased).	('Cyclin_B1', 'Gene', '891', (285, 294))	('ran', 'Gene', (171, 174))	('ran', 'Gene', '5901', (171, 174))	('beta-Catenin', 'Gene', '1499', (206, 218))	('ASNS', 'Gene', (296, 300))	('Src_pY527', 'Var', (188, 197))	('PTEN', 'Gene', '5728', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('increased', 'PosReg', (337, 346))	('ACC_pS79', 'MPA', (302, 310))	('ACC1', 'Gene', (279, 283))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (32, 58))	('beta-Catenin', 'Gene', (206, 218))	('MAPK_pT202_Y204', 'Gene', (226, 241))	('renal clear cell carcinoma', 'Disease', (32, 58))	('decreased', 'NegReg', (246, 255))	('ACC1', 'Gene', '597', (279, 283))	('Cyclin_B1', 'Gene', (285, 294))	('ran', 'Gene', (317, 320))	('ran', 'Gene', '5901', (317, 320))	('sdis', 'Chemical', '-', (146, 150))	('Bcl-2', 'Gene', (199, 204))	('ASNS', 'Gene', '440', (296, 300))	('PTEN', 'Gene', (220, 224))	('Bcl-2', 'Gene', '596', (199, 204))
74726	30442178	PIK3CA activating mutations are actionable for breast cancer (OncoKB evidence level 3).	('breast cancer', 'Disease', (47, 60))	('activating', 'PosReg', (7, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('mutations', 'Var', (18, 27))
74728	30442178	OncoKB level 4 data lists all available histological tumor types as possibly actionable for PIK3CA activating mutations.	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', '5290', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PIK3CA', 'Gene', (92, 98))
74730	30442178	Breast cancer cases with PIK3CA-activating mutations are discriminable from those without (sdis = - 0.52; p = 0.0; srand = 6.2e-6) with specific proteins (increased levels) PR, ER-alpha, MAPK_pT202_Y204, Fibronectin, AR, and GATA3 in mutated cases and Cyclin_B1, Cyclin_E1, ASNS, and HER2 being decreased.	('ran', 'Gene', (116, 119))	('ran', 'Gene', '5901', (116, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cyclin_B1', 'Gene', '891', (252, 261))	('PIK3CA', 'Gene', '5290', (25, 31))	('increased', 'PosReg', (155, 164))	('HER2', 'Gene', '2064', (284, 288))	('Cyclin_E1', 'Gene', '898', (263, 272))	('ASNS', 'Gene', '440', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutated', 'Var', (234, 241))	('GATA3', 'Gene', '2625', (225, 230))	('PIK3CA', 'Gene', (25, 31))	('Cyclin_E1', 'Gene', (263, 272))	('Fibronectin', 'Gene', '2335', (204, 215))	('Cyclin_B1', 'Gene', (252, 261))	('sdis', 'Chemical', '-', (91, 95))	('ASNS', 'Gene', (274, 278))	('ER-alpha', 'Gene', (177, 185))	('GATA3', 'Gene', (225, 230))	('HER2', 'Gene', (284, 288))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))
74734	30442178	However, many open questions remain because apart from mutations with unknown functional effects, it is often not possible even for oncogenic mutations with established clinical relevance in one cancer type to transfer knowledge of actionability to another cancer type.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ran', 'Gene', (211, 214))	('ran', 'Gene', '5901', (211, 214))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
74740	30442178	This indicates that identical genetic alterations are not translated into protein profiles in the same way in different histotypes.	('ran', 'Gene', '5901', (59, 62))	('ran', 'Gene', (59, 62))	('genetic alterations', 'Var', (30, 49))
74744	30442178	In addition to showing that our analysis identifies protein-level effects for known actionable genes and corresponding cancer types, our approach also identified protein-level alterations indicative of potential novel actionable gene:cancer combinations that are so far unknown according to OncoKB including level 4 evidence (biological information).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('combinations', 'Var', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
74745	30442178	This includes ERBB2/HER2 amplification in endometrial carcinoma, renal papillary carcinoma, testicular germ cell tumors, urothelial carcinoma, renal clear cell carcinoma, colon carcinoma, ovarian carcinoma, thymoma, thyroid carcinoma, cervical carcinoma, and head and neck squamous cell carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (171, 186))	('tumors', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HER2', 'Gene', (20, 24))	('thymoma', 'Disease', 'MESH:D013945', (207, 214))	('renal papillary carcinoma', 'Disease', (65, 90))	('cervical carcinoma', 'Disease', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinoma', 'Disease', (42, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (216, 233))	('ERBB2', 'Gene', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('thyroid carcinoma', 'Disease', (216, 233))	('thymoma', 'Disease', (207, 214))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 169))	('cervical carcinoma', 'Disease', 'MESH:D002575', (235, 253))	('renal clear cell carcinoma', 'Disease', (143, 169))	('thymoma', 'Phenotype', 'HP:0100522', (207, 214))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('ERBB2', 'Gene', '2064', (14, 19))	('ovarian carcinoma', 'Disease', (188, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (42, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (216, 233))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (65, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (42, 63))	('colon carcinoma', 'Disease', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('urothelial carcinoma', 'Disease', (121, 141))
74749	30442178	Interestingly, actionable genes with copy number alterations showed effects on protein expression for more histotypes than those with simple somatic mutations (10.2 affected tumor types on average for amplifications vs. 2.14 for simple somatic mutations).	('tumor', 'Disease', (174, 179))	('protein expression', 'MPA', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('effects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('copy number alterations', 'Var', (37, 60))
74753	30442178	With respect to the actionable gene analysis, our approach may underestimate the number of potentially druggable genes, but the fact that it readily identifies many well-established actionable gene, cancer combinations, such as, for instance, HER2 amplification in breast and gastric cancer, indicates its validity.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('HER2', 'Gene', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HER2', 'Gene', '2064', (243, 247))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (265, 290))	('amplification', 'Var', (248, 261))
74760	30442178	By evaluating protein-level effects of genetic aberrations, our approach facilitates the identification of functionally relevant mutations and may therefore contribute to predicting actionable mutations across cancers and to guide basket trial design.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (129, 138))	('facilitates', 'PosReg', (73, 84))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
75003	29379115	Overall, results show that cisplatin, doxorubicin and cyclophosphamide all specifically induce loss of germ cells, including of spermatogonial stem cells, in the prepubertal mouse testis at concentrations relevant to human therapeutic exposures.	('mouse', 'Species', '10090', (174, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('human', 'Species', '9606', (217, 222))	('rat', 'Species', '10116', (197, 200))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (54, 70))	('doxorubicin', 'Chemical', 'MESH:D004317', (38, 49))	('cyclophosphamide', 'Var', (54, 70))	('cisplatin', 'Var', (27, 36))	('germ cells', 'CPA', (103, 113))	('loss', 'NegReg', (95, 99))
75037	29379115	The difference between Control and treatment group germ cell numbers was as follows: Low PM 1.5-fold difference, Mid PM 20-fold difference; High PM no Mvh+ cells remaining; Low CIS 40-fold difference; Mid/High CIS 500- to 1000-fold difference; Low and Mid DOX 50-fold difference; and High DOX 100-fold difference.	('PM', 'Chemical', 'MESH:C030090', (145, 147))	('Mvh', 'Gene', (151, 154))	('DOX', 'Chemical', 'MESH:D004317', (289, 292))	('Mvh', 'Gene', '13206', (151, 154))	('PM', 'Chemical', 'MESH:C030090', (89, 91))	('DOX', 'Chemical', 'MESH:D004317', (256, 259))	('PM', 'Chemical', 'MESH:C030090', (117, 119))	('Low CIS', 'Var', (173, 180))
75039	29379115	IHC was carried out for PLZF, expressed specifically in SSCs, after exposure to Mid PM, Low CIS or Low DOX: the Mid PM concentration was used due to the markedly higher survival of germ cells after Low PM compared to Low CIS or Low DOX exposure (Fig.	('survival', 'CPA', (169, 177))	('PLZF', 'Gene', (24, 28))	('higher', 'PosReg', (162, 168))	('PM', 'Chemical', 'MESH:C030090', (84, 86))	('DOX', 'Chemical', 'MESH:D004317', (103, 106))	('rat', 'Species', '10116', (126, 129))	('DOX', 'Chemical', 'MESH:D004317', (232, 235))	('PM', 'Chemical', 'MESH:C030090', (116, 118))	('PLZF', 'Gene', '7704', (24, 28))	('Low PM', 'Var', (198, 204))	('PM', 'Chemical', 'MESH:C030090', (202, 204))
75053	29379115	Testis fragments were cultured for 24 h in control medium, and then exposed to Mid PM, Low CIS or Low DOX: the Mid PM concentration was used due to the markedly higher survival of germ cells after Low PM compared to Low CIS or Low DOX exposure (Fig.	('PM', 'Chemical', 'MESH:C030090', (83, 85))	('DOX', 'Chemical', 'MESH:D004317', (102, 105))	('rat', 'Species', '10116', (125, 128))	('Low PM', 'Var', (197, 203))	('PM', 'Chemical', 'MESH:C030090', (201, 203))	('PM', 'Chemical', 'MESH:C030090', (115, 117))	('survival', 'CPA', (168, 176))	('higher', 'PosReg', (161, 167))	('DOX', 'Chemical', 'MESH:D004317', (231, 234))
75075	29379115	The majority of work examining the effects of chemotherapy drugs on gonadal function in rodents have looked at the post-pubertal testis, with exposure to CYP, CIS and DOX all resulting in germ cell damage [for example].	('resulting in', 'Reg', (175, 187))	('CYP', 'Var', (154, 157))	('germ cell damage', 'CPA', (188, 204))	('CIS', 'Var', (159, 162))	('DOX', 'Chemical', 'MESH:D004317', (167, 170))
75096	29379115	At the end of the four day culture period, 48 h after the drug exposure period had ended, there was little evidence of apoptosis, with significant increases in CC3 expression seen only after exposure to High CIS, or to Mid or High DOX, and with no significant increase found after PM exposure.	('increases', 'PosReg', (147, 156))	('expression', 'MPA', (164, 174))	('High CIS', 'Var', (203, 211))	('DOX', 'Chemical', 'MESH:D004317', (231, 234))	('CC3', 'Chemical', '-', (160, 163))	('CC3', 'Gene', (160, 163))	('PM', 'Chemical', 'MESH:C030090', (281, 283))
75102	29379115	Results showed a significant, marked increase in such foci in response to all three drugs after 16 h, with DOX exposure leading to the largest increase: CYP and CIS have previously been shown to result in an increase in gammaH2AX in a mouse spermatogonial cell line.	('gammaH2AX', 'Gene', (220, 229))	('CYP', 'Var', (153, 156))	('DOX', 'Chemical', 'MESH:D004317', (107, 110))	('increase', 'PosReg', (208, 216))	('gammaH2AX', 'Gene', '15270', (220, 229))	('CIS', 'Var', (161, 164))	('mouse', 'Species', '10090', (235, 240))
75105	29379115	Alternatively, Sertoli cell damage following repeated administration of CIS to adult mice has been shown to result in long-term spermatogenesis problems despite the survival of stem germ cells.	('mice', 'Species', '10090', (85, 89))	('Sertoli cell', 'Phenotype', 'HP:0100619', (15, 27))	('damage', 'Var', (28, 34))	('rat', 'Species', '10116', (62, 65))	('spermatogenesis problems', 'Phenotype', 'HP:0008669', (128, 152))	('result', 'Reg', (108, 114))	('spermatogenesis problems', 'CPA', (128, 152))
75111	29379115	In summary, the work here, using an in vitro model of the mouse prepubertal testis, shows that the three chemotherapy drugs CYP (through use of its active metabolite PM), CIS and DOX each induced a rapid and marked decrease in the germ cell population after exposure to clinically relevant concentrations, and that this includes a decrease in the stem germ cell population.	('decrease', 'NegReg', (215, 223))	('stem germ cell population', 'CPA', (347, 372))	('mouse', 'Species', '10090', (58, 63))	('DOX', 'Chemical', 'MESH:D004317', (179, 182))	('rat', 'Species', '10116', (297, 300))	('PM', 'Chemical', 'MESH:C030090', (166, 168))	('CIS', 'Var', (171, 174))	('germ cell population', 'CPA', (231, 251))	('decrease', 'NegReg', (331, 339))
75162	19876845	Conversely, by IHC, SOX2 protein was not detected in seminomas using either the AB5603 or AF2018 antibodies (Fig.	('AB5603', 'Var', (80, 86))	('seminomas', 'Disease', 'MESH:D018239', (53, 62))	('seminomas', 'Disease', (53, 62))	('AF2018 antibodies', 'Var', (90, 107))
75169	19876845	Of note, cross-reactivity with SOX17 is highly unlikely as this latter protein is readily detected in human fetal gonad during the first trimester when staining using anti-SOX2 antibodies AB5603 (or AF2018) is absent (N Hanley, unpublished findings).	('AB5603', 'Var', (188, 194))	('SOX17', 'Gene', '64321', (31, 36))	('SOX17', 'Gene', (31, 36))	('human', 'Species', '9606', (102, 107))
75189	19876845	For SOX2 antibodies, dewaxed and rehydrated sections were heated in a microwave oven in sodium citrate buffer (10 mM, pH 6) for AB5603 or TEG buffer (10 mM TRIS, 0.5 mM EGTA, pH 9) for AF2018 to unmask the antigen.	('SOX2', 'Gene', (4, 8))	('sodium citrate', 'Chemical', 'MESH:D000077559', (88, 102))	('EGTA', 'Chemical', 'MESH:D004533', (169, 173))	('AB5603', 'Var', (128, 134))	('TEG', 'Chemical', 'MESH:C028914', (138, 141))	('AF2018', 'Var', (185, 191))	('TRIS', 'Chemical', '-', (156, 160))
75190	19876845	Subsequently, the sections were incubated with 0.5% H2O2 to inhibit endogenous peroxidase, followed by diluted non-immune goat serum (Zymed, San Francisco, CA, US) or horse serum (Vector Laboratories, Burlingame, CA, US) to block unspecific binding sites.	('endogenous peroxidase', 'Enzyme', (68, 89))	('H2O2', 'Chemical', 'MESH:D006861', (52, 56))	('unspecific', 'Interaction', (230, 240))	('inhibit', 'NegReg', (60, 67))	('H2O2', 'Var', (52, 56))	('goat', 'Species', '9925', (122, 126))	('horse', 'Species', '9796', (167, 172))
75310	31244770	For example, 15-30% of patients 45XO/46XY DSD and 46XY DSD (with different degrees of gonadal dysgenesis) show the highest risk for TGCT.	('46XY DSD', 'Var', (50, 58))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (86, 104))	('gonadal dysgenesis', 'Disease', (86, 104))	('patients', 'Species', '9606', (23, 31))	('45XO/46XY DSD', 'Var', (32, 45))	('gonadal dysgenesis', 'Disease', 'MESH:D006059', (86, 104))	('TGCT', 'Disease', (132, 136))
75316	31244770	So, altered testosterone levels could affect the normal development of somatic Sertoli cells leading them to an insufficient germ cell stimulation and to an abnormal differentiation.	('insufficient', 'Disease', 'MESH:D000309', (112, 124))	('men', 'Species', '9606', (63, 66))	('insufficient', 'Disease', (112, 124))	('altered', 'Var', (4, 11))	('Sertoli cell', 'Phenotype', 'HP:0100619', (79, 91))	('altered testosterone levels', 'Phenotype', 'HP:0030088', (4, 31))	('Sertoli cells', 'Phenotype', 'HP:0100619', (79, 92))	('testosterone', 'Chemical', 'MESH:D013739', (12, 24))	('affect', 'Reg', (38, 44))
75349	31244770	Regarding the epigenetic modifications, genes involved in germ cell development are strictly regulated by epigenetic changes, such as DNA methylation, and microRNA (miRNA) activity (see below).	('epigenetic changes', 'Var', (106, 124))	('DNA', 'MPA', (134, 137))	('men', 'Species', '9606', (75, 78))	('microRNA', 'MPA', (155, 163))	('regulated', 'Reg', (93, 102))
75360	31244770	These genes could similarly induce pluripotency in GCNIS.	('pluripotency', 'Disease', (35, 47))	('pluripotency', 'Disease', 'None', (35, 47))	('induce', 'Reg', (28, 34))	('genes', 'Var', (6, 11))	('GCNIS', 'Chemical', '-', (51, 56))
75374	31244770	In particular, miRNAs from miR-371-373 (mapped to chromosome 19) and miR- 302-367 (mapped to chromosome 4) family members are upregulated in all TGCT and elevated values could be detected in the serum, regardless of pediatric or adult age, gonadal or extragonadal localization or tumor subtype (seminomas, yolk sac tumors, or embryonal carcinomas).	('embryonal carcinomas', 'Disease', 'MESH:D018236', (326, 346))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('upregulated', 'PosReg', (126, 137))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('carcinomas', 'Phenotype', 'HP:0030731', (336, 346))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('miR-371', 'Gene', '442916', (27, 34))	('TGCT', 'Disease', (145, 149))	('tumor', 'Disease', (280, 285))	('tumors', 'Disease', (315, 321))	('miR-371', 'Gene', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('embryonal carcinomas', 'Phenotype', 'HP:0002898', (326, 346))	('miRNAs', 'MPA', (15, 21))	('embryonal carcinomas', 'Disease', (326, 346))	('miR- 302-367', 'Var', (69, 81))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('seminomas', 'Disease', 'MESH:D018239', (295, 304))	('seminomas', 'Disease', (295, 304))	('tumor', 'Disease', (315, 320))
75377	31244770	A more recent study based on microarray gene expression profiling and gene methylation datasets, suggests that hypomethylation-high expressed genes such as CSF1R, PTPRC, and MMP9, could be involved in TGCT.	('PTPRC', 'Gene', '5788', (163, 168))	('MMP9', 'Gene', '4318', (174, 178))	('hypomethylation-high', 'Var', (111, 131))	('involved', 'Reg', (189, 197))	('CSF1R', 'Gene', (156, 161))	('TGCT', 'Disease', (201, 205))	('PTPRC', 'Gene', (163, 168))	('MMP9', 'Gene', (174, 178))	('CSF1R', 'Gene', '1436', (156, 161))
75392	31244770	Instead, the detection of specific TGCT's miRNAs (miR-371~373 and miR-302/367) in semen could be considered a promising non-invasive marker of GCNIS being highly overexpressed both in serum (in all TGCT) and in semen.	('miR-302/367', 'Var', (66, 77))	('miR-371', 'Gene', '442916', (50, 57))	('TGCT', 'Gene', (35, 39))	('overexpressed', 'PosReg', (162, 175))	('GCNIS', 'Chemical', '-', (143, 148))	('men', 'Species', '9606', (84, 87))	('miR-371', 'Gene', (50, 57))	('men', 'Species', '9606', (213, 216))
75434	24603594	Pharmacological and Molecular Effects of Platinum(II) Complexes Involving 7-Azaindole Derivatives The in vitro antitumour activity studies on a panel of human cancer cell lines (A549, HeLa, G-361, A2780, and A2780R) and the combined in vivo and ex vivo antitumour testing on the L1210 lymphocytic leukaemia model were performed on the cis-[PtCl2(naza)2] complexes (1-3) involving the 7-azaindole derivatives (naza).	('A549', 'CellLine', 'CVCL:0023', (178, 182))	('Platinum(II)', 'Chemical', '-', (41, 53))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('human', 'Species', '9606', (153, 158))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))	('cancer', 'Disease', (159, 165))	('7-azaindole', 'Chemical', 'MESH:C023422', (384, 395))	('7-Azaindole', 'Chemical', 'MESH:C023422', (74, 85))	('L1210 lymphocytic leukaemia', 'Disease', (279, 306))	('HeLa', 'CellLine', 'CVCL:0030', (184, 188))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Disease', (257, 263))	('naza', 'Chemical', '-', (346, 350))	('naza', 'Chemical', '-', (409, 413))	('A2780R', 'Var', (208, 214))	('A2780', 'Var', (197, 202))	('A2780R', 'Mutation', 'p.A2780R', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cis-[PtCl2(naza)2]', 'Chemical', '-', (335, 353))	('L1210 lymphocytic leukaemia', 'Disease', 'MESH:D007939', (279, 306))
75453	24603594	Bearing this in mind, we aimed to find a simple, planar and well-coordinating N-donor heterocycle, whose incorporation into the cisplatin molecule, instead of one or both NH3 molecules, could bring in the similar effect on the antitumour properties as in the case of picoplatin.	('donor', 'Species', '9606', (80, 85))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('tumour', 'Disease', (231, 237))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('incorporation', 'Var', (105, 118))	('picoplatin', 'Chemical', 'MESH:C110525', (267, 277))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('bring in', 'Reg', (192, 200))
75459	24603594	Following the previous promising results of in vitro studies, we were determined to perform an advanced study of in vitro cytotoxicity on an extended panel of human cancer cell lines (A549, HeLa, G-361, A2780 and cisplatin-resistant A2780R), together with the in vivo and ex vivo studies on L1210 lymphocytic leukaemia model complemented by the histological and immunohistochemical investigation on the cancerous tissues and studies of expression of caspases 3 and 8, p53 and VEGF-A, i.e.	('cytotoxicity', 'Disease', (122, 134))	('cancerous', 'Disease', (403, 412))	('A549', 'CellLine', 'CVCL:0023', (184, 188))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cytotoxicity', 'Disease', 'MESH:D064420', (122, 134))	('L1210 lymphocytic leukaemia', 'Disease', 'MESH:D007939', (291, 318))	('human', 'Species', '9606', (159, 164))	('A2780R', 'Var', (233, 239))	('VEGF-A', 'Gene', (476, 482))	('p53', 'Gene', (468, 471))	('cisplatin', 'Chemical', 'MESH:D002945', (213, 222))	('cancer', 'Disease', (403, 409))	('A2780R', 'Mutation', 'p.A2780R', (233, 239))	('HeLa', 'CellLine', 'CVCL:0030', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('cancer', 'Disease', (165, 171))	('L1210 lymphocytic leukaemia', 'Disease', (291, 318))	('cancerous', 'Disease', 'MESH:D009369', (403, 412))	('A2780', 'Var', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('VEGF-A', 'Gene', '7422', (476, 482))	('cancer', 'Disease', 'MESH:D009369', (403, 409))
75548	24603594	These results indirectly proved that the studied platinum(II) complexes with 7-azaindoles are able to overcome intrinsic resistance to cisplatin on the A549, A2780 and A2780R (1-3), and HeLa and G-361 (1, 3) human cancer cell lines in vitro.	('A2780', 'Var', (158, 163))	('cancer', 'Disease', (214, 220))	('HeLa', 'CellLine', 'CVCL:0030', (186, 190))	('A2780R', 'Mutation', 'p.A2780R', (168, 174))	('intrinsic resistance to cisplatin', 'MPA', (111, 144))	('platinum(II)', 'Chemical', '-', (49, 61))	('A549', 'CellLine', 'CVCL:0023', (152, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('7-azaindoles', 'Chemical', 'MESH:C023422', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('human', 'Species', '9606', (208, 213))	('overcome', 'PosReg', (102, 110))	('A2780R', 'Var', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
75550	24603594	The antitumour activity in vitro of the complexes 1-3 can be evaluated also by means of the resistance factors, since the substances were tested on both cisplatin-sensitive (A2780) and resistant (A2780R) ovarian carcinoma cell lines (Figure 4).	('tumour', 'Disease', (8, 14))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (204, 221))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (204, 221))	('ovarian carcinoma', 'Disease', (204, 221))	('A2780R', 'Mutation', 'p.A2780R', (196, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('A2780R', 'Var', (196, 202))	('tested', 'Reg', (138, 144))
75555	24603594	Two of the studied complexes (1, 3) have significantly higher in vitro antitumour activity (p<0.05) than cisplatin against all eight human cancer cell lines, while the complex 2 only on the A549, A2780, A2780R and HOS cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('A2780R', 'Mutation', 'p.A2780R', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', (75, 81))	('HOS', 'Disease', 'MESH:C535326', (214, 217))	('human', 'Species', '9606', (133, 138))	('HOS', 'Disease', (214, 217))	('A549', 'CellLine', 'CVCL:0023', (190, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('A2780R', 'Var', (203, 209))	('higher', 'PosReg', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (139, 145))
75602	24603594	Platination of DNA molecule induces DNA damage which results in a cell cycle arrest or in apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('Platination', 'Var', (0, 11))	('results in', 'Reg', (53, 63))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('DNA damage', 'MPA', (36, 46))	('apoptosis', 'CPA', (90, 99))	('arrest', 'Disease', (77, 83))
75616	24603594	In this paper, we extended the scope of in vitro cytotoxicity testing to the expanded panel of human cancer cell lines (A549, HeLa, A2780 and cisplatin-resistant A2780R, and G-361) and found significant antitumour activity in vitro (the IC50 values were as low as 1 microM level), which surpassed that of cisplatin considerably.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Disease', (207, 213))	('human', 'Species', '9606', (95, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('A2780R', 'Var', (162, 168))	('cancer', 'Disease', (101, 107))	('cytotoxicity', 'Disease', (49, 61))	('A2780R', 'Mutation', 'p.A2780R', (162, 168))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('HeLa', 'CellLine', 'CVCL:0030', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (305, 314))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
75625	23737712	The Effect of Mirtazapine on Cisplatin-Induced Oxidative Damage and Infertility in Rat Ovaries Cisplatin causes infertility due to ovarian toxicity.	('infertility', 'Disease', (112, 123))	('Mirtazapine', 'Chemical', 'MESH:D000078785', (14, 25))	('causes', 'Reg', (105, 111))	('Cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('Infertility', 'Phenotype', 'HP:0000789', (68, 79))	('Cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('Rat', 'Species', '10116', (83, 86))	('Cisplatin', 'Var', (95, 104))	('ovarian toxicity', 'Disease', 'MESH:D010049', (131, 147))	('ovarian toxicity', 'Disease', (131, 147))	('infertility', 'Disease', 'MESH:D007247', (112, 123))	('infertility', 'Phenotype', 'HP:0000789', (112, 123))	('infertility due to ovarian toxicity', 'Phenotype', 'HP:0008209', (112, 147))
75634	23737712	The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups.	('mirtazapine', 'Chemical', 'MESH:D000078785', (137, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('MDA', 'MPA', (4, 7))	('cisplatin-treated', 'Var', (63, 80))	('MPO', 'Gene', '303413', (9, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('MPO', 'Gene', (9, 12))	('8-OH Gua', 'Chemical', '-', (28, 36))	('higher', 'PosReg', (49, 55))
75635	23737712	GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine.	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('GSH', 'MPA', (0, 3))	('GPx', 'MPA', (5, 8))	('GPx', 'Chemical', '-', (5, 8))	('reduced', 'NegReg', (30, 37))	('cisplatin', 'Var', (41, 50))	('mirtazapine', 'Chemical', 'MESH:D000078785', (75, 86))	('GSH', 'Chemical', '-', (0, 3))
75638	23737712	In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats.	('rat', 'Species', '10116', (110, 113))	('causes', 'Reg', (77, 83))	('infertility in the female', 'Phenotype', 'HP:0008222', (84, 109))	('cisplatin', 'Var', (43, 52))	('rat', 'Species', '10116', (60, 63))	('oxidative stress', 'MPA', (15, 31))	('rats', 'Species', '10116', (110, 114))	('infertility', 'Phenotype', 'HP:0000789', (84, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('infertility', 'Disease', 'MESH:D007247', (84, 95))	('infertility', 'Disease', (84, 95))	('oxidative stress', 'Phenotype', 'HP:0025464', (15, 31))
75642	23737712	Moreover, it has been demonstrated that cisplatin-associated infertility is caused by the toxic effect on the primordial follicles.	('rat', 'Species', '10116', (29, 32))	('infertility', 'Phenotype', 'HP:0000789', (61, 72))	('infertility', 'Disease', 'MESH:D007247', (61, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('cisplatin-associated', 'Var', (40, 60))	('infertility', 'Disease', (61, 72))
75701	23737712	The MDA levels of the Mirt-15 and the Mirt-30 groups were found to be less than the Cis group (resp., P < 0.05, P < 0.01) (Figure 1).	('less', 'NegReg', (70, 74))	('Mirt-15', 'Var', (22, 29))	('Mirt-30', 'Chemical', '-', (38, 45))	('MDA levels', 'MPA', (4, 14))	('Mirt-30', 'Var', (38, 45))
75703	23737712	MPO, NO, and 8-OH Gua levels of the Mirt-15 and the Mirt-30 groups were found to be lower than the Cis group (P < 0.001) (Figures 2, 3, and 4).	('MPO', 'Gene', (0, 3))	('Mirt-15', 'Var', (36, 43))	('8-OH Gua', 'Chemical', '-', (13, 21))	('Mirt-30', 'Chemical', '-', (52, 59))	('Mirt-30', 'Var', (52, 59))	('lower', 'NegReg', (84, 89))	('MPO', 'Gene', '303413', (0, 3))
75705	23737712	The amount of tGSH in the Mirt-15 and the Mirt-30 groups was found to be higher than the Cis group (resp., P < 0.05, P < 0.001) (Figure 5).	('Mirt-15', 'Var', (26, 33))	('tGSH', 'Chemical', '-', (14, 18))	('Mirt-30', 'Chemical', '-', (42, 49))	('Mirt-30', 'Var', (42, 49))	('tGSH', 'CPA', (14, 18))	('higher', 'PosReg', (73, 79))
75707	23737712	GRx activity of the Mirt-30 group was higher than in the Cis group (P < 0.001) (Figure 6).	('GRx', 'Gene', '64045', (0, 3))	('GRx', 'Gene', (0, 3))	('Mirt-30', 'Chemical', '-', (20, 27))	('Mirt-30', 'Var', (20, 27))	('higher', 'PosReg', (38, 44))	('activity', 'MPA', (4, 12))
75708	23737712	The activities of SOD in the Mirt-15 and the Mirt-30 groups were measured higher than in the Cis group (P < 0.001) (Figure 7).	('activities', 'MPA', (4, 14))	('Mirt-15', 'Var', (29, 36))	('higher', 'PosReg', (74, 80))	('Mirt-30', 'Chemical', '-', (45, 52))	('Mirt-30', 'Var', (45, 52))
75709	23737712	As shown in Table 2, Cisplatin caused infertility by 70% in the Cis group.	('infertility', 'Disease', (38, 49))	('Cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('Cisplatin', 'Var', (21, 30))	('infertility', 'Disease', 'MESH:D007247', (38, 49))	('infertility', 'Phenotype', 'HP:0000789', (38, 49))
75710	23737712	The infertility rates decreased by 40% and 10% for the Mirt-15 and Mirt-30 groups, respectively.	('infertility', 'Phenotype', 'HP:0000789', (4, 15))	('infertility', 'Disease', 'MESH:D007247', (4, 15))	('rat', 'Species', '10116', (16, 19))	('infertility', 'Disease', (4, 15))	('Mirt-15', 'Var', (55, 62))	('Mirt-30', 'Chemical', '-', (67, 74))	('Mirt-30', 'Var', (67, 74))	('decreased', 'NegReg', (22, 31))
75712	23737712	The data obtained in the study demonstrated that cisplatin caused significant oxidative stress in the ovarian tissues of rats.	('oxidative stress', 'Phenotype', 'HP:0025464', (78, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('rats', 'Species', '10116', (121, 125))	('oxidative stress', 'MPA', (78, 94))	('rat', 'Species', '10116', (38, 41))	('cisplatin', 'Var', (49, 58))	('rat', 'Species', '10116', (121, 124))
75715	23737712	However, it was reported that cisplatin caused severe adverse effects such as nephrotoxicity, neurotoxicity, gastric toxicity, and infertility.	('gastric toxicity', 'Disease', (109, 125))	('neurotoxicity', 'Disease', (94, 107))	('cisplatin', 'Var', (30, 39))	('gastric toxicity', 'Disease', 'MESH:D013274', (109, 125))	('infertility', 'Disease', 'MESH:D007247', (131, 142))	('nephrotoxicity', 'Disease', (78, 92))	('infertility', 'Phenotype', 'HP:0000789', (131, 142))	('nephrotoxicity', 'Disease', 'MESH:D007674', (78, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('infertility', 'Disease', (131, 142))	('neurotoxicity', 'Disease', 'MESH:D020258', (94, 107))
75718	23737712	As the results of our study demonstrated, in ovarian tissues of animals administered cisplatin, there was an increase in the levels of MDA and MPO, which are oxidant parameters, while the levels of antioxidants such as tGSH, GPx, and SOD were decreased.	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('levels', 'MPA', (125, 131))	('tGSH', 'Chemical', '-', (219, 223))	('GPx', 'Chemical', '-', (225, 228))	('increase', 'PosReg', (109, 117))	('cisplatin', 'Var', (85, 94))	('MPO', 'Gene', '303413', (143, 146))	('rat', 'Species', '10116', (35, 38))	('MDA', 'MPA', (135, 138))	('MPO', 'Gene', (143, 146))
75725	23737712	The hypochlorous acid is a powerful oxidant and causes damage to vascular endothelium.	('hypochlorous acid', 'Chemical', 'MESH:D006997', (4, 21))	('damage', 'MPA', (55, 61))	('hypochlorous acid', 'Var', (4, 21))	('causes', 'Reg', (48, 54))
75727	23737712	However, in the kidney tissue of rats given cisplatin, a significant increase in MPO activity was noticed.	('increase', 'PosReg', (69, 77))	('cisplatin', 'Var', (44, 53))	('MPO', 'Gene', '303413', (81, 84))	('MPO', 'Gene', (81, 84))	('rats', 'Species', '10116', (33, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))
75747	23737712	In conclusion, cisplatin leads to oxidative stress in the ovarian tissue of rats.	('cisplatin', 'Var', (15, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('oxidative stress', 'Phenotype', 'HP:0025464', (34, 50))	('rats', 'Species', '10116', (76, 80))	('oxidative stress', 'MPA', (34, 50))
75748	23737712	Cisplatin also causes infertility in female rats.	('causes', 'Reg', (15, 21))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('infertility', 'Disease', 'MESH:D007247', (22, 33))	('infertility in female', 'Phenotype', 'HP:0008222', (22, 43))	('infertility', 'Phenotype', 'HP:0000789', (22, 33))	('Cisplatin', 'Var', (0, 9))	('infertility', 'Disease', (22, 33))	('rats', 'Species', '10116', (44, 48))
75768	33562293	Each monofunctional complex could form at most one covalent bond with the N7-guanine on the DNA strands rather than two covalent Pt-DNA cross-links as cisplatin does.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('form', 'Reg', (34, 38))	('covalent', 'MPA', (51, 59))	('N7-guanine', 'Chemical', '-', (74, 84))	('N7-guanine', 'Var', (74, 84))	('Pt', 'Chemical', 'MESH:D010984', (129, 131))
75770	33562293	However, the preconceived belief was overturned by the finding that cis-[Pt(NH3)2(Am)Cl]+ (Am is an aromatic N-heterocyclic amine) inhibited tumor cells in vitro and leukemia (L1210 and P388) in mouse models, where PtII formed stable Pt-DNA adducts and the complex intercalated into DNA.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cis-', 'Var', (68, 72))	('L1210', 'CellLine', 'CVCL:0382', (176, 181))	('tumor', 'Disease', (141, 146))	('Pt', 'Chemical', 'MESH:D010984', (234, 236))	('Pt', 'Chemical', 'MESH:D010984', (73, 75))	('mouse', 'Species', '10090', (195, 200))	('leukemia', 'Disease', 'MESH:D007938', (166, 174))	('PtII', 'Chemical', '-', (215, 219))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('leukemia', 'Disease', (166, 174))	('inhibited', 'NegReg', (131, 140))	('cis-[Pt(NH3)2(Am)Cl]+', 'Chemical', '-', (68, 89))	('Pt', 'Chemical', 'MESH:D010984', (215, 217))	('aromatic N-heterocyclic amine', 'Chemical', '-', (100, 129))
75771	33562293	Afterwards, it was found that the cationic PtII complex pyriplatin (Figure 2) only formed a monofunctional adduct with DNA and induced little distortion in the DNA double helix upon binding.	('distortion', 'MPA', (142, 152))	('monofunctional adduct', 'MPA', (92, 113))	('binding', 'Interaction', (182, 189))	('pyriplatin', 'Var', (56, 66))	('PtII complex pyriplatin', 'Chemical', '-', (43, 66))
75774	33562293	Phenanthriplatin-DNA adducts generate steric hindrance in the major groove of DNA and thus, stall the progression of RNA polymerase II on the damaged DNA templates and inhibit DNA polymerases.	('Phenanthriplatin', 'Chemical', 'MESH:C587603', (0, 16))	('DNA polymerases', 'Enzyme', (176, 191))	('steric hindrance', 'MPA', (38, 54))	('stall', 'NegReg', (92, 97))	('adducts', 'Var', (21, 28))	('progression', 'MPA', (102, 113))	('inhibit', 'NegReg', (168, 175))	('RNA polymerase II', 'Enzyme', (117, 134))
75812	33562293	The binding to DNA involves both covalent bonding with N7-guanine by PtII and intercalation by the porphyrin unit.	('PtII', 'Chemical', '-', (69, 73))	('N7-guanine', 'Var', (55, 65))	('intercalation', 'Interaction', (78, 91))	('binding', 'Interaction', (4, 11))	('porphyrin', 'Chemical', 'MESH:D011166', (99, 108))	('covalent', 'MPA', (33, 41))	('N7-guanine', 'Chemical', '-', (55, 65))
75813	33562293	Complex 9 demonstrated a promising photocytotoxicity with extremely high toxicity towards human cancer cell lines upon irradiation (6.95 J cm-2, 420 nm, 15 min, HeLa: IC50 = 37 nM; A2780: IC50 = 21 nM; CP70: IC50 = 19 nM), and a phototoxic index up to 5000 in the cisplatin-resistant CP70 cell line.	('photocytotoxicity', 'Disease', (35, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (264, 273))	('A2780', 'Var', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('phototoxic', 'Disease', (229, 239))	('photocytotoxicity', 'Disease', 'None', (35, 52))	('human', 'Species', '9606', (90, 95))	('HeLa', 'CellLine', 'CVCL:0030', (161, 165))	('phototoxic', 'Disease', 'MESH:D017484', (229, 239))	('toxicity', 'Disease', (73, 81))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('cancer', 'Disease', (96, 102))	('toxicity', 'Disease', (44, 52))
75835	33562293	Therefore, silencing Pt complexes in lysosomes and then activating them specifically in the tumor tissue might be a method for improving the antitumor activity and alleviating side effects.	('silencing', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Pt', 'Chemical', 'MESH:D010984', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (145, 150))	('improving', 'PosReg', (127, 136))	('tumor', 'Disease', (92, 97))	('Pt complexes', 'Protein', (21, 33))
75839	33562293	Apart from damaging lysosomes to release 17 into the cytosol and nucleus, ROS also decreased intracellular GSH levels to impede its deactivation in the cytosol and further increased its accessibility to nDNA favorable for the antitumor activity.	('tumor', 'Disease', (230, 235))	('impede', 'NegReg', (121, 127))	('increased', 'PosReg', (172, 181))	('GSH', 'Chemical', '-', (107, 110))	('OS', 'Phenotype', 'HP:0002669', (75, 77))	('decreased', 'NegReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('intracellular GSH levels', 'MPA', (93, 117))	('deactivation in the cytosol', 'MPA', (132, 159))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('ROS', 'Var', (74, 77))	('accessibility', 'MPA', (186, 199))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))
75872	33562293	In the case of tumor-induced angiogenesis, transmembrane receptors such as integrins (alphavbeta3 and alphavbeta5) are highly expressed, which have a very high affinity for peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) sequences.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Asn-Gly', 'Chemical', '-', (220, 227))	('NGR', 'Gene', '65078', (215, 218))	('affinity', 'Interaction', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Arg', 'Chemical', 'MESH:D001120', (228, 231))	('Arg-Gly-Asp', 'Chemical', 'MESH:C047981', (198, 209))	('tumor', 'Disease', (15, 20))	('Arg', 'Chemical', 'MESH:D001120', (198, 201))	('peptides', 'Chemical', 'MESH:D010455', (173, 181))	('NGR', 'Gene', (215, 218))	('RGD (Arg-Gly-Asp', 'Var', (193, 209))
75910	33562293	Complexes 37-39 (Figure 14), anchoring lonidamine (an inhibitor of hexokinase) to the PtII center, could selectively reduce the bioenergetics of cancer cells.	('cancer', 'Disease', (145, 151))	('lonidamine', 'Var', (39, 49))	('PtII', 'Chemical', '-', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('hexokinase', 'Gene', (67, 77))	('reduce', 'NegReg', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('hexokinase', 'Gene', '3098', (67, 77))	('lonidamine', 'Chemical', 'MESH:C016371', (39, 49))
75934	33562293	In complex 54 (Figure 17), ferrocenyl terpyridine led to a dramatic decrease in the dark toxicity.	('decrease', 'NegReg', (68, 76))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('ferrocenyl terpyridine', 'Chemical', '-', (27, 49))	('ferrocenyl terpyridine', 'Var', (27, 49))
75974	31906360	In recent years, different clusters of microRNAs (miR-371-373 and miR-302) have been shown to be expressed in TGCTs regardless of patient age, tumor site and subtype.	('TGCTs', 'Disease', (110, 115))	('miR-302', 'Var', (66, 73))	('patient', 'Species', '9606', (130, 137))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('miR-371-373', 'Var', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
75976	31906360	Very recently, a prospective multi-center study conducted in more than 600 TGCTs patients demonstrated a sensitivity of 90.1% and a specificity of 94.0% for microRNA-371a-3p to detect TGCTs in patients.	('patients', 'Species', '9606', (193, 201))	('microRNA-371a-3p', 'Var', (157, 173))	('patients', 'Species', '9606', (81, 89))	('TGCTs', 'Disease', (184, 189))
76000	31906360	Interestingly, though the housekeeping miRNAs were detectable, we could not detect any levels of circulating miR-371a-3p or miR-367-3p (CT-value > 35) in serum samples of this patient.	('miR-371a', 'Gene', (109, 117))	('amp', 'Chemical', 'MESH:D000249', (161, 164))	('miR-367-3p', 'Var', (124, 134))	('patient', 'Species', '9606', (176, 183))	('miR-371a', 'Gene', '442916', (109, 117))
76007	31906360	MiR-371a-3p has been introduced as a potential novel biomarker in detecting and monitoring primary and metastatic TGCTs.	('primary and', 'Disease', (91, 102))	('MiR-371a-3p', 'Var', (0, 11))	('MiR-371a-3p', 'Chemical', '-', (0, 11))
76022	31906360	Afterwards, a pre-amplification step was performed using a pre-amp primer pool of four specific 20x TaqMan miRNA assays (TaqMan miRNA assay specific for miR-371a-3p, miR-367-3p, miR-93-5p, and miR30b-5p, Thermo Fisher) and the TaqMan PreAmp Mastermix (Thermo Fisher) following the manufacturer's instructions.	('miR-371a', 'Gene', (153, 161))	('amp', 'Chemical', 'MESH:D000249', (63, 66))	('miR30b', 'Gene', (193, 199))	('miR-371a', 'Gene', '442916', (153, 161))	('amp', 'Chemical', 'MESH:D000249', (18, 21))	('miR30b', 'Gene', '407030', (193, 199))	('miR-367-3p', 'Var', (166, 176))	('miR-93-5p', 'Gene', '100126325', (178, 187))	('miR-93-5p', 'Gene', (178, 187))
76027	31906360	As an external positive control for the assay, we used a paralleled measured serum pool of samples with radiologically confirmed disease and previous positively tested miR-371a-3p and miR-367-3p samples.	('miR-371a', 'Gene', '442916', (168, 176))	('amp', 'Chemical', 'MESH:D000249', (92, 95))	('miR-371a', 'Gene', (168, 176))	('amp', 'Chemical', 'MESH:D000249', (196, 199))	('miR-367-3p', 'Var', (184, 194))
76028	31906360	Only samples where this serum sample pool gave a positive signal for miR-371a-3p and miR-367-3p (positive means a CT-value below 32), as well as positive signals for the housekeeping miRNAs, were considered as valid.	('miR-367-3p', 'Var', (85, 95))	('miR-371a', 'Gene', '442916', (69, 77))	('amp', 'Chemical', 'MESH:D000249', (6, 9))	('miR-371a', 'Gene', (69, 77))	('amp', 'Chemical', 'MESH:D000249', (31, 34))
76139	29663630	From humans to hydra: patterns of cancer across the tree of life Cancer is a disease of multicellularity; it originates when cells become dysregulated due to mutations and grow out of control, invading other tissues and provoking discomfort, disability, and eventually death.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('discomfort', 'Disease', (230, 240))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('humans', 'Species', '9606', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Cancer', 'Disease', (65, 71))	('cancer', 'Disease', (34, 40))	('disability', 'Disease', (242, 252))	('death', 'Disease', 'MESH:D003643', (269, 274))	('Cancer', 'Disease', 'MESH:D009369', (65, 71))	('death', 'Disease', (269, 274))	('mutations', 'Var', (158, 167))	('provoking', 'Reg', (220, 229))
76165	29663630	Besides, as cancer is primarily caused by accumulating mutations with age (de Magalhaes, 2013), it may be expected to affect all organisms with dividing cells as adults that live long enough.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (12, 18))	('affect', 'Reg', (118, 124))	('caused', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
76168	29663630	This concept of evolutionary trade-offs has contributed to investigations on the ties between cancer and aging: if some genes can increase reproductive success in young individuals, they might undergo positive selection even if they cause problems later in life.	('genes', 'Var', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('increase', 'PosReg', (130, 138))	('reproductive success', 'CPA', (139, 159))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
76199	29663630	Hormonal status influences the incidence of this type of cancer, and risk factors include total age, use of oral contraceptives, hormone replacement, age at menarche and menopause, age at first pregnancy and nulliparity, a previous case of breast cancer, and family history (McPherson, Steel & Dixon, 2000).	('nulliparity', 'Var', (208, 219))	('men', 'Species', '9606', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('cancer', 'Disease', (57, 63))	('breast cancer', 'Disease', (240, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('men', 'Species', '9606', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('men', 'Species', '9606', (157, 160))
76220	29663630	However, an explanation for childhood leukaemia may be more complex, as suggested by the delayed infection hypothesis, which considers the excessive protection of young children as a cause for an evolutionary mismatch in their immune system, leading to aberrant responses in the immune system that may contribute to cancer (Greaves, 2006).	('responses', 'MPA', (262, 271))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('infection', 'Disease', (97, 106))	('leukaemia', 'Disease', 'MESH:D007938', (38, 47))	('children', 'Species', '9606', (169, 177))	('infection', 'Disease', 'MESH:D007239', (97, 106))	('contribute', 'Reg', (302, 312))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('aberrant', 'Var', (253, 261))	('cancer', 'Disease', (316, 322))	('leukaemia', 'Disease', (38, 47))
76222	29663630	There is a possibility that other common childhood cancers appear due to genetic drift, and more research in this area would be beneficial (Rozhok, Salstrom & DeGregori, 2016).	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('due', 'Reg', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('genetic drift', 'Var', (73, 86))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
76294	29663630	Scientists have investigated these animals and identified key genomic variations that may have contributed to the evolution of longevity and resistance to cancer (Keane et al., 2014; Davies et al., 2015).	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('variations', 'Var', (70, 80))	('contributed', 'Reg', (95, 106))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
76300	29663630	Researchers have found that high-molecular-mass hyaluronan is involved in the arresting of cell growth once cells come into contact with extracellular matrix (Seluanov et al., 2009) and also the activation of a modified version of the inhibitors of cyclin-dependent kinase 4 (INK4a) locus, which contains tumour-suppressor genes (Tian et al., 2015).	('modified', 'Var', (211, 219))	('mole', 'Phenotype', 'HP:0003764', (33, 37))	('hyaluronan', 'Chemical', 'MESH:D006820', (48, 58))	('tumour', 'Disease', 'MESH:D009369', (305, 311))	('cell growth', 'CPA', (91, 102))	('tumour', 'Disease', (305, 311))	('arresting', 'CPA', (78, 87))	('cyclin-dependent kinase 4', 'Gene', '1019', (249, 274))	('activation', 'PosReg', (195, 205))	('INK4a', 'Gene', (276, 281))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('cyclin-dependent kinase 4', 'Gene', (249, 274))
76301	29663630	(2015) found that high-molecular-mass hyaluronan is generated from two different mutations in the hyaluronan synthase 2 gene (HAS2), one of which is shared among all African mole-rats.	('hyaluronan synthase 2', 'Gene', '3037', (98, 119))	('rat', 'Species', '10116', (179, 182))	('rat', 'Species', '10116', (56, 59))	('mole', 'Phenotype', 'HP:0003764', (23, 27))	('hyaluronan', 'Chemical', 'MESH:D006820', (38, 48))	('HAS2', 'Gene', (126, 130))	('HAS2', 'Gene', '3037', (126, 130))	('mole', 'Phenotype', 'HP:0003764', (174, 178))	('mutations', 'Var', (81, 90))	('hyaluronan', 'Chemical', 'MESH:D006820', (98, 108))	('African mole-rats', 'Species', '10175', (166, 183))	('hyaluronan synthase 2', 'Gene', (98, 119))
76374	29663630	Comparisons between canine and human osteosarcoma have allowed advancements such as identification of several subtypes (Scott et al., 2011), driver mutations (Angstadt et al., 2012), and biomarkers (Rankin et al., 2012; Ren & Khanna, 2014), and have led to new therapeutic investigations (Rankin et al., 2012; Yin et al., 2016).	('mutations', 'Var', (148, 157))	('Ren', 'Gene', (220, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('Ren', 'Gene', '5972', (220, 223))	('men', 'Species', '9606', (70, 73))	('human', 'Species', '9606', (31, 36))	('have led', 'Reg', (245, 253))	('canine', 'Species', '9615', (20, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (37, 49))	('osteosarcoma', 'Disease', (37, 49))	('osteosarcoma', 'Disease', 'MESH:D012516', (37, 49))
76430	29663630	Researchers have discovered mutations in the growth hormone receptor (GHR) and in the insulin-like growth factor 1 receptor genes (IGF1R) in these bats, both of which may contribute to their longevity (Seim et al., 2013).	('growth hormone receptor', 'Gene', (45, 68))	('growth hormone receptor', 'Gene', '2690', (45, 68))	('IGF1R', 'Gene', '3480', (131, 136))	('contribute', 'Reg', (171, 181))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (86, 123))	('GHR', 'Gene', (70, 73))	('GHR', 'Gene', '2690', (70, 73))	('insulin-like growth factor 1 receptor', 'Gene', (86, 123))	('longevity', 'CPA', (191, 200))	('mutations', 'Var', (28, 37))	('IGF1R', 'Gene', (131, 136))
76431	29663630	GH and IGF1 both play roles in cell growth and proliferation, and these mutations could also affect the rate of cancer in these species.	('mutations', 'Var', (72, 81))	('IGF1', 'Gene', '3479', (7, 11))	('cancer', 'Disease', (112, 118))	('affect', 'Reg', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('rate', 'MPA', (104, 108))	('rat', 'Species', '10116', (54, 57))	('play', 'Reg', (17, 21))	('IGF1', 'Gene', (7, 11))	('GH', 'Gene', '2688', (0, 2))	('proliferation', 'CPA', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cell growth', 'CPA', (31, 42))	('rat', 'Species', '10116', (104, 107))
76455	29663630	Dietary changes and improvements in cancer treatment have extended the lifespan of pet birds, along with the incidence of neoplasia observed by veterinarians.	('changes', 'Var', (8, 15))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('men', 'Species', '9606', (48, 51))	('cancer', 'Disease', (36, 42))	('lifespan', 'CPA', (71, 79))	('neoplasia', 'Disease', (122, 131))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))	('extended', 'PosReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('men', 'Species', '9606', (27, 30))	('neoplasia', 'Disease', 'MESH:D009369', (122, 131))
76486	29663630	Hepatic tumours in fish are associated with polycyclic aromatic hydrocarbons, chemical contaminants that are implied in carcinogenesis in humans (Masahito et al., 1988).	('humans', 'Species', '9606', (138, 144))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (44, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))	('associated', 'Reg', (28, 38))	('polycyclic aromatic', 'Var', (44, 63))	('carcinogenesis', 'Disease', (120, 134))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('Hepatic tumours', 'Disease', (0, 15))	('Hepatic tumours', 'Disease', 'MESH:D008113', (0, 15))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))
76505	29663630	Plants have orthologous genes of many mammalian tumour-suppressor genes and oncogenes, but it seems that mutations in these genes are not oncogenic, possibly due to redundancy of some cell cycle regulators (Doonan & Sablowski, 2010).	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (105, 114))	('tumour', 'Disease', (48, 54))	('mammalian', 'Species', '9606', (38, 47))
76538	29663630	(3) We do not yet know if the mechanisms identified in long-lived, cancer-resistant animals are responsible for their longevity and resistance to cancer, but some studies suggest that only a few mutations (or even a single mutation) can greatly increase cancer resistance.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (67, 73))	('increase', 'PosReg', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (254, 260))	('mutations', 'Var', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
76623	32576890	Administration of bleomycin, etoposide, cisplatin chemotherapy led to lower locomotor- and exploratory activity, higher anxiety-like behaviour and worse spatial memory in mice tested after the end of the third cycle of the treatment.	('anxiety', 'Phenotype', 'HP:0000739', (120, 127))	('rat', 'Species', '10116', (8, 11))	('anxiety', 'Gene', (120, 127))	('worse', 'NegReg', (147, 152))	('cisplatin', 'Var', (40, 49))	('bleomycin', 'Chemical', 'MESH:D001761', (18, 27))	('etoposide', 'Chemical', 'MESH:D005047', (29, 38))	('mice', 'Species', '10090', (171, 175))	('anxiety', 'Gene', '493091', (120, 127))	('higher', 'PosReg', (113, 119))	('lower', 'NegReg', (70, 75))	('men', 'Species', '9606', (228, 231))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('rat', 'Species', '10116', (96, 99))
76767	21806789	Exercise for cancer patients undergoing treatment with chemotherapy has been shown to improve the patient's physical capacity and to reduce side effects such as fatigue.	('fatigue', 'Disease', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('patient', 'Species', '9606', (98, 105))	('men', 'Species', '9606', (45, 48))	('fatigue', 'Phenotype', 'HP:0012378', (161, 168))	('reduce', 'NegReg', (133, 139))	('Exercise', 'Var', (0, 8))	('improve', 'PosReg', (86, 93))	('cancer', 'Disease', (13, 19))	('physical capacity', 'CPA', (108, 125))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('patient', 'Species', '9606', (20, 27))	('patients', 'Species', '9606', (20, 28))	('fatigue', 'Disease', 'MESH:D005221', (161, 168))
76846	19399630	Greater weekly duration of moderate-intensity activity (but not vigorous) was associated with an increased risk of non-seminoma/mixed tumors (>= 9 hrs vs. <2, p for trend = 0.006), but was not associated with seminomas (Table 4).	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('seminomas', 'Disease', 'MESH:D018239', (209, 218))	('non-seminoma', 'Disease', (115, 127))	('moderate-intensity', 'Var', (27, 45))	('seminomas', 'Disease', (209, 218))	('non-seminoma', 'Disease', 'MESH:D018239', (115, 127))
76850	19399630	A second proposed hypothesis is that PA such as bicycling or horseback riding could result in testicular trauma or injury that is sufficient to cause testicular atrophy, a putative risk factor for TGCC.	('bicycling', 'Var', (48, 57))	('horseback riding', 'Disease', (61, 77))	('testicular atrophy', 'Disease', (150, 168))	('cause', 'Reg', (144, 149))	('testicular trauma or injury', 'Disease', 'MESH:D014947', (94, 121))	('testicular atrophy', 'Phenotype', 'HP:0000029', (150, 168))	('testicular atrophy', 'Disease', 'MESH:C567108', (150, 168))	('testicular trauma or injury', 'Disease', (94, 121))	('result', 'Reg', (84, 90))
76899	19842050	We also grouped cancer sites into the following categories based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) groupings: (1) lip, oral cavity and pharynx (140-149); (2) esophagus, stomach, and small intestine (150-152); (3) colon, rectum (153-154); (4) liver, gallbladder, pancreas (155-157); (5) lung (162); (6) melanoma (172); (7) breast (174); (8) uterus, ovary (179-184); (9) prostate (185); (10) testis (186); (11) bladder, kidney (188-189); (12) lymphatic, hematologic (200-208); and (13) other sites.	('colon', 'Disease', (273, 278))	('melanoma', 'Disease', 'MESH:D008545', (362, 370))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('melanoma', 'Disease', (362, 370))	('ovary', 'Disease', (408, 413))	('melanoma', 'Phenotype', 'HP:0002861', (362, 370))	('cancer', 'Disease', (16, 22))	('ovary', 'Disease', 'MESH:D010051', (408, 413))	('188-189', 'Var', (486, 493))	('colon', 'Disease', 'MESH:D015179', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
76988	31886233	TIG1 is expressed in most normal tissues, and downregulation of TIG1 expression in multiple cancers is caused by promoter hypermethylation.	('downregulation', 'NegReg', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('TIG1', 'Gene', (64, 68))	('expression', 'Species', '29278', (69, 79))	('multiple cancers', 'Disease', 'MESH:D009369', (83, 99))	('expression', 'MPA', (69, 79))	('promoter hypermethylation', 'Var', (113, 138))	('TIG1', 'Gene', '5918', (64, 68))	('TIG1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TIG1', 'Gene', '5918', (0, 4))	('multiple cancers', 'Disease', (83, 99))
76994	31886233	SPINK2 enhanced TIG1-regulated uPA activity and EMT suppression, while silencing SPINK2 alleviated TIG1-mediated EMT regulation, cell migration, and invasion.	('SPINK2', 'Gene', '6691', (81, 87))	('invasion', 'CPA', (149, 157))	('EMT suppression', 'CPA', (48, 63))	('SPINK2', 'Gene', (81, 87))	('TIG1', 'Gene', (16, 20))	('TIG1', 'Gene', (99, 103))	('alleviated', 'NegReg', (88, 98))	('SPINK2', 'Gene', '6691', (0, 6))	('enhanced', 'PosReg', (7, 15))	('silencing', 'Var', (71, 80))	('SPINK2', 'Gene', (0, 6))	('TIG1', 'Gene', '5918', (16, 20))	('TIG1', 'Gene', '5918', (99, 103))	('uPA', 'Gene', (31, 34))	('uPA', 'Gene', '5328', (31, 34))	('cell migration', 'CPA', (129, 143))
76997	31886233	Downregulation of TIG1 in multiple cancers is mediated by common CpG hypermethylation in the TIG1 promoter region.	('TIG1', 'Gene', '5918', (18, 22))	('TIG1', 'Gene', '5918', (93, 97))	('hypermethylation', 'Var', (69, 85))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('multiple cancers', 'Disease', (26, 42))	('multiple cancers', 'Disease', 'MESH:D009369', (26, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('TIG1', 'Gene', (18, 22))	('CpG hypermethylation', 'Var', (65, 85))	('TIG1', 'Gene', (93, 97))
76999	31886233	In addition to regulation of alpha-tubulin, which is related to mitochondrial function, ectopic TIG1 exhibits cell growth suppression and induction of autophagy in cervical, colon, and nasopharyngeal cancer cells.	('TIG1', 'Gene', '5918', (96, 100))	('cell growth suppression', 'CPA', (110, 133))	('autophagy', 'CPA', (151, 160))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (185, 206))	('ectopic', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('TIG1', 'Gene', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
77008	31886233	Loss of SPINK7 has been shown to increase uPA activity in esophageal epithelial cells, indicating that SPINK7 may represent a key checkpoint in regulating mucosal barrier function in esophageal cells.	('increase', 'PosReg', (33, 41))	('uPA', 'Gene', '5328', (42, 45))	('uPA', 'Gene', (42, 45))	('Loss', 'Var', (0, 4))	('SPINK7', 'Gene', (8, 14))
77009	31886233	Similarly, a recent study has shown that downregulation of SPINK13 promotes metastasis through the uPA system in ovarian cancer cells.	('metastasis', 'CPA', (76, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('promotes', 'PosReg', (67, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('SPINK13', 'Gene', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('downregulation', 'Var', (41, 55))	('uPA', 'Gene', '5328', (99, 102))	('uPA', 'Gene', (99, 102))	('ovarian cancer', 'Disease', (113, 127))
77023	31886233	To generate the pSPINK2-flag expression vector, SPINK2 cDNA was first amplified from human NT2/D1 testicular cancer cells using SPINK2-specific primers (5'-TGGCTAGCATGGCGCTGTCGGTGCTGCGC-3' and 5'-GACTCGAGGCAGGGTCCATTTCGAATGATTTTA-3').	("5'-TGGCTAGCATGGCGCTGTCGGTGCTGCGC-3", 'Var', (153, 187))	('SPINK2', 'Gene', '6691', (17, 23))	('SPINK2', 'Gene', '6691', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('SPINK2', 'Gene', (17, 23))	('testicular cancer', 'Phenotype', 'HP:0010788', (98, 115))	('cancer', 'Disease', (109, 115))	('SPINK2', 'Gene', '6691', (128, 134))	('SPINK2', 'Gene', (48, 54))	('expression', 'Species', '29278', (29, 39))	('SPINK2', 'Gene', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('human', 'Species', '9606', (85, 90))
77056	31886233	In contrast, TIG1 or SPINK2 expression in NT2/D1 cells significantly inhibited cell migration by 56.4% and 42.9%, respectively, compared to cell migration of NT2/D1 cells transfected with empty control vector.	('expression', 'Species', '29278', (28, 38))	('cell migration', 'CPA', (79, 93))	('SPINK2', 'Gene', '6691', (21, 27))	('TIG1', 'Gene', (13, 17))	('SPINK2', 'Gene', (21, 27))	('expression', 'Var', (28, 38))	('TIG1', 'Gene', '5918', (13, 17))	('inhibited', 'NegReg', (69, 78))	('NT2/D1', 'Var', (42, 48))
77057	31886233	Furthermore, the number of migrated cells decreased by 57.4% in TIG1and SPINK2 coexpressing cells compared to cells transfected with TIG1-myc expression vector for 24 h (Figure 2(b) and Supplementary ).	('decreased', 'NegReg', (42, 51))	('myc', 'Gene', (138, 141))	('TIG1', 'Gene', (64, 68))	('coexpressing', 'Var', (79, 91))	('TIG1', 'Gene', (133, 137))	('expression', 'Species', '29278', (142, 152))	('TIG1', 'Gene', '5918', (64, 68))	('SPINK2', 'Gene', '6691', (72, 78))	('TIG1', 'Gene', '5918', (133, 137))	('SPINK2', 'Gene', (72, 78))	('myc', 'Gene', '4609', (138, 141))
77075	31886233	uPA activity was decreased by 34.9% in TIG1-expressing NT2/D1 cells, and silencing of SPINK2 significantly alleviated TIG1-mediated uPA activity suppression by 73.7% (Figure 6(a)).	('silencing', 'Var', (73, 82))	('uPA', 'Gene', '5328', (132, 135))	('TIG1', 'Gene', (118, 122))	('decreased', 'NegReg', (17, 26))	('uPA', 'Gene', (132, 135))	('suppression', 'NegReg', (145, 156))	('TIG1', 'Gene', (39, 43))	('SPINK2', 'Gene', '6691', (86, 92))	('TIG1', 'Gene', '5918', (118, 122))	('TIG1', 'Gene', '5918', (39, 43))	('uPA', 'Gene', '5328', (0, 3))	('uPA', 'Gene', (0, 3))	('SPINK2', 'Gene', (86, 92))	('alleviated', 'NegReg', (107, 117))
77078	31886233	In addition, silencing expression of SPINK2 significantly alleviated TIG1-mediated cell migration and invasion suppression by 51.1% (Figure 7(a) and Supplementary ) and 64.2% (Figure 7(b) and Supplementary ), respectively.	('SPINK2', 'Gene', (37, 43))	('invasion suppression', 'CPA', (102, 122))	('TIG1', 'Gene', '5918', (69, 73))	('silencing', 'Var', (13, 22))	('SPINK2', 'Gene', '6691', (37, 43))	('expression', 'Species', '29278', (23, 33))	('TIG1', 'Gene', (69, 73))	('alleviated', 'NegReg', (58, 68))
77079	31886233	Our results indicate that expression of TIG1 in NT2/D1 testicular carcinoma cells leads to decreased uPA activity, EMT reduction, and inhibition of cell migration and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('uPA', 'Gene', '5328', (101, 104))	('uPA', 'Gene', (101, 104))	('TIG1', 'Gene', (40, 44))	('expression', 'Var', (26, 36))	('testicular carcinoma', 'Disease', 'MESH:D013736', (55, 75))	('TIG1', 'Gene', '5918', (40, 44))	('EMT', 'CPA', (115, 118))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (55, 75))	('inhibition', 'NegReg', (134, 144))	('testicular carcinoma', 'Disease', (55, 75))	('reduction', 'NegReg', (119, 128))	('expression', 'Species', '29278', (26, 36))	('decreased', 'NegReg', (91, 100))
77080	31886233	We also found that TIG1 interacts with SPINK2 within cells, and coexpression of SPINK2 enhanced TIG1-mediated inhibition of uPA activity and cell invasion, while TIG1-mediated cell invasion was reversed in SPINK2-silenced cells.	('inhibition', 'NegReg', (110, 120))	('TIG1', 'Gene', '5918', (162, 166))	('TIG1', 'Gene', '5918', (19, 23))	('enhanced', 'PosReg', (87, 95))	('SPINK2', 'Gene', (80, 86))	('uPA', 'Gene', (124, 127))	('TIG1', 'Gene', (162, 166))	('uPA', 'Gene', '5328', (124, 127))	('SPINK2', 'Gene', (39, 45))	('TIG1', 'Gene', '5918', (96, 100))	('TIG1', 'Gene', (19, 23))	('expression', 'Species', '29278', (66, 76))	('SPINK2', 'Gene', (206, 212))	('TIG1', 'Gene', (96, 100))	('SPINK2', 'Gene', '6691', (80, 86))	('SPINK2', 'Gene', '6691', (39, 45))	('coexpression', 'Var', (64, 76))	('SPINK2', 'Gene', '6691', (206, 212))	('cell invasion', 'CPA', (141, 154))
77090	31886233	Dysregulated expression of the uPA/uPAR system results in cell invasion in multiple cancer cell lines.	('uPA', 'Gene', (35, 38))	('expression', 'Species', '29278', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('expression', 'MPA', (13, 23))	('uPAR', 'Gene', '5329', (35, 39))	('results in', 'Reg', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Dysregulated', 'Var', (0, 12))	('uPA', 'Gene', (31, 34))	('uPAR', 'Gene', (35, 39))	('uPA', 'Gene', '5328', (31, 34))	('uPA', 'Gene', '5328', (35, 38))
77099	31886233	Our study demonstrated that expression of TIG1 inhibits cell migration and invasion in testicular carcinoma cells.	('expression', 'Species', '29278', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('testicular carcinoma', 'Disease', 'MESH:D013736', (87, 107))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (87, 107))	('expression', 'Var', (28, 38))	('TIG1', 'Gene', (42, 46))	('testicular carcinoma', 'Disease', (87, 107))	('TIG1', 'Gene', '5918', (42, 46))	('inhibits', 'NegReg', (47, 55))
77101	31886233	Silencing of SPINK2 alleviated the effects induced by TIG1 in testicular carcinoma cells.	('SPINK2', 'Gene', '6691', (13, 19))	('TIG1', 'Gene', (54, 58))	('TIG1', 'Gene', '5918', (54, 58))	('SPINK2', 'Gene', (13, 19))	('testicular carcinoma', 'Disease', 'MESH:D013736', (62, 82))	('testicular carcinoma', 'Disease', (62, 82))	('testicular carcinoma', 'Phenotype', 'HP:0010788', (62, 82))	('alleviated', 'NegReg', (20, 30))	('Silencing', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
77107	31614500	Results: PD-L1 and CTLA-4 positivity in ICs was frequent (85.5% and 96.3%).	('CTLA-4', 'Gene', '1493', (19, 25))	('ICs', 'Disease', (40, 43))	('PD-L1', 'Gene', '29126', (9, 14))	('CTLA-4', 'Gene', (19, 25))	('PD-L1', 'Gene', (9, 14))	('positivity', 'Var', (26, 36))
77127	31614500	Since then, both high PD-L1 immunoexpression in tumor cells (TCs) and low immunoexpression in immune cells (ICs) were found associated with poorer prognosis in two different studies.	('tumor', 'Disease', (48, 53))	('PD-L1', 'Gene', (22, 27))	('high', 'Var', (17, 21))	('PD-L1', 'Gene', '29126', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
77140	31614500	PD-L1 and CTLA-4 positivity was overall observed in 137/158 (85.5%) and 158/164 (96.3%) of TGCTs.	('CTLA-4', 'Gene', (10, 16))	('TGCTs', 'Disease', (91, 96))	('positivity', 'Var', (17, 27))	('observed', 'Reg', (40, 48))	('PD-L1', 'Gene', (0, 5))	('CTLA-4', 'Gene', '1493', (10, 16))	('PD-L1', 'Gene', '29126', (0, 5))
77142	31614500	CTLA-4 positivity in ICs did not associate with clinicopathological variables (Table 2).	('CTLA-4', 'Gene', '1493', (0, 6))	('CTLA-4', 'Gene', (0, 6))	('positivity', 'Var', (7, 17))	('ICs', 'Disease', (21, 24))
77144	31614500	Positivity of CTLA-4 in ICs did not significantly impact relapse-free survival (RFS) (Supplementary Figure S2).	('CTLA-4', 'Gene', (14, 20))	('relapse-free survival', 'CPA', (57, 78))	('Positivity', 'Var', (0, 10))	('men', 'Species', '9606', (92, 95))	('CTLA-4', 'Gene', '1493', (14, 20))
77145	31614500	Regarding PD-L1 positivity in ICs, it did not differ significantly among subgroups of patients with different clinicopathological variables (lymphovascular invasion, TNM staging, presence of metastases or IGCCCG prognostic grouping) (Table 2).	('TNM', 'Gene', (166, 169))	('ICs', 'Disease', (30, 33))	('metastases', 'Disease', (191, 201))	('TNM', 'Gene', '10178', (166, 169))	('PD-L1', 'Gene', '29126', (10, 15))	('PD-L1', 'Gene', (10, 15))	('metastases', 'Disease', 'MESH:D009362', (191, 201))	('positivity', 'Var', (16, 26))	('lymphovascular', 'Disease', (141, 155))	('patients', 'Species', '9606', (86, 94))
77148	31614500	Among the 86 pure SE patients, 43 (50.0%) and 59 (68.6%) were classified as being highly infiltrated with CD20- and CD3-positive ICs, respectively (specific criteria for considering IC infiltration are detailed in Methods section) (Supplementary Figure S3A,B).	('SE', 'Disease', 'None', (18, 20))	('CD20', 'Gene', (106, 110))	('CD20', 'Gene', '931', (106, 110))	('men', 'Species', '9606', (238, 241))	('patients', 'Species', '9606', (21, 29))	('CD3-positive', 'Var', (116, 128))
77163	31614500	However, there were significant differences in PD-L1 immunoexpression among the various subtypes of TCs (p < 0.0001); specifically, PD-L1 positivity in TCs was significantly more common in CH and less common in TE (Figure 5D).	('CH', 'Chemical', 'MESH:C103208', (189, 191))	('PD-L1', 'Gene', (132, 137))	('PD-L1', 'Gene', (47, 52))	('PD-L1', 'Gene', '29126', (132, 137))	('positivity', 'Var', (138, 148))	('PD-L1', 'Gene', '29126', (47, 52))	('TCs', 'Disease', (152, 155))
77180	31614500	Positivity for PD-L1 in ICs was seen in 1-10% of cells in 8 samples, in 10-20% of cells in 6 samples, in 20-30% of cells in 2 samples and in 50-60% of cells in 1 sample.	('PD-L1', 'Gene', (15, 20))	('Positivity', 'Var', (0, 10))	('ICs', 'Disease', (24, 27))	('PD-L1', 'Gene', '29126', (15, 20))
77182	31614500	Importantly, all six metastatic samples with cisplatin-resistant viable non-TE disease showed positivity in TCs for PD-L1, but none of the nine residual mature TE masses showed PD-L1-positive TCs (p = 0.0002, Figure 9B).	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('PD-L1', 'Gene', (177, 182))	('PD-L1', 'Gene', (116, 121))	('PD-L1', 'Gene', '29126', (177, 182))	('positivity', 'Var', (94, 104))	('PD-L1', 'Gene', '29126', (116, 121))
77208	31614500	Moreover, as in the previous work, we too corroborated the association of high PD-L1 scoring in TCs with poor prognostic features, including disease stage.	('high', 'Var', (74, 78))	('PD-L1', 'Gene', (79, 84))	('TCs', 'Disease', (96, 99))	('PD-L1', 'Gene', '29126', (79, 84))
77230	31614500	A recent report found that methylation of homologous recombinant genes was associated with the expression of the immune checkpoint PD-L1 in squamous cell carcinoma of the head and neck, lung and cervix, and promoter methylation of homologous recombination-related genes was found to be frequent in TGCTs.	('frequent', 'Reg', (286, 294))	('PD-L1', 'Gene', '29126', (131, 136))	('squamous cell carcinoma of the head', 'Disease', 'MESH:D002294', (140, 175))	('methylation', 'Var', (27, 38))	('TGCTs', 'Disease', (298, 303))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('squamous cell carcinoma of the head', 'Disease', (140, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('associated', 'Reg', (75, 85))	('PD-L1', 'Gene', (131, 136))	('expression', 'MPA', (95, 105))
77260	31614500	Overall, the immunobiology of (testicular) germ cell tumors remains an understudied field, and the key to achieve sound clinical effects might reside in uncovering the most relevant biomarkers (both histological, genetic or epigenetic) that might really indicate a favorable response to immunotherapies.	('epigenetic', 'Var', (224, 234))	('germ cell tumor', 'Phenotype', 'HP:0100728', (43, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('germ cell tumors', 'Phenotype', 'HP:0100728', (43, 59))	('tumors', 'Disease', (53, 59))
77266	27111068	Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2.	('SMN2', 'Gene', (180, 184))	('Spinal Muscular Atrophy', 'Disease', (70, 93))	('SMN2', 'Gene', '6607', (180, 184))	('Skipping', 'Var', (36, 44))	('Spinal Muscular Atrophy', 'Disease', 'MESH:D009134', (70, 93))	('Stress', 'Disease', (10, 16))	('Stress', 'Disease', 'MESH:D000079225', (10, 16))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (0, 16))	('Humans', 'Species', '9606', (99, 105))	('Muscular Atrophy', 'Phenotype', 'HP:0003202', (77, 93))	('Spinal Muscular Atrophy', 'Phenotype', 'HP:0007269', (70, 93))
77267	27111068	Loss of SMN1 leads to spinal muscular atrophy (SMA), the most frequent genetic cause of infant mortality.	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (22, 45))	('muscular atrophy', 'Phenotype', 'HP:0003202', (29, 45))	('SMN1', 'Gene', (8, 12))	('mortality', 'Disease', 'MESH:D003643', (95, 104))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (22, 45))	('SMA', 'Phenotype', 'HP:0007269', (47, 50))	('spinal muscular atrophy', 'Disease', (22, 45))	('mortality', 'Disease', (95, 104))	('Loss', 'Var', (0, 4))	('leads to', 'Reg', (13, 21))
77268	27111068	While SMN2 cannot compensate for the loss of SMN1 due to predominant skipping of exon 7, correction of SMN2 exon 7 splicing holds the promise of a cure for SMA.	('SMN2', 'Gene', '6607', (103, 107))	('correction', 'Var', (89, 99))	('skipping', 'Var', (69, 77))	('SMA', 'Phenotype', 'HP:0007269', (156, 159))	('SMN2', 'Gene', '6607', (6, 10))	('SMN2', 'Gene', (6, 10))	('SMN2', 'Gene', (103, 107))	('SMA', 'Disease', (156, 159))
77269	27111068	Previously, we used cell-based models coupled with a multi-exon-skipping detection assay (MESDA) to demonstrate the vulnerability of SMN2 exons to aberrant splicing under the conditions of oxidative stress (OS).	('aberrant', 'Var', (147, 155))	('MESDA', 'Chemical', '-', (90, 95))	('oxidative stress', 'Phenotype', 'HP:0025464', (189, 205))	('SMN2', 'Gene', '6607', (133, 137))	('SMN2', 'Gene', (133, 137))	('OS', 'Phenotype', 'HP:0025464', (207, 209))
77281	27111068	Mutations within regulatory sequences cause defective splicing and result in genetic diseases.	('splicing', 'MPA', (54, 62))	('defective', 'Var', (44, 53))	('result in', 'Reg', (67, 76))	('cause', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('genetic diseases', 'Disease', 'MESH:D030342', (77, 93))	('genetic diseases', 'Disease', (77, 93))
77283	27111068	A full-length (FL) transcript and FL SMN protein are the major products of the SMN1 gene, whereas the SMN2 gene predominantly generates a truncated transcript and a truncated protein (SMNDelta7) due to skipping of exon 7.	('SMN2', 'Gene', '6607', (102, 106))	('SMN2', 'Gene', (102, 106))	('SMN1', 'Gene', (79, 83))	('Delta7', 'Mutation', 'c.del7', (187, 193))	('FL', 'Gene', '2323', (15, 17))	('gene', 'Var', (84, 88))	('FL', 'Gene', '2323', (34, 36))
77286	27111068	Deletion of and/or mutations in SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1 leads to spinal muscular atrophy (SMA), a leading genetic disease of children and infants.	('SMN1', 'Gene', (32, 36))	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (116, 139))	('SMN1', 'Gene', (102, 106))	('genetic disease', 'Disease', 'MESH:D030342', (157, 172))	('SMN2', 'Gene', (67, 71))	('genetic disease', 'Disease', (157, 172))	('SMN2', 'Gene', '6607', (67, 71))	('children', 'Species', '9606', (176, 184))	('mutations', 'Var', (19, 28))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (116, 139))	('muscular atrophy', 'Phenotype', 'HP:0003202', (123, 139))	('leads to', 'Reg', (107, 115))	('infants', 'Species', '9606', (189, 196))	('spinal muscular atrophy', 'Disease', (116, 139))	('SMA', 'Phenotype', 'HP:0007269', (141, 144))	('Deletion', 'Var', (0, 8))
77288	27111068	Consistent with the indispensable nature of SMN, deletion of Smn gene leads to embryonic lethality.	('Smn', 'Gene', (61, 64))	('embryonic lethality', 'Disease', 'MESH:D020964', (79, 98))	('embryonic lethality', 'Disease', (79, 98))	('leads to', 'Reg', (70, 78))	('deletion', 'Var', (49, 57))
77289	27111068	However, introduction of SMN2 into the null Smn-/- background recapitulates a SMA phenotype.	('SMA', 'Disease', (78, 81))	('SMA', 'Phenotype', 'HP:0007269', (78, 81))	('introduction', 'Var', (9, 21))	('SMN2', 'Gene', (25, 29))	('SMN2', 'Gene', '6607', (25, 29))
77291	27111068	Since SMN2 contributes towards the overall cellular pool of SMN, its copy number impacts the severity of SMA.	('SMA', 'Phenotype', 'HP:0007269', (105, 108))	('cellular pool', 'MPA', (43, 56))	('impacts', 'Reg', (81, 88))	('severity', 'Disease', (93, 101))	('SMN2', 'Gene', '6607', (6, 10))	('copy number', 'Var', (69, 80))	('SMN2', 'Gene', (6, 10))
77297	27111068	A previous study has shown increased skipping of SMN2 exons 5 and 7 in neuronal cells treated with PQ.	('PQ', 'Chemical', 'MESH:D010269', (99, 101))	('skipping', 'Var', (37, 45))	('SMN2', 'Gene', '6607', (49, 53))	('SMN2', 'Gene', (49, 53))
77298	27111068	Employing a multi-exon-skipping detection assay (MESDA), we have recently demonstrated that splicing of multiple exons of SMN1 and SMN2 are affected by PQ-induced OS in both neuronal and non-neuronal cells.	('PQ', 'Chemical', 'MESH:D010269', (152, 154))	('SMN2', 'Gene', (131, 135))	('SMN2', 'Gene', '6607', (131, 135))	('splicing', 'MPA', (92, 100))	('MESDA', 'Chemical', '-', (49, 54))	('SMN1', 'Gene', (122, 126))	('affected', 'Reg', (140, 148))	('PQ-induced OS', 'Var', (152, 165))	('OS', 'Phenotype', 'HP:0025464', (163, 165))
77338	27111068	For SBP2, PCR amplification was done using primers 5hSBP2E1 and 3hSBP2E4 (S1 Table).	('5hSBP2E1', 'Var', (51, 59))	('R', 'Chemical', 'MESH:D001120', (12, 13))	('3hSBP2E4', 'Var', (64, 72))
77380	27111068	For PQ treatment of SH-SY5Y and GM03813, cells were pre-plated in 60 mm culture dishes at a density of 4.2X106 and 3.3X105 per dish, respectively.	('SH-SY5Y', 'CellLine', 'CVCL:0019', (20, 27))	('PQ', 'Chemical', 'MESH:D010269', (4, 6))	('SH-SY5Y', 'Var', (20, 27))	('GM03813', 'Var', (32, 39))
77412	27111068	These results underscore that co-skipping of SMN2 exons 5 and 7 is a signature event of PQ-induced OS observed during the first 24 h of treatment.	('OS', 'Phenotype', 'HP:0025464', (99, 101))	('PQ', 'Chemical', 'MESH:D010269', (88, 90))	('co-skipping', 'Var', (30, 41))	('SMN2', 'Gene', '6607', (45, 49))	('SMN2', 'Gene', (45, 49))
77414	27111068	Our results also revealed novel splice isoforms generated during the conditions of OS, such as Delta5-7, Delta3,5-7, Delta3-5,7 and Delta3-7 (Fig 1B, marked with pound signs).	('Delta3', 'Gene', (132, 138))	('Delta5-7', 'Var', (95, 103))	('Delta3', 'Gene', '13389', (117, 123))	('Delta3-7', 'Gene', '13389;54485', (132, 140))	('Delta3', 'Gene', '13389', (132, 138))	('Delta3', 'Gene', (105, 111))	('Delta3-7', 'Gene', (132, 140))	('Delta5', 'Mutation', 'c.del5', (95, 101))	('Delta3', 'Gene', '13389', (105, 111))	('Delta3', 'Gene', (117, 123))	('OS', 'Phenotype', 'HP:0025464', (83, 85))
77415	27111068	Based on our results described above we chose 24 h post PQ injection as the time point to collect samples for analysis of all aberrantly spliced SMN2 variants.	('PQ', 'Chemical', 'MESH:D010269', (56, 58))	('variants', 'Var', (150, 158))	('SMN2', 'Gene', (145, 149))	('SMN2', 'Gene', '6607', (145, 149))
77419	27111068	Overall, our results confirmed that co-skipping of exons 5 and 7 is the hallmark of SMN2 aberrant splicing under the severe conditions of OS (50 and 70 mg/kg PQ treatment).	('co-skipping', 'Var', (36, 47))	('SMN2', 'Gene', (84, 88))	('SMN2', 'Gene', '6607', (84, 88))	('aberrant splicing', 'Var', (89, 106))	('PQ', 'Chemical', 'MESH:D010269', (158, 160))	('OS', 'Phenotype', 'HP:0025464', (138, 140))
77427	27111068	Interestingly, heart and muscle were the only two organs in which PQ treatment resulted in a more than 10% increase in individual skipping of exon 7 (Fig 2A, Delta7 transcript).	('skipping', 'Var', (130, 138))	('increase', 'PosReg', (107, 115))	('Delta7', 'Mutation', 'c.del7', (158, 164))	('treatment', 'Var', (69, 78))	('PQ', 'Chemical', 'MESH:D010269', (66, 68))	('PQ treatment', 'Var', (66, 78))
77438	27111068	Consistent with the results of MESDA, PQ-induced OS caused small but noticeable skipping of SMN2 exon 5 in all tissues tested (S2C Fig).	('MESDA', 'Chemical', '-', (31, 36))	('PQ-induced', 'Var', (38, 48))	('SMN2', 'Gene', '6607', (92, 96))	('SMN2', 'Gene', (92, 96))	('PQ', 'Chemical', 'MESH:D010269', (38, 40))	('skipping', 'MPA', (80, 88))	('OS', 'Phenotype', 'HP:0025464', (49, 51))
77448	27111068	Both exons 3 and 3b of Sbp2 share the same 5' ss that forms extensive base pairing with U1 snRNA, a component of U1 snRNP (S3B Fig); however, the 5' ss of exons 3/3b is predicted to be sequestered in a stem-loop structure that may in part account for an OS-induced skipping of Sbp2 exon 3 in kidney and lung (S3C Fig).	('R', 'Chemical', 'MESH:D001120', (118, 119))	('skipping', 'Var', (265, 273))	('snRNP', 'Gene', (116, 121))	('S3B', 'Gene', (123, 126))	('snRNP', 'Gene', '27756', (116, 121))	('Sbp2', 'Gene', '75420', (277, 281))	('R', 'Chemical', 'MESH:D001120', (93, 94))	('OS', 'Phenotype', 'HP:0025464', (254, 256))	('Sbp2', 'Gene', '75420', (23, 27))	('S3B', 'Gene', '11778', (123, 126))	('Sbp2', 'Gene', (23, 27))	('Sbp2', 'Gene', (277, 281))
77451	27111068	Consequently, we did not observe any PQ-induced skipping of SBP2 exon 3a in human neuronal SH-SY5Y cells (S3D Fig).	('SH-SY5Y', 'CellLine', 'CVCL:0019', (91, 98))	('SBP2', 'Gene', (60, 64))	('skipping', 'Var', (48, 56))	('PQ', 'Chemical', 'MESH:D010269', (37, 39))	('human', 'Species', '9606', (76, 81))
77466	27111068	As per MESDA results, the levels of the latter transcripts were increased in PQ-treated animals (Fig 2A).	('PQ-treated', 'Var', (77, 87))	('MESDA', 'Chemical', '-', (7, 12))	('PQ', 'Chemical', 'MESH:D010269', (77, 79))	('levels', 'MPA', (26, 32))	('increased', 'PosReg', (64, 73))
77480	27111068	Also, most of the OS-induced skipping of SMN2 exon 5 in uterus/ovary occurred in transcripts that lacked exon 7.	('uterus/ovary', 'Disease', 'MESH:D010051', (56, 68))	('uterus/ovary', 'Disease', (56, 68))	('lacked', 'NegReg', (98, 104))	('OS-induced', 'Disease', (18, 28))	('exon 7', 'MPA', (105, 111))	('skipping', 'Var', (29, 37))	('SMN2', 'Gene', (41, 45))	('SMN2', 'Gene', '6607', (41, 45))	('OS', 'Phenotype', 'HP:0025464', (18, 20))
77485	27111068	Exceptions to this rule were exon 6 of Tcerg1 and exon 18 of Smarcc2.	('Smarcc2', 'Gene', (61, 68))	('Tcerg1', 'Gene', (39, 45))	('exon', 'Var', (50, 54))	('Tcerg1', 'Gene', '56070', (39, 45))	('Smarcc2', 'Gene', '68094', (61, 68))
77486	27111068	For instance, the presence of a U residue at the 5th position of Tcerg1 intron 6 shortens the region base-paired with U1 snRNA, thus, hampering an efficient recruitment of the U1 snRNP to the 5' ss of Tcerg1 exon 6 (Fig 5A).	('presence', 'Var', (18, 26))	('Tcerg1', 'Gene', (65, 71))	('shortens', 'NegReg', (81, 89))	('Tcerg1', 'Gene', '56070', (65, 71))	('snRNP', 'Gene', (179, 184))	('Tcerg1', 'Gene', (201, 207))	('R', 'Chemical', 'MESH:D001120', (181, 182))	('R', 'Chemical', 'MESH:D001120', (123, 124))	('Tcerg1', 'Gene', '56070', (201, 207))	('snRNP', 'Gene', '27756', (179, 184))	('hampering', 'NegReg', (134, 143))	('region base-paired', 'MPA', (94, 112))	('U residue', 'Var', (32, 41))	('recruitment', 'MPA', (157, 168))
77505	27111068	Skipping of SMN2 exon 7 results in the generation of a protein degradation signal at the C-terminus of SMN.	('SMN2', 'Gene', '6607', (12, 16))	('generation of a protein degradation signal at the', 'MPA', (39, 88))	('Skipping', 'Var', (0, 8))	('SMN2', 'Gene', (12, 16))
77521	27111068	Level of another splicing factor, SRp55, that is known to interact with the 5' ss of an exon, showed a noticeable but statistically insignificant increase in PQ-treated brain (Fig 6).	('SRp55', 'Gene', '6431', (34, 39))	('PQ-treated', 'Var', (158, 168))	('increase', 'PosReg', (146, 154))	('SRp55', 'Gene', (34, 39))	('PQ', 'Chemical', 'MESH:D010269', (158, 160))
77529	27111068	Moreover, the conditions of OS could cause post-translational modifications in hnRNP H. Such modified hnRNP H can then affect splicing of SMN2 exons.	('hnRNP H', 'Gene', (102, 109))	('OS', 'Phenotype', 'HP:0025464', (28, 30))	('affect', 'Reg', (119, 125))	('modified', 'Var', (93, 101))	('SMN2', 'Gene', '6607', (138, 142))	('SMN2', 'Gene', (138, 142))
77534	27111068	Here we report a comprehensive analysis of OS-induced aberrant splicing of multiple exons of SMN2, an ubiquitously expressed human gene associated with SMA, which is the most frequent genetic cause of infant mortality.	('associated', 'Reg', (136, 146))	('SMN2', 'Gene', (93, 97))	('SMN2', 'Gene', '6607', (93, 97))	('SMA', 'Phenotype', 'HP:0007269', (152, 155))	('mortality', 'Disease', (208, 217))	('human', 'Species', '9606', (125, 130))	('SMA', 'Disease', (152, 155))	('mortality', 'Disease', 'MESH:D003643', (208, 217))	('aberrant splicing', 'Var', (54, 71))	('OS', 'Phenotype', 'HP:0025464', (43, 45))
77539	27111068	Of note, while levels of DeltaC5,7 transcript significantly increased in a tissue-independent manner, level of DeltaC7 transcript was not significantly affected by OS (Fig 3).	('OS', 'Phenotype', 'HP:0025464', (164, 166))	('DeltaC7', 'Var', (111, 118))	('DeltaC5', 'DELETION', 'None', (25, 32))	('DeltaC7', 'DELETION', 'None', (111, 118))	('DeltaC5', 'Var', (25, 32))	('increased', 'PosReg', (60, 69))
77543	27111068	The results of MESDA indicate that expression of DeltaC7 and DeltaC5,7 transcripts in the liver of TG mice peaked at 8 h and 24 h post PQ treatment, respectively (Fig 1B).	('mice', 'Species', '10090', (102, 106))	('expression', 'Species', '29278', (35, 45))	('DeltaC7', 'DELETION', 'None', (49, 56))	('DeltaC5', 'DELETION', 'None', (61, 68))	('expression', 'MPA', (35, 45))	('MESDA', 'Chemical', '-', (15, 20))	('DeltaC5', 'Var', (61, 68))	('PQ', 'Chemical', 'MESH:D010269', (135, 137))	('DeltaC7', 'Var', (49, 56))
77552	27111068	In addition, low SMN causes c-Jun NH2-terminal kinase (JNK) signaling pathway activation that is associated with the testicular toxicity.	('c-Jun NH2-terminal kinase', 'Gene', '26419', (28, 53))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('low SMN', 'Var', (13, 20))	('JNK', 'Gene', '26419', (55, 58))	('activation', 'PosReg', (78, 88))	('c-Jun NH2-terminal kinase', 'Gene', (28, 53))	('JNK', 'Gene', (55, 58))
77554	27111068	Hence, high SMN level might at least partly contribute to the prevention of OS-induced skipping of SMN2 exons in testis.	('OS-induced', 'Disease', (76, 86))	('skipping', 'Var', (87, 95))	('SMN2', 'Gene', '6607', (99, 103))	('SMN2', 'Gene', (99, 103))	('OS', 'Phenotype', 'HP:0025464', (76, 78))
77561	27111068	While a direct role of a promoter element(s) on splicing of SMN exons is yet to be established, a number of exonic and intronic cis-elements that weaken the 3' and 5' ss of SMN2 exon 7 have been implicated in skipping SMN2 exon 7.	('skipping', 'Var', (209, 217))	('SMN2', 'Gene', '6607', (218, 222))	('SMN2', 'Gene', '6607', (173, 177))	('SMN2', 'Gene', (173, 177))	('SMN2', 'Gene', (218, 222))	('weaken', 'NegReg', (146, 152))
77564	27111068	Lack of a G residue at the last position of an exon weakens the base pairing between U1 RNA and the 5' ss.	('R', 'Chemical', 'MESH:D001120', (88, 89))	('weakens', 'NegReg', (52, 59))	('Lack', 'Var', (0, 4))	('base pairing', 'MPA', (64, 76))
77567	27111068	We have previously shown an inhibitory structural context as one of the limiting factors for skipping of SMN2 exon 7.	('SMN2', 'Gene', (105, 109))	('skipping', 'Var', (93, 101))	('SMN2', 'Gene', '6607', (105, 109))
77569	27111068	Due to the insertion of a protein degradation signal upon skipping of exon 7, we were unable to detect proteins translated from aberrantly spliced SMN2 transcripts, the majority of which lacked exon 7.	('protein degradation', 'MPA', (26, 45))	('skipping', 'Var', (58, 66))	('SMN2', 'Gene', (147, 151))	('SMN2', 'Gene', '6607', (147, 151))
77900	25141773	The described mutations in SDHB, SDHC and SDHD genes cause one out of four paraganglioma syndromes with similar clinical features.	('cause', 'Reg', (53, 58))	('SDHC', 'Gene', '6391', (33, 37))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('SDHB', 'Gene', '6390', (27, 31))	('SDHC', 'Gene', (33, 37))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (75, 98))	('SDHD', 'Gene', (42, 46))	('SDHB', 'Gene', (27, 31))	('mutations', 'Var', (14, 23))	('paraganglioma syndromes', 'Disease', (75, 98))
78056	31731436	In experimental animal models, BPA has been shown to affect the brain, liver, gut, adipose tissue, pancreas, mammary gland and reproductive tract of exposed animals.	('reproductive', 'CPA', (127, 139))	('affect', 'Reg', (53, 59))	('men', 'Species', '9606', (9, 12))	('BPA', 'Chemical', 'MESH:C006780', (31, 34))	('liver', 'MPA', (71, 76))	('BPA', 'Var', (31, 34))	('brain', 'CPA', (64, 69))
78068	31731436	In vivo, neonatal exposure to BPA in male mice modifies the prostate gland development, increasing the susceptibility to cancer generation through activation of epigenetic mechanisms.	('prostate gland development', 'CPA', (60, 86))	('rat', 'Species', '10116', (132, 135))	('neonatal exposure', 'Phenotype', 'HP:0031437', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mice', 'Species', '10090', (42, 46))	('modifies', 'Reg', (47, 55))	('epigenetic', 'Var', (161, 171))	('increasing', 'PosReg', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('activation', 'PosReg', (147, 157))	('men', 'Species', '9606', (82, 85))	('cancer', 'Disease', (121, 127))	('BPA', 'Chemical', 'MESH:C006780', (30, 33))
78110	31731436	Figure 1 clearly shows that although all animals had baseline levels of this compound, only the sons of the mothers exposed to BPA had a significant increase of serum BPA levels around ten-fold compared to the control or vehicle groups.	('serum BPA levels', 'MPA', (161, 177))	('BPA', 'Chemical', 'MESH:C006780', (167, 170))	('increase', 'PosReg', (149, 157))	('BPA', 'Var', (127, 130))	('BPA', 'Chemical', 'MESH:C006780', (127, 130))
78124	31731436	The results demonstrated that the Treg population was significantly diminished only in PLN by BPA action (Figure 5A,B).	('PLN', 'Var', (87, 90))	('diminished', 'NegReg', (68, 78))	('rat', 'Species', '10116', (19, 22))	('BPA', 'Chemical', 'MESH:C006780', (94, 97))	('Treg population', 'CPA', (34, 49))
78128	31731436	Figure 6 shows that the percentage of macrophages in the spleen of the scrotal cancer model offspring of BPA treated mice was not altered by the exposure to the EDC (6A).	('scrotal cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mice', 'Species', '10090', (117, 121))	('scrotal cancer', 'Phenotype', 'HP:0100849', (71, 85))	('scrotal cancer', 'Disease', 'MESH:D009369', (71, 85))	('EDC', 'Var', (161, 164))	('BPA', 'Chemical', 'MESH:C006780', (105, 108))
78170	31731436	These results appear to contravene other reports where perinatal BPA exposure induces the secretion of pro-inflammatory mediators in the bone marrow-derived mast cells of 6-month-old adult mice offspring.	('induces', 'Reg', (78, 85))	('secretion of pro-inflammatory mediators', 'MPA', (90, 129))	('mice', 'Species', '10090', (189, 193))	('BPA', 'Chemical', 'MESH:C006780', (65, 68))	('exposure', 'Var', (69, 77))	('BPA', 'Gene', (65, 68))
78208	31338064	A significant association was also found for PRDM14 and DMRT1 genes, involved in germ cell specification-sex determination, and the SALL4 gene through the disruption of the POU5F1 binding motif, the latter associated with the maintenance of pluripotency in embryonic stem cells.	('SALL4', 'Gene', (132, 137))	('DMRT1', 'Gene', (56, 61))	('pluripotency', 'Disease', (241, 253))	('PRDM14', 'Gene', '63978', (45, 51))	('POU5F1', 'Gene', (173, 179))	('pluripotency', 'Disease', 'None', (241, 253))	('POU5F1', 'Gene', '5460', (173, 179))	('PRDM14', 'Gene', (45, 51))	('DMRT1', 'Gene', '1761', (56, 61))	('binding', 'Interaction', (180, 187))	('disruption', 'Var', (155, 165))	('SALL4', 'Gene', '57167', (132, 137))
78213	31338064	Recently, a great deal of interest has been sparked by the role of gene copy number variations (CNVs) in cancer development and, particularly, in TC.	('TC', 'Phenotype', 'HP:0010788', (146, 148))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('gene copy number variations', 'Var', (67, 94))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
78215	31338064	As a member of the E2F protein family, E2F1 is a transcription factor that regulates the transition of the cell cycle from the G1 phase to the S phase, through an interaction with the retinoblastoma tumor suppressor (RB) protein.	('RB', 'Disease', 'MESH:D012175', (217, 219))	('retinoblastoma tumor', 'Disease', 'MESH:D012175', (184, 204))	('E2F1', 'Var', (39, 43))	('retinoblastoma tumor', 'Disease', (184, 204))	('regulates', 'Reg', (75, 84))	('interaction', 'Interaction', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('retinoblastoma', 'Phenotype', 'HP:0009919', (184, 198))
78216	31338064	Deregulation of E2F1-pRB binding increases the access of E2F1 to E2F1-binding target genes, containing the E2F-binding site, and this is thought to increase the susceptibility of tumor development.	('access', 'MPA', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('increase', 'PosReg', (148, 156))	('binding', 'Interaction', (25, 32))	('Deregulation', 'Var', (0, 12))	('E2F1', 'Gene', (57, 61))	('increases', 'PosReg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('RB', 'Disease', 'MESH:D012175', (22, 24))	('men', 'Species', '9606', (192, 195))	('tumor', 'Disease', (179, 184))
78218	31338064	Interestingly, in our study group of the 261 patients with an history of testicular germ cell tumors and the 165 controls, we found duplications of the E2F1 gene only in TC patients with a global prevalence of 6.5 percent.	('patients', 'Species', '9606', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('E2F1', 'Gene', (152, 156))	('TC', 'Phenotype', 'HP:0010788', (170, 172))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('germ cell tumors', 'Phenotype', 'HP:0100728', (84, 100))	('duplications', 'Var', (132, 144))
78219	31338064	This was associated with the increased expression of the E2F1 protein only in tumor tissue specimens obtained from those patients harboring three copies of E2F1, whilst surrounding non tumor-tissue showed both lower E2F1 protein expression and downstream-mTOR phosphorylation.	('E2F1', 'Var', (156, 160))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', (185, 190))	('men', 'Species', '9606', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('E2F1', 'Gene', (57, 61))	('protein', 'Protein', (221, 228))	('increased', 'PosReg', (29, 38))	('lower', 'NegReg', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('E2F1 protein', 'Protein', (216, 228))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('patients', 'Species', '9606', (121, 129))	('downstream-mTOR phosphorylation', 'MPA', (244, 275))
78225	31338064	Genetic screening in cryptorchid boys showed, respectively, a 2 and 4% prevalence of mutations in the INSL3 and RXFP2 genes, more frequently in bilateral forms, whilst there is less agreement for a causative role of polymorphic variants.	('INSL3', 'Gene', (102, 107))	('RXFP2', 'Gene', (112, 117))	('men', 'Species', '9606', (187, 190))	('boys', 'Species', '9606', (33, 37))	('mutations', 'Var', (85, 94))	('INSL3', 'Gene', '3640', (102, 107))	('cryptorchid boys', 'Phenotype', 'HP:0000028', (21, 37))	('RXFP2', 'Gene', '122042', (112, 117))
78226	31338064	In addition, expansion sites in the first exon of the AR gene, also known as poly CAG and GGN repeats, are acknowledged as a modulator of AR transactivation activity but their causative role in undescended testis is still under debate.	('GGN', 'Gene', (90, 93))	('AR transactivation activity', 'MPA', (138, 165))	('undescended testis', 'Disease', (194, 212))	('GGN', 'Gene', '199720', (90, 93))	('undescended testis', 'Phenotype', 'HP:0000028', (194, 212))	('modulator', 'Reg', (125, 134))	('expansion sites', 'Var', (13, 28))
78230	31338064	Other genetic causes of isolated cryptorchidism are ascribed to mutations of the AMH gene or its receptor in the persistent mullerian duct syndrome described below.	('duct syndrome', 'Disease', 'MESH:D001649', (134, 147))	('isolated cryptorchidism', 'Disease', (24, 47))	('AMH', 'Gene', (81, 84))	('AMH', 'Gene', '268', (81, 84))	('causes', 'Reg', (14, 20))	('mutations', 'Var', (64, 73))	('cryptorchidism', 'Phenotype', 'HP:0000028', (33, 47))	('duct syndrome', 'Disease', (134, 147))
78269	31338064	In fact, organochlorines pesticides are supposed to act as endocrine disruptors (see below) whilst pyrethroids are likely to exert a direct effect on the cell cycle.	('endocrine', 'MPA', (59, 68))	('organochlorines pesticides', 'Var', (9, 35))	('organochlorines', 'Chemical', 'MESH:D006843', (9, 24))	('pyrethroids', 'Chemical', 'MESH:D011722', (99, 110))
78276	31338064	The early disruption of this hormonal circuit reverberates on testis function in adult life and represents a major risk factor for TC.	('disruption', 'Var', (10, 20))	('reverberates', 'Reg', (46, 58))	('TC', 'Phenotype', 'HP:0010788', (131, 133))	('rat', 'Species', '10116', (53, 56))
78279	31338064	The disruption of the hormonal milieu of germ cells would then result in misleading signals altering the cell phase-switch toward mitosis and meiosis, with the consequent risk of a neoplastic transformation in adult life.	('result', 'Reg', (63, 69))	('disruption', 'Var', (4, 14))	('neoplastic transformation', 'CPA', (181, 206))	('mitosis and meiosis', 'Disease', 'MESH:C536875', (130, 149))	('altering', 'Reg', (92, 100))	('cell', 'MPA', (105, 109))
78283	31338064	In PAIS however, mutations of the AR gene are detected in <25% of patients whilst a complementary causative role has been ascribed to genetic variants of the protein and cofactors that concur to the AR signaling pathway, such as the deficiency 17beta-hydroxysteroid dehydrogenase (17beta-HSD), a key enzyme in steroidogenesis.	('men', 'Species', '9606', (90, 93))	('deficiency 17beta-hydroxysteroid dehydrogenase (17beta-HSD)', 'Disease', 'MESH:C564560', (233, 292))	('variants', 'Var', (142, 150))	('AR signaling pathway', 'Pathway', (199, 219))	('AIS', 'Phenotype', 'HP:0008226', (4, 7))	('patients', 'Species', '9606', (66, 74))
78284	31338064	Also, persistent mullerian duct syndrome (PMDS) is a form of disorder of sex differentiation in 46, XY males caused by an inactivating mutation of the gene for AMH/MIS (45% of cases) or its type II receptor (39% of cases).	('PMDS', 'Disease', (42, 46))	('MIS', 'Gene', (164, 167))	('inactivating mutation', 'Var', (122, 143))	('AMH', 'Gene', (160, 163))	('duct syndrome', 'Disease', (27, 40))	('MIS', 'Gene', '268', (164, 167))	('duct syndrome', 'Disease', 'MESH:D001649', (27, 40))	('caused by', 'Reg', (109, 118))	('AMH', 'Gene', '268', (160, 163))	('PMDS', 'Disease', 'MESH:C536665', (42, 46))
78292	31338064	In particular, activating and inactivating mutations of the LR-receptor (LHR) gene are causative of DSD forms like isosexual precocious puberty in boys and Leydig cell hypoplasia, respectively.	('DSD forms', 'Disease', (100, 109))	('causative', 'Reg', (87, 96))	('precocious puberty in boys', 'Phenotype', 'HP:0008185', (125, 151))	('isosexual precocious puberty', 'Phenotype', 'HP:0008236', (115, 143))	('LHR', 'Gene', '3973', (73, 76))	('activating', 'PosReg', (15, 25))	('LHR', 'Gene', (73, 76))	('precocious puberty', 'Phenotype', 'HP:0000826', (125, 143))	('boys', 'Species', '9606', (147, 151))	('inactivating mutations', 'Var', (30, 52))	('Leydig cell hypoplasia', 'Disease', 'MESH:C562567', (156, 178))	('Leydig cell hypoplasia', 'Disease', (156, 178))	('isosexual precocious puberty', 'Disease', (115, 143))
78294	31338064	However, few available data documented TC only in patients with isosexual precocious puberty, particularly for testicular interstitial cell tumor observed in a 9 years old boy (with no available genetic screening at the time of the analysis), and two cases of activating mutations of the LHR gene reporting testicular seminoma in adult life.	('seminoma', 'Disease', (318, 326))	('testicular seminoma', 'Phenotype', 'HP:0100617', (307, 326))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TC', 'Phenotype', 'HP:0010788', (39, 41))	('activating mutations', 'Var', (260, 280))	('men', 'Species', '9606', (32, 35))	('precocious puberty', 'Phenotype', 'HP:0000826', (74, 92))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('boy', 'Species', '9606', (172, 175))	('LHR', 'Gene', '3973', (288, 291))	('isosexual precocious puberty', 'Phenotype', 'HP:0008236', (64, 92))	('seminoma', 'Disease', 'MESH:D018239', (318, 326))	('LHR', 'Gene', (288, 291))	('tumor', 'Disease', (140, 145))
78315	31338064	As cited above, altered E2F1 expression has been significantly associated to several testis disorders such as spermatogenic impairment, cryptorchidism, and TC, particular in those cases of increased gene expression related to supernumerary gene copy numbers.	('cryptorchidism', 'Phenotype', 'HP:0000028', (136, 150))	('testis disorders', 'Disease', 'MESH:D013736', (85, 101))	('associated', 'Reg', (63, 73))	('TC', 'Phenotype', 'HP:0010788', (156, 158))	('altered', 'Var', (16, 23))	('cryptorchidism', 'Disease', (136, 150))	('gene expression', 'MPA', (199, 214))	('testis disorders', 'Phenotype', 'HP:0000035', (85, 101))	('testis disorders', 'Disease', (85, 101))	('spermatogenic impairment', 'Disease', (110, 134))	('expression', 'MPA', (29, 39))	('spermatogenic impairment', 'Disease', 'MESH:D009422', (110, 134))	('E2F1', 'Gene', (24, 28))	('increased', 'PosReg', (189, 198))
78317	31338064	Altogether, these results suggest that the clinical condition associated with abnormal E2F1 expression, due to copy number variation, can be worsened even more by other concomitant environmental conditions, such as heat stress or an history of cryptorchidism, with a likely impact on TC development.	('E2F1', 'Gene', (87, 91))	('cryptorchidism', 'Disease', (244, 258))	('impact', 'Reg', (274, 280))	('cryptorchidism', 'Phenotype', 'HP:0000028', (244, 258))	('TC', 'Phenotype', 'HP:0010788', (284, 286))	('TC development', 'CPA', (284, 298))	('men', 'Species', '9606', (294, 297))	('copy number variation', 'Var', (111, 132))	('men', 'Species', '9606', (188, 191))	('abnormal', 'Var', (78, 86))	('expression', 'MPA', (92, 102))
78339	28333256	CRD42016041414 Although rare in absolute terms, cryptorchidism - failure of the testes to descend permanently into their terminal scrotal position - is one of the most common congenital anomalies to affect boys.	('congenital anomalies', 'Disease', 'MESH:D000013', (175, 195))	('cryptorchidism', 'Phenotype', 'HP:0000028', (48, 62))	('cryptorchidism - failure', 'Disease', (48, 72))	('cryptorchidism - failure', 'Disease', 'MESH:D003456', (48, 72))	('failure of the testes', 'Phenotype', 'HP:0010469', (65, 86))	('CRD42016041414', 'Var', (0, 14))	('congenital anomalies', 'Disease', (175, 195))	('boys', 'Species', '9606', (206, 210))
78340	28333256	Cryptorchidism is one of the few known risk factors for testicular cancer, wherein males who have suffered cryptorchidism are nearly five times more likely to develop testicular cancer than those who have not (relative risk: 4.8, 95% CI 4.0-5.7).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (67, 73))	('develop', 'PosReg', (159, 166))	('testicular cancer', 'Phenotype', 'HP:0010788', (167, 184))	('cryptorchidism', 'Phenotype', 'HP:0000028', (107, 121))	('cryptorchidism', 'Var', (107, 121))	('Cryptorchidism', 'Phenotype', 'HP:0000028', (0, 14))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('testicular cancer', 'Phenotype', 'HP:0010788', (56, 73))
78420	28118455	The model for mj,t,a contained 6 components: an intercept (beta0), fixed covariate effects (beta1),random age-time effects (gamma1,a,t),random spatial effects (gamma2,j), random space-time effects (gamma3,j and gamma4,j,t), and random space-age effects (gamma5,j and gamma6,j,a).	('gamma2', 'Gene', (160, 166))	('beta1', 'Gene', (92, 97))	('beta1', 'Gene', '10678', (92, 97))	('gamma2', 'Gene', '7453', (160, 166))	('gamma4', 'Var', (211, 217))	('gamma3', 'Var', (198, 204))
78591	26794280	Similarly, we could not demonstrate any increased risk for preterm birth (22-36 completed weeks of gestation), low birth weight (500-2499 g) or being SGA, in the offspring of male cancer survivors (Table 2).	('preterm birth', 'Disease', (59, 72))	('preterm birth', 'Phenotype', 'HP:0001622', (59, 72))	('low birth weight', 'Phenotype', 'HP:0001518', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('male cancer', 'Disease', (175, 186))	('low birth weight (500-2499 g', 'Var', (111, 139))	('male cancer', 'Disease', 'MESH:D018567', (175, 186))
78617	26794280	ART has been associated with adverse pregnancy outcomes; however, despite an increased use of ART among the male cancer survivors in our study, we could not demonstrate an increased risk of negative outcomes among their offspring.	('ART', 'Var', (94, 97))	('male cancer', 'Disease', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('male cancer', 'Disease', 'MESH:D018567', (108, 119))
78710	23781383	Current radiation therapy standards include doses of 20-25 Gy at 1.5-2.0 Gy/day, treated with AP/PA fields, directed to the retroperitoneal lymph nodes, typically T10/T11 through L5 S1, 8-10 cm wide, and with consideration for accounting for left renal vein/IVC confluence (Figure 3).	('left renal vein', 'Disease', (242, 257))	('PA', 'Chemical', 'MESH:D011478', (97, 99))	('left renal vein', 'Disease', 'MESH:D007674', (242, 257))	('T10/T11', 'Var', (163, 170))
78714	23781383	In addition, at a median followup of 6.5 years, the carboplatin arm experienced a reduced number of contralateral GCT compared to the radiotherapy arm, HR 0.22 (P = 0.03).	('reduced', 'NegReg', (82, 89))	('carboplatin', 'Chemical', 'MESH:D016190', (52, 63))	('carboplatin', 'Var', (52, 63))
78925	27936464	EC-derived cisplatin resistant cells and tumors were highly sensitive to guadecitabine and in vivo guadecitabine was also able to sensitize cisplatin resistant tumors to cisplatin.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (11, 20))	('guadecitabine', 'Chemical', 'MESH:C580831', (99, 112))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (170, 179))	('guadecitabine', 'Chemical', 'MESH:C580831', (73, 86))	('sensitize', 'Reg', (130, 139))	('cisplatin resistant', 'MPA', (140, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EC', 'Phenotype', 'HP:0002898', (0, 2))	('guadecitabine', 'Var', (99, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
78927	27936464	Interestingly, immune pathway genes were also induced in EC tumors by guadecitabine, suggesting that tumor immune activation could enhance antitumor activity in the clinic.	('EC tumors', 'Disease', (57, 66))	('guadecitabine', 'Var', (70, 83))	('induced', 'Reg', (46, 53))	('immune pathway genes', 'Gene', (15, 35))	('tumor', 'Disease', (143, 148))	('EC', 'Phenotype', 'HP:0002898', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('guadecitabine', 'Chemical', 'MESH:C580831', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('EC tumors', 'Disease', 'MESH:D009369', (57, 66))	('enhance', 'PosReg', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
78937	27936464	The sensitivity of cisplatin sensitive and resistant EC cells to guadecitabine was highly dependent on DNMT3B as DNMT3B knockdown results in robust guadecitabine resistance in NT2/D1 and NT2/D1-R1 cells (Figure 2).	('NT2', 'Gene', (187, 190))	('NT2', 'Gene', (176, 179))	('NT2', 'Gene', '74120', (187, 190))	('EC', 'Phenotype', 'HP:0002898', (53, 55))	('guadecitabine', 'Chemical', 'MESH:C580831', (65, 78))	('results in', 'Reg', (130, 140))	('DNMT3B', 'Gene', (113, 119))	('DNMT3B', 'Gene', '1789', (113, 119))	('knockdown', 'Var', (120, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('guadecitabine resistance', 'MPA', (148, 172))	('NT2', 'Gene', '74120', (176, 179))	('guadecitabine', 'Chemical', 'MESH:C580831', (148, 161))	('DNMT3B', 'Gene', '1789', (103, 109))	('DNMT3B', 'Gene', (103, 109))
78941	27936464	In addition, a gene known to be highly methylated in TGCTs, RASSF1, and a gene we identified as a novel methylated gene in EC cells, SOX15, were both induced with 5-aza and guadecitabine (Figure 3).	('RASSF1', 'Gene', '11186', (60, 66))	('5-aza', 'Chemical', 'MESH:D001374', (163, 168))	('SOX15', 'Gene', (133, 138))	('EC', 'Phenotype', 'HP:0002898', (123, 125))	('SOX15', 'Gene', '6665', (133, 138))	('RASSF1', 'Gene', (60, 66))	('5-aza', 'Var', (163, 168))	('induced', 'PosReg', (150, 157))	('guadecitabine', 'Chemical', 'MESH:C580831', (173, 186))
78973	27936464	Due in part to advances in our understanding of epigenetic deregulations in cancer, there has been a recent revisiting of the concept of demethylation therapy, especially the use of demethylation inhibitors to resensitize refractory cancers to no-longer effective therapies.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('epigenetic', 'Var', (48, 58))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
78976	27936464	Cisplatin resistant TGCT-derived EC were highly sensitive to guadecitabine in vitro and in vivo and guadecitabine was also able to sensitize cisplatin resistant tumors to cisplatin.	('sensitize', 'Reg', (131, 140))	('cisplatin resistant', 'MPA', (141, 160))	('guadecitabine', 'Chemical', 'MESH:C580831', (61, 74))	('EC', 'Phenotype', 'HP:0002898', (33, 35))	('tumors', 'Disease', (161, 167))	('guadecitabine', 'Var', (100, 113))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sensitive', 'MPA', (48, 57))	('guadecitabine', 'Chemical', 'MESH:C580831', (100, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))
78979	27936464	In de novo, genome-wide analysis, we provide evidence that guadecitabine induces early and extensive p53 pathway activation in vivo and interestingly also induces immune tumor cell recognition components including HLA class I and cancer testis antigens.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('induces', 'PosReg', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer testis', 'Disease', (230, 243))	('guadecitabine', 'Chemical', 'MESH:C580831', (59, 72))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumor', 'Disease', (170, 175))	('activation', 'PosReg', (113, 123))	('cancer testis', 'Phenotype', 'HP:0010788', (230, 243))	('immune', 'MPA', (163, 169))	('cancer testis', 'Disease', 'MESH:D013736', (230, 243))	('HLA class I', 'Protein', (214, 225))	('guadecitabine', 'Var', (59, 72))
78989	27936464	Our data demonstrates that testicular cancer cells are uniquely sensitive to extremely low doses of DNMTIs suggesting that these agents can potentially be used at doses with very little toxicity.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('testicular cancer', 'Disease', (27, 44))	('DNMTIs', 'Chemical', '-', (100, 106))	('toxicity', 'Disease', 'MESH:D064420', (186, 194))	('testicular cancer', 'Phenotype', 'HP:0010788', (27, 44))	('toxicity', 'Disease', (186, 194))	('DNMTIs', 'Var', (100, 106))	('testicular cancer', 'Disease', 'MESH:D013736', (27, 44))
79003	27936464	In the current study we provide evidence that guadecitabine induces immune signatures including induction of HLA class I, cancer testis antigens and the NFKB pathway in EC tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('EC', 'Phenotype', 'HP:0002898', (169, 171))	('cancer testis', 'Disease', (122, 135))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('guadecitabine', 'Var', (46, 59))	('cancer testis', 'Phenotype', 'HP:0010788', (122, 135))	('EC tumors', 'Disease', 'MESH:D009369', (169, 178))	('induction', 'PosReg', (96, 105))	('immune', 'MPA', (68, 74))	('cancer testis', 'Disease', 'MESH:D013736', (122, 135))	('NFKB pathway', 'Pathway', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('guadecitabine', 'Chemical', 'MESH:C580831', (46, 59))	('EC tumors', 'Disease', (169, 178))	('HLA class I', 'Protein', (109, 120))
79066	26816727	Using a global score for overall sexual functioning based on sexual interest, ability, enjoyment and satisfaction, identity, and frequency of intercourse, they reported that patients after a penectomy had lower scores than patients after either radiation or local surgery.	('sexual interest', 'Phenotype', 'HP:0030214', (61, 76))	('patients', 'Species', '9606', (174, 182))	('penectomy', 'Var', (191, 200))	('men', 'Species', '9606', (92, 95))	('lower', 'NegReg', (205, 210))	('patients', 'Species', '9606', (223, 231))
79081	26816727	Polychemotherapy induces loss of libido, decreased arousal, and potentially decreased erectile function in patients with testicular cancer.	('Polychemotherapy', 'Var', (0, 16))	('potentially decreased erectile function', 'Phenotype', 'HP:0000802', (64, 103))	('testicular cancer', 'Disease', 'MESH:D013736', (121, 138))	('decreased', 'NegReg', (41, 50))	('testicular cancer', 'Disease', (121, 138))	('arousal', 'MPA', (51, 58))	('decreased', 'NegReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('libido', 'MPA', (33, 39))	('loss', 'NegReg', (25, 29))	('testicular cancer', 'Phenotype', 'HP:0010788', (121, 138))	('erectile function', 'CPA', (86, 103))	('patients', 'Species', '9606', (107, 115))
79089	26816727	The main cause of sexual dysfunction after proctectomy appears to be injury to the autonomic nerves in the pelvis and along the distal aorta and anterior surface of the rectum.	('sexual dysfunction', 'Disease', 'MESH:D012735', (18, 36))	('autonomic', 'Protein', (83, 92))	('sexual dysfunction', 'Disease', (18, 36))	('cause', 'Reg', (9, 14))	('injury', 'Var', (69, 75))
79159	25822223	Heightened awareness is warranted for patients who received myeloablative TBI, those who had HCT at ages < 18 years, those with prior or concurrent GVHD of any form and those who had HCT for hereditary disorders, such as Fanconi anemia.	('Fanconi anemia', 'Phenotype', 'HP:0001994', (221, 235))	('GVHD', 'Disease', 'MESH:D006086', (148, 152))	('TBI', 'Chemical', 'MESH:D013828', (74, 77))	('GVHD', 'Disease', (148, 152))	('Fanconi anemia', 'Disease', (221, 235))	('hereditary disorders', 'Disease', (191, 211))	('Fanconi anemia', 'Disease', 'MESH:D005199', (221, 235))	('patients', 'Species', '9606', (38, 46))	('anemia', 'Phenotype', 'HP:0001903', (229, 235))	('hereditary disorders', 'Disease', 'MESH:D030342', (191, 211))	('myeloablative', 'Var', (60, 73))
79185	25822223	A pediatric study showed an increased incidence of pharyngeal cancer after autologous HCT, whereas an adult study did not report oropharyngeal cancer after autologous HCT.	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('oropharyngeal cancer', 'Disease', (129, 149))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('autologous HCT', 'Var', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (129, 149))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (51, 68))
79200	25822223	In particular, extensive-type cGVHD was a risk factor for esophageal cancer (RR = 5.3).	('esophageal cancer', 'Disease', (58, 75))	('cGVHD', 'Chemical', '-', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('extensive-type', 'Var', (15, 29))
79258	25822223	The incidence of breast cancer was increased among patients > 50 years of age who received BU-CY conditioning regimen, but the incidence was not increased among patients of similar age in another study.	('increased', 'PosReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('breast cancer', 'Disease', (17, 30))	('men', 'Species', '9606', (114, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('BU-CY', 'Chemical', '-', (91, 96))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (51, 59))	('BU-CY', 'Var', (91, 96))
79270	25822223	As HPV of high-risk subtypes such as HPV16 and HPV18 causes > 90% of cases, routine HPV vaccination is recommended for females aged 9-26 years.	('causes', 'Reg', (53, 59))	('HPV18', 'Gene', (47, 52))	('HPV16', 'Species', '333760', (37, 42))	('HPV16', 'Var', (37, 42))	('men', 'Species', '9606', (108, 111))	('HPV', 'Species', '10566', (84, 87))	('HPV', 'Species', '10566', (37, 40))	('HPV', 'Species', '10566', (47, 50))	('HPV', 'Species', '10566', (3, 6))
79347	21771862	Aberrant expression of syncytins outside of the placenta could trigger pathogenic changes, particularly chronic inflammation and inadvertent cell-to-cell fusions.	('syncytins', 'Gene', (23, 32))	('Aberrant', 'Var', (0, 8))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('expression', 'MPA', (9, 19))	('inflammation', 'Disease', (112, 124))	('trigger', 'Reg', (63, 70))
79357	21771862	We have shown that CpG methylation of ERVWE1 5'-LTR occurs in non-placental tissues and cell lines but not in trophoblastic cells from the placenta or choriocarcinoma BeWo cell line.	('choriocarcinoma', 'Disease', (151, 166))	('methylation', 'Var', (23, 34))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (151, 166))	('ERVWE1', 'Gene', '30816', (38, 44))	('ERVWE1', 'Gene', (38, 44))	('choriocarcinoma', 'Disease', 'MESH:D002822', (151, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))
79373	21771862	Histologically normal testicular tissues surrounding the tumors were obtained by macrodissection (T5-h, T6-h, T7-h and T8-h).	('T6', 'CellLine', 'CVCL:0601', (104, 106))	('T7-h', 'Var', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('T8-h', 'Var', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('T6-h', 'Var', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
79384	21771862	The antibodies used for ChIP were as follows: anti-acetyl-histone H3 (Lys 9), anti-trimethyl-histone H3 (Lys 9), anti-trimethyl-histone H3 (Lys 36) (ab4441, ab8898 and ab9050, respectively, all from Abcam, Cambridge, UK) and anti-histone H3 (07-690 Millipore).	('Lys', 'Chemical', 'MESH:D008239', (70, 73))	('anti-acetyl-histone', 'Var', (46, 65))	('anti-trimethyl-histone', 'Var', (78, 100))	('H3', 'Gene', '126961', (66, 68))	('ab4441', 'Var', (149, 155))	('trimethyl-histone', 'Chemical', '-', (83, 100))	('acetyl-histone', 'Chemical', '-', (51, 65))	('Lys', 'Chemical', 'MESH:D008239', (105, 108))	('anti-trimethyl-histone', 'Var', (113, 135))	('H3', 'Gene', '126961', (238, 240))	('trimethyl-histone', 'Chemical', '-', (118, 135))	('Lys', 'Chemical', 'MESH:D008239', (140, 143))	('H3', 'Gene', '126961', (101, 103))	('H3', 'Gene', '126961', (136, 138))
79395	21771862	To investigate this epigenetic level of transcriptional regulation, we compared H3K9 modifications associated with ERVWE1 and ERVFRDE1 5'-LTRs by ChIP in choriocarcinoma BeWo cells and cervical carcinoma HeLa cells, which show transcriptional activity or gene repression of both promoters, respectively.	('choriocarcinoma', 'Phenotype', 'HP:0100768', (154, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('ERVFRDE1', 'Gene', '405754', (126, 134))	('choriocarcinoma', 'Disease', 'MESH:D002822', (154, 169))	('carcinoma HeLa', 'Disease', 'MESH:D002277', (194, 208))	('H3', 'Gene', '126961', (80, 82))	('ERVFRDE1', 'Gene', (126, 134))	('modifications', 'Var', (85, 98))	('ERVWE1', 'Gene', '30816', (115, 121))	('carcinoma HeLa', 'Disease', (194, 208))	('choriocarcinoma', 'Disease', (154, 169))	('ERVWE1', 'Gene', (115, 121))
79436	21771862	The inefficient splicing of ERVWE1 transcripts prevents improper syncytin-1 expression in normal testes but not in seminomas, where both non-spliced and spliced forms of ERVWE1 mRNAs occur.	('inefficient', 'Var', (4, 15))	('ERVWE1', 'Gene', (170, 176))	('syncytin-1', 'Gene', '30816', (65, 75))	('syncytin-1', 'Gene', (65, 75))	('ERVWE1', 'Gene', '30816', (28, 34))	('prevents', 'NegReg', (47, 55))	('seminomas', 'Disease', (115, 124))	('seminomas', 'Disease', 'MESH:D018239', (115, 124))	('ERVWE1', 'Gene', (28, 34))	('ERVWE1', 'Gene', '30816', (170, 176))
79444	21771862	Among the histone post-translational modifications, the trimethylation of lysine 36 of H3 (H3K36me3) has been reported to be enriched on exons and to mark the expressed exons.	('H3K36me3', 'Gene', (91, 99))	('H3K36me3', 'Gene', '126961', (91, 99))	('H3', 'Gene', '126961', (87, 89))	('lysine', 'Chemical', 'MESH:D008239', (74, 80))	('H3', 'Gene', '126961', (91, 93))	('trimethylation', 'Var', (56, 70))
79453	21771862	We further tested the H3 occupancy and H3K36me3 level in two independent HeLa cell clones with stable insertions of ectopic ERVWE1.	('H3', 'Gene', '126961', (22, 24))	('H3K36me3', 'Gene', (39, 47))	('insertions', 'Var', (102, 112))	('H3', 'Gene', '126961', (39, 41))	('tested', 'Reg', (11, 17))	('ERVWE1', 'Gene', '30816', (124, 130))	('H3K36me3', 'Gene', '126961', (39, 47))	('HeLa', 'CellLine', 'CVCL:0030', (73, 77))	('ERVWE1', 'Gene', (124, 130))
79454	21771862	Here, we took into account the increased copy numbers of ERVWE1, up to five proviruses introduced into unknown genomic positions.	('copy numbers', 'Var', (41, 53))	('ERVWE1', 'Gene', (57, 63))	('ERVWE1', 'Gene', '30816', (57, 63))	('increased', 'PosReg', (31, 40))
79465	21771862	Heavy CpG methylation of ERVWE1 in non-placental cells is accompanied by deacetylation and trimethylation at H3K9, which results in a strong resistance against reactivation by 5-azacytidine and trichostatin A.	('H3', 'Gene', '126961', (109, 111))	('trimethylation', 'MPA', (91, 105))	('deacetylation', 'MPA', (73, 86))	('resistance against reactivation by 5-azacytidine', 'MPA', (141, 189))	('ERVWE1', 'Gene', '30816', (25, 31))	('ERVWE1', 'Gene', (25, 31))	('methylation', 'Var', (10, 21))	('results in', 'Reg', (121, 131))
79473	21771862	demonstrated the increasing level of pseudo-spliced ERVWE1 mRNA in term placenta and suggested that the relative amounts of spliced and pseudo-spliced mRNAs could regulate syncytin-1 expression during pregnancy.	('regulate', 'Reg', (163, 171))	('syncytin-1', 'Gene', '30816', (172, 182))	('syncytin-1', 'Gene', (172, 182))	('ERVWE1', 'Gene', '30816', (52, 58))	('pseudo-spliced', 'Var', (37, 51))	('expression', 'MPA', (183, 193))	('ERVWE1', 'Gene', (52, 58))
79483	21771862	The weak correlation between ERVWE1 expression and hypomethylation of its 5'-LTR could be explained by exceptional epigenetic features of male germ cells such as high level of CpG methylation, presence of rare histone variants, protamine occupancy, mimicking methylcytosine by hydroxymethylcytosine, etc.	('methylcytosine', 'Chemical', '-', (259, 273))	('methylcytosine', 'MPA', (259, 273))	('methylcytosine', 'Chemical', '-', (284, 298))	('hydroxymethylcytosine', 'Chemical', '-', (277, 298))	('ERVWE1', 'Gene', '30816', (29, 35))	('ERVWE1', 'Gene', (29, 35))	('mimicking', 'Var', (249, 258))	('variants', 'Var', (218, 226))
79627	19505907	In regard to prostate cancer, although the results have been inconsistent, depleted uranium (the material used in armor penetrators) has been suggested to increase the risk of prostate cancer.	('increase', 'PosReg', (155, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('uranium', 'Chemical', 'MESH:D014501', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('prostate cancer', 'Disease', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('depleted uranium', 'Var', (75, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('prostate cancer', 'Disease', (176, 191))
79642	30854207	In the alvimopan cohort compared with those who did not receive alvimopan median time to return of flatus was 2 versus 4 days (p=0.0002), and median time to first bowel movement was 2.5 versus 5 days (p=0.046), respectively.	('alvimopan', 'Var', (7, 16))	('alvimopan', 'Chemical', 'MESH:C419502', (7, 16))	('bowel movement', 'Disease', 'MESH:D009069', (163, 177))	('bowel movement', 'Disease', (163, 177))	('alvimopan', 'Chemical', 'MESH:C419502', (64, 73))
79686	30854207	Both unadjusted and adjusted regression analyses demonstrate that LOS is influenced mainly by Clavien grade complications, and was not associated with alvimopan use or with the setting in which RPLND was performed (primary vs. post-chemotherapy) (Table 3).	('complications', 'Var', (108, 121))	('Clavien grade', 'Disease', (94, 107))	('influenced', 'Reg', (73, 83))	('alvimopan', 'Chemical', 'MESH:C419502', (151, 160))
79687	30854207	For example, on adjusted analyses, there was an incremental increase in hospital LOS (days) according to Clavien grade classification, with patients who had Clavien grade 1, 2 and 3a complications staying 1.9, 3.1 and 4.1 days longer, respectively, than those without complications (Clavien grade 0), (p=0.10, p=0.0006, p=0.0002, respectively).	('hospital LOS', 'MPA', (72, 84))	('longer', 'PosReg', (227, 233))	('increase', 'PosReg', (60, 68))	('Clavien', 'Var', (157, 164))	('patients', 'Species', '9606', (140, 148))	('men', 'Species', '9606', (53, 56))	('complications', 'Var', (183, 196))
79734	27871274	With such a routine but dramatic and reproducible divide in chemotherapy sensitivity and treatment outcomes between these differing tumor cell types, the conventional explanations that ascribe chemotherapy resistance to the two main continuous variable parameters of the rate of tumour cell growth and the development of genetic mutations that lead to resistance are perhaps worthy of an updated review.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('men', 'Species', '9606', (313, 316))	('men', 'Species', '9606', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('tumor', 'Disease', (132, 137))	('mutations', 'Var', (329, 338))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))
79764	27871274	A number of studies have indicated that the expression of this family of molecules is associated with a reduction in the efficacy of chemotherapy as a result of the increased efflux of drugs from cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('reduction', 'NegReg', (104, 113))	('expression', 'Var', (44, 54))	('efflux of drugs from', 'MPA', (175, 195))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('increased', 'PosReg', (165, 174))	('efficacy of chemotherapy', 'CPA', (121, 145))
79807	27871274	As in the other B cell and T cell malignancies, the events of VDJ recombination breaks the link from the original chemotherapy resistant tissue HSC.	('malignancies', 'Disease', 'MESH:D009369', (34, 46))	('recombination', 'Var', (66, 79))	('T cell malignancies', 'Phenotype', 'HP:0005517', (27, 46))	('VDJ', 'Gene', (62, 65))	('malignancies', 'Disease', (34, 46))	('link', 'MPA', (91, 95))
79835	27871274	In the common solid malignancies the hierarchical relationship of the tissue specific somatic stem cell, the cancer stem cell and the cancer cells is relatively simple with the tissue specific stem cell giving rise through mutation to the cancer stem cell and the cancer stem cells in turn giving rise to the more rapidly growing standard cancer cells.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('cancer', 'Disease', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (339, 345))	('mutation', 'Var', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('malignancies', 'Disease', 'MESH:D009369', (20, 32))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('malignancies', 'Disease', (20, 32))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('giving rise', 'Reg', (203, 214))	('giving rise to', 'Reg', (290, 304))
79840	27871274	These processes in which DNA is cut, rearranged, mutated, rejoined and repaired contain much of the risk of DNA damage that leads to leukamagenesis and lymphomagenesis but also provide the pathways that allow these malignancies to be chemotherapy curable.	('lymphomagenesis', 'Disease', (152, 167))	('malignancies', 'Disease', (215, 227))	('leukamagenesis', 'Disease', (133, 147))	('leads to', 'Reg', (124, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('damage', 'Var', (112, 118))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))
79842	27871274	Whilst HSC that carry mutations have been recognised to confirm a risk of development of CLL, these cells are not directly clonally related to a current diagnosis of CLL and cannot serve to repopulate the pool of established CLL cells after chemotherapy treatment.	('CLL', 'Phenotype', 'HP:0005550', (166, 169))	('men', 'Species', '9606', (259, 262))	('men', 'Species', '9606', (81, 84))	('CLL', 'Phenotype', 'HP:0005550', (225, 228))	('mutations', 'Var', (22, 31))	('CLL', 'Phenotype', 'HP:0005550', (89, 92))	('CLL', 'Disease', (89, 92))
79855	27871274	We would hypothesise that the ongoing activity of these genetic recombination related apoptotic pathways are sufficiently active to overcome the degree of resistance associated with development of stemness in the stochastic cancer stem cell and leave these biologically unique cancer stem cells sensitive to chemotherapy treatment.	('men', 'Species', '9606', (189, 192))	('stemness in the stochastic cancer', 'Disease', 'MESH:D009369', (197, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('apoptotic', 'Pathway', (86, 95))	('leave', 'Reg', (245, 250))	('genetic', 'Var', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('stemness in the stochastic cancer', 'Disease', (197, 230))	('men', 'Species', '9606', (326, 329))	('cancer', 'Disease', (224, 230))
79905	22508459	For example, two meta-analyses of perinatal factors found that, in addition to cryptorchidism, the factors most consistently associated with increased risk of testicular cancer are prior inguinal hernia, low birth order, maternal bleeding, small sibship size, and being a twin.	('low birth order', 'Phenotype', 'HP:0001518', (204, 219))	('ship', 'Gene', (249, 253))	('hernia', 'Phenotype', 'HP:0100790', (196, 202))	('hernia', 'Disease', 'MESH:D006547', (196, 202))	('inguinal hernia', 'Phenotype', 'HP:0000023', (187, 202))	('associated', 'Reg', (125, 135))	('bleeding', 'Disease', 'MESH:D006470', (230, 238))	('testicular cancer', 'Disease', (159, 176))	('cryptorchidism', 'Phenotype', 'HP:0000028', (79, 93))	('low birth', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('bleeding', 'Disease', (230, 238))	('ship', 'Gene', '3635', (249, 253))	('hernia', 'Disease', (196, 202))	('testicular cancer', 'Phenotype', 'HP:0010788', (159, 176))	('testicular cancer', 'Disease', 'MESH:D013736', (159, 176))
79926	22508459	An early recreational activity study conducted in Canada found that bicycle riding and horseback riding were both associated with significantly increased risks of testicular cancer, but motorcycle riding was not.	('testicular cancer', 'Phenotype', 'HP:0010788', (163, 180))	('testicular cancer', 'Disease', 'MESH:D013736', (163, 180))	('bicycle', 'Var', (68, 75))	('testicular cancer', 'Disease', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('horseback riding', 'CPA', (87, 103))
79927	22508459	By contrast, a second study by the same group found that bicycle riding was associated with a significantly decreased risk of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('testicular cancer', 'Phenotype', 'HP:0010788', (126, 143))	('decreased', 'NegReg', (108, 117))	('bicycle', 'Var', (57, 64))	('testicular cancer', 'Disease', 'MESH:D013736', (126, 143))	('testicular cancer', 'Disease', (126, 143))
79965	22508459	What the specific exposure might be is uncertain, but has been speculated to be hydrocarbon carcinogens, such as methylcholanthene, which induces testicular tumors in animals.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('induces', 'Reg', (138, 145))	('hydrocarbon', 'Chemical', 'MESH:D006838', (80, 91))	('testicular tumors', 'Disease', (146, 163))	('methylcholanthene', 'Var', (113, 130))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('testicular tumors', 'Disease', 'MESH:D013736', (146, 163))	('methylcholanthene', 'Chemical', '-', (113, 130))	('testicular tumors', 'Phenotype', 'HP:0010788', (146, 163))
79978	22508459	Cadmium is classified as a group 1 carcinogen by the International Agency for Research on Cancer and, in animal studies, has deleterious effects on the testes.	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('testes', 'CPA', (152, 158))	('Cadmium', 'Var', (0, 7))	('Cancer', 'Disease', (90, 96))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))
80006	22508459	The sum of the epidemiological data suggests that nonionizing radiation might be associated with a slightly increased risk of testicular cancer, although these results require validation in future studies.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('nonionizing radiation', 'Var', (50, 71))	('testicular cancer', 'Phenotype', 'HP:0010788', (126, 143))	('testicular cancer', 'Disease', 'MESH:D013736', (126, 143))	('testicular cancer', 'Disease', (126, 143))
80030	22508459	Chlordane and its derivatives (oxychlordane, cis-nonachlor, trans-nonachlor and MC6) have been assessed in at least four molecular epidemiological studies, of which all save one supported associations between both cis-nonachlor and trans-nonachlor and increased risk of testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (214, 227))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (232, 247))	('testicular cancer', 'Phenotype', 'HP:0010788', (270, 287))	('MC6', 'Chemical', '-', (80, 83))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (60, 75))	('testicular cancer', 'Disease', 'MESH:D013736', (270, 287))	('Chlordane', 'Chemical', 'MESH:D002706', (0, 9))	('oxychlordane', 'Chemical', 'MESH:C008743', (31, 43))	('trans-nonachlor', 'Var', (232, 247))	('associations', 'Interaction', (188, 200))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (45, 58))	('testicular cancer', 'Disease', (270, 287))	('cis-nonachlor', 'Var', (214, 227))
80031	22508459	Conversely, little evidence indicates that oxychlordane and MC6 are associated with TGCT, as is also the case for other important hexachlorocyclopentadiene derivatives (heptachlor, dieldrin and mirex).	('MC6', 'Var', (60, 63))	('associated', 'Reg', (68, 78))	('hexachlorocyclopentadiene', 'Chemical', 'MESH:C016488', (130, 155))	('oxychlordane', 'Chemical', 'MESH:C008743', (43, 55))	('MC6', 'Chemical', '-', (60, 63))	('mirex', 'Chemical', 'MESH:D008917', (194, 199))	('heptachlor', 'Chemical', 'MESH:D006533', (169, 179))	('dieldrin', 'Chemical', 'MESH:D004026', (181, 189))	('TGCT', 'Disease', (84, 88))
80036	22508459	Current evidence suggests that of the organochlorine pesticides examined, only DDE and chlordanes, particularly cis-nonachlor and trans-nonachlor, are associated with an increased risk of testicular cancer.	('cis-nonachlor', 'Var', (112, 125))	('trans-nonachlor', 'Var', (130, 145))	('chlordanes', 'Chemical', 'MESH:D002706', (87, 97))	('organochlorine', 'Chemical', 'MESH:D006843', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('testicular cancer', 'Phenotype', 'HP:0010788', (188, 205))	('associated', 'Reg', (151, 161))	('cis-nonachlor', 'Chemical', 'MESH:C001870', (112, 125))	('testicular cancer', 'Disease', 'MESH:D013736', (188, 205))	('trans-nonachlor', 'Chemical', 'MESH:C001870', (130, 145))	('DDE', 'Chemical', 'MESH:D003633', (79, 82))	('testicular cancer', 'Disease', (188, 205))
80072	24276357	Using ICD-O-2/ICD-O-3 morphology codes, these were classified as seminomas (9060-9064) and non-seminomas (9065-9101).	('9065-9101', 'Var', (106, 115))	('seminomas', 'Disease', 'MESH:D018239', (65, 74))	('seminomas', 'Disease', (65, 74))	('non-seminomas', 'Disease', 'MESH:D018239', (91, 104))	('9060-9064', 'Var', (76, 85))	('seminomas', 'Disease', 'MESH:D018239', (95, 104))	('non-seminomas', 'Disease', (91, 104))	('seminomas', 'Disease', (95, 104))
80073	24276357	Non-seminomas included embryonal carcinomas (9070), yolk sac tumors (9071), teratomas (9080, 9082-9084), mixed histology (9081, 9085, 9101), and choriocarcinomas (9100).	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('embryonal carcinomas', 'Disease', 'MESH:D018236', (23, 43))	('9081', 'Var', (122, 126))	('Non-seminomas', 'Disease', (0, 13))	('teratomas', 'Phenotype', 'HP:0009792', (76, 85))	('Non-seminomas', 'Disease', 'MESH:D018239', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('9080', 'Var', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (151, 161))	('tumors', 'Disease', (61, 67))	('mixed', 'Disease', (105, 110))	('teratomas', 'Disease', 'MESH:D013724', (76, 85))	('choriocarcinomas', 'Disease', (145, 161))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('embryonal carcinomas', 'Phenotype', 'HP:0002898', (23, 43))	('9071', 'Var', (69, 73))	('embryonal carcinomas', 'Disease', (23, 43))	('teratomas', 'Disease', (76, 85))	('choriocarcinomas', 'Disease', 'MESH:D002822', (145, 161))
80112	24276357	Having observed an approximate 2 1/2 -fold increased risk of testicular cancer with fluoxetine and paroxetine in our screening study, with a possible biological link of these drugs to testicular effects in animal experiments we believed it important to pursue these leads with more detailed study that included all antidepressant drugs for which we had data.	('men', 'Species', '9606', (219, 222))	('fluoxetine', 'Chemical', 'MESH:D005473', (84, 94))	('testicular cancer', 'Phenotype', 'HP:0010788', (61, 78))	('fluoxetine', 'Var', (84, 94))	('testicular cancer', 'Disease', 'MESH:D013736', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('paroxetine', 'Var', (99, 109))	('testicular cancer', 'Disease', (61, 78))	('paroxetine', 'Chemical', 'MESH:D017374', (99, 109))
80123	24276357	The tricyclics, amitriptyline, doxepin, and nortriptyline, and the atypical antidepressant bupropion have been reported to produce testicular swelling in men but no carcinogenic effects.	('doxepin', 'Var', (31, 38))	('bupropion', 'Chemical', 'MESH:D016642', (91, 100))	('carcinogenic', 'Disease', 'MESH:D063646', (165, 177))	('testicular swelling', 'CPA', (131, 150))	('nortriptyline', 'Chemical', 'MESH:D009661', (44, 57))	('carcinogenic', 'Disease', (165, 177))	('doxepin', 'Chemical', 'MESH:D004316', (31, 38))	('nortriptyline', 'Var', (44, 57))	('men', 'Species', '9606', (154, 157))	('amitriptyline', 'Chemical', 'MESH:D000639', (16, 29))	('amitriptyline', 'Var', (16, 29))
80194	21976922	Van Basten and colleagues, in their review of testicular cancer in Dutch men, noted that a three-times lower incidence rate of a contralateral testicular tumor was found in the chemotherapy subgroup compared with those on surveillance.	('testicular cancer', 'Phenotype', 'HP:0010788', (46, 63))	('testicular cancer', 'Disease', 'MESH:D013736', (46, 63))	('men', 'Species', '9606', (73, 76))	('testicular cancer', 'Disease', (46, 63))	('lower', 'NegReg', (103, 108))	('testicular tumor', 'Disease', 'MESH:D013736', (143, 159))	('testicular tumor', 'Phenotype', 'HP:0010788', (143, 159))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('testicular tumor', 'Disease', (143, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('chemotherapy', 'Var', (177, 189))
80220	20805325	To characterize new "orphan" glycosyltransferases, candidates may be expressed in wild-type CHO cells or CHO mutants with altered glycosylation that have a well-characterized glycan complement.	('glycan', 'Chemical', 'MESH:D011134', (175, 181))	('glycosylation', 'MPA', (130, 143))	('mutants', 'Var', (109, 116))	('glycosyltransferase', 'Gene', '215494', (29, 48))	('men', 'Species', '9606', (188, 191))	('glycosyltransferase', 'Gene', (29, 48))	('altered', 'Reg', (122, 129))
80221	20805325	CHO glycosylation mutants express changes in cell surface glycans that are recognized by cytotoxic plant lectins.	('cell surface glycans', 'MPA', (45, 65))	('mutants', 'Var', (18, 25))	('CHO glycosylation', 'Disease', (0, 17))	('changes', 'Reg', (34, 41))	('CHO glycosylation', 'Disease', 'MESH:D018981', (0, 17))	('glycans', 'Chemical', 'MESH:D011134', (58, 65))
80222	20805325	Lectin-resistant phenotypes reflect mutations in glycosylation genes, such as glycosyltransferase, glycosidase, or nucleotide-sugar transporter genes.	('glycosyltransferase', 'Gene', '215494', (78, 97))	('nucleotide-sugar transporter', 'Gene', (115, 143))	('glycosyltransferase', 'Gene', (78, 97))	('glycosidase', 'Gene', (99, 110))	('nucleotide-sugar', 'Chemical', '-', (115, 131))	('mutations', 'Var', (36, 45))	('glycosylation genes', 'Gene', (49, 68))	('Lectin-resistant', 'Disease', (0, 16))
80223	20805325	For instance, LEC10 CHO mutants have a gain-of-function mutation that induces expression of the Mgat3 gene and Mgat3 (GlcNAcT-III) catalyzes the transfer of the bisecting GlcNAc to complex N-glycans.	('N-glycans', 'Chemical', '-', (189, 198))	('expression', 'MPA', (78, 88))	('LEC10', 'Gene', (14, 19))	('gain-of-function', 'PosReg', (39, 55))	('induces', 'PosReg', (70, 77))	('mutants', 'Var', (24, 31))	('GlcNAcT-III', 'Gene', '17309', (118, 129))	('GlcNAcT-III', 'Gene', (118, 129))	('GlcNAc', 'Chemical', 'MESH:D000117', (118, 124))	('Mgat3 gene', 'Gene', (96, 106))	('GlcNAc', 'Chemical', 'MESH:D000117', (171, 177))	('LEC10', 'CellLine', 'CVCL:0A09', (14, 19))	('expression', 'Species', '29278', (78, 88))	('Mgat3', 'Gene', (111, 116))
80225	20805325	Lec1 CHO glycosylation mutants have a loss-of-function mutation in the Mgat1 gene and lack Mgat1 (GlcNAcT-I) activity.	('Mgat1', 'Gene', (91, 96))	('Mgat1', 'Gene', '17308', (71, 76))	('CHO glycosylation', 'Disease', (5, 22))	('loss-of-function', 'NegReg', (38, 54))	('Mgat1', 'Gene', (71, 76))	('CHO glycosylation', 'Disease', 'MESH:D018981', (5, 22))	('lack', 'NegReg', (86, 90))	('Lec1', 'Gene', (0, 4))	('activity', 'MPA', (109, 117))	('mutation', 'Var', (55, 63))	('mutants', 'Var', (23, 30))	('Mgat1', 'Gene', '17308', (91, 96))
80227	20805325	Lec1 mutants lack hybrid and complex N-glycans and are consequently resistant to many plant lectins that bind to terminal sugars of N-glycans.	('lack', 'NegReg', (13, 17))	('sugars', 'Chemical', 'MESH:D000073893', (122, 128))	('hybrid', 'Protein', (18, 24))	('Lec1', 'Gene', (0, 4))	('N-glycans', 'Chemical', '-', (132, 141))	('mutants', 'Var', (5, 12))	('N-glycans', 'Chemical', '-', (37, 46))
80229	20805325	Expression of an orphan glycosyltransferase that alters the lectin resistance phenotype of wild-type CHO cells or of CHO glycosylation mutants allows identification of the new activity.	('lectin resistance phenotype', 'MPA', (60, 87))	('Expression', 'Species', '29278', (0, 10))	('glycosyltransferase', 'Gene', (24, 43))	('mutants', 'Var', (135, 142))	('glycosyltransferase', 'Gene', '215494', (24, 43))	('CHO glycosylation', 'Disease', (117, 134))	('alters', 'Reg', (49, 55))	('CHO glycosylation', 'Disease', 'MESH:D018981', (117, 134))
80231	20805325	The novel activity, termed GlcNAcT-I inhibitory protein (GnT1IP), is expressed mainly in spermatocytes and spermatids of mammalian testis, its transcription and translation are tightly regulated during mouse spermatogenesis, and the changes in glycan complement it induces cause cells to adhere strongly to TM4 Sertoli cells.	('men', 'Species', '9606', (257, 260))	('mammalian', 'Species', '9606', (121, 130))	('Sertoli cells', 'Phenotype', 'HP:0100619', (311, 324))	('mouse', 'Species', '10090', (202, 207))	('Sertoli cell', 'Phenotype', 'HP:0100619', (311, 323))	('induces', 'Reg', (265, 272))	('cells', 'CPA', (279, 284))	('glycan', 'Chemical', 'MESH:D011134', (244, 250))	('changes', 'Var', (233, 240))
80234	20805325	The TMpred program predicted that NP_080509.2 contains a transmembrane domain from aa 5-25, whereas SignalP 3.0 predicted a signal peptide from aa 1-26, and a GlcNAcT-IV-like domain from aa 79-373.	('N', 'Chemical', 'MESH:D009584', (162, 163))	('transmembrane domain', 'MPA', (57, 77))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('NP_080509.2', 'Var', (34, 45))
80235	20805325	N-terminal Myc-tagged BAB30173.1 was previously shown to localize to the ER when transiently expressed in HeLa cells.	('localize', 'MPA', (57, 65))	('tag', 'Gene', (15, 18))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('BAB30173.1', 'Var', (22, 32))	('HeLa', 'CellLine', 'CVCL:0030', (106, 110))	('BAB30173', 'Chemical', '-', (22, 30))	('tag', 'Gene', '107423', (15, 18))
80237	20805325	1 A, line 4) contained cells highly resistant to the leukoagglutinin L-PHA, similar to Lec1 mutant cells (Fig.	('PHA', 'Gene', '40170', (71, 74))	('PHA', 'Gene', (71, 74))	('mutant', 'Var', (92, 98))	('Lec1', 'Gene', (87, 91))
80240	20805325	Both proteins contain 253EDD255, a motif that might mediate nucleotide-sugar and metal ion binding in a glycosyltransferase reaction.	('mediate', 'Reg', (52, 59))	('glycosyltransferase', 'Gene', '215494', (104, 123))	('nucleotide-sugar', 'Chemical', '-', (60, 76))	('glycosyltransferase', 'Gene', (104, 123))	('253EDD255', 'Var', (22, 31))	('metal', 'Chemical', 'MESH:D008670', (81, 86))
80241	20805325	However, mutation to either E253A (ADD) or D255A (EDA) did not diminish the L-PHA resistance induced by Myc-NP_080509.2 (not depicted).	('PHA', 'Gene', '40170', (78, 81))	('N', 'Chemical', 'MESH:D009584', (108, 109))	('PHA', 'Gene', (78, 81))	('EDA', 'Gene', '13607', (50, 53))	('E253A', 'Var', (28, 33))	('E253A', 'Mutation', 'p.E253A', (28, 33))	('D255A', 'Mutation', 'p.D255A', (43, 48))	('EDA', 'Gene', (50, 53))	('D255A', 'Var', (43, 48))	('diminish', 'NegReg', (63, 71))
80243	20805325	In vitro GlcNAcT-I activity was also inhibited in lysates from GFP-sorted CHO/Myc-NP_080509.2 transfectants, but beta4GalT activity was not affected (Fig.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('inhibited', 'NegReg', (37, 46))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('activity', 'MPA', (19, 27))	('GlcNAcT-I', 'Enzyme', (9, 18))	('transfectants', 'Var', (94, 107))
80244	20805325	Similarly, when mouse GlcNAcT-I was coexpressed with Myc-NP_080509.2 in Lec1 mutant cells, GlcNAcT-I activity was inhibited, but beta4GalT activity was not (Fig.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('GlcNAcT-I activity', 'MPA', (91, 109))	('mouse', 'Species', '10090', (16, 21))	('mutant', 'Var', (77, 83))	('Lec1', 'Gene', (72, 76))	('inhibited', 'NegReg', (114, 123))	('N', 'Chemical', 'MESH:D009584', (94, 95))
80246	20805325	Thus, the introduction of NP_080509.2 into wild-type CHO cells inhibited GlcNAcT-I but not beta4GalT activity, and induced a lectin resistance phenotype characteristic of Lec1 cells that lack GlcNAcT-I.	('NP_080509.2', 'Var', (26, 37))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('GlcNAcT-I', 'MPA', (73, 82))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('inhibited', 'NegReg', (63, 72))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('induced', 'Reg', (115, 122))	('lectin resistance phenotype', 'MPA', (125, 152))
80268	20805325	S2 A), but internally tagged SP-HA-GnT1IP-S (Fig.	('SP-HA', 'Chemical', '-', (29, 34))	('SP-HA-GnT1IP-S', 'Var', (29, 43))	('tag', 'Gene', '107423', (22, 25))	('tag', 'Gene', (22, 25))
80270	20805325	By contrast, N-terminally tagged FL-HA-GnT1IP-S (Fig.	('tag', 'Gene', '107423', (26, 29))	('tag', 'Gene', (26, 29))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('FL-HA-GnT1IP-S', 'Var', (33, 47))
80273	20805325	The C-terminal sequence of GnT1IP is KDNYY, which could be an ER membrane retention signal.	('GnT1IP', 'Gene', (27, 33))	('KDNYY', 'Var', (37, 42))	('N', 'Chemical', 'MESH:D009584', (39, 40))
80286	20805325	3 B), and was more resistant to L-PHA (not depicted), similar to cells expressing untagged GnT1IP-L. To determine which region(s) of GnT1IP are important for inducing L-PHA resistance, deletion mutants of GnT1IP-S lacking 39 aa (Fig.	('tag', 'Gene', '107423', (84, 87))	('GnT1IP-L', 'Gene', (91, 99))	('kin', 'Gene', '16588', (217, 220))	('PHA', 'Gene', '40170', (34, 37))	('GnT1IP-L', 'Gene', '67555', (91, 99))	('tag', 'Gene', (84, 87))	('39 aa', 'MPA', (222, 227))	('kin', 'Gene', (217, 220))	('PHA', 'Gene', (34, 37))	('deletion mutants', 'Var', (185, 201))	('PHA', 'Gene', '40170', (169, 172))	('GnT1IP-S', 'Gene', (205, 213))	('inducing', 'PosReg', (158, 166))	('PHA', 'Gene', (169, 172))
80290	20805325	None of the deletion mutants induced L-PHA resistance in CHO transfectants (Fig.	('deletion', 'Var', (12, 20))	('induced', 'Reg', (29, 36))	('PHA', 'Gene', (39, 42))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('PHA', 'Gene', '40170', (39, 42))
80291	20805325	All membrane-bound GnT1IP-L and GnT1IP-S deletion mutants were sensitive to Endo H digestion (not depicted), and thus were localized to the ER and early Golgi compartments.	('GnT1IP-L', 'Gene', (19, 27))	('Endo H digestion', 'MPA', (76, 92))	('sensitive', 'Reg', (63, 72))	('GnT1IP-L', 'Gene', '67555', (19, 27))	('deletion mutants', 'Var', (41, 57))	('men', 'Species', '9606', (166, 169))	('GnT1IP-S', 'Gene', (32, 40))
80294	20805325	To determine if GnT1IP inhibits an unrelated medial-Golgi enzyme, GlcNAcT-III that is endogenously expressed in LEC10 CHO glycosylation mutant cells was examined.	('GlcNAcT-III', 'Gene', (66, 77))	('CHO glycosylation', 'Disease', (118, 135))	('LEC10', 'CellLine', 'CVCL:0A09', (112, 117))	('CHO glycosylation', 'Disease', 'MESH:D018981', (118, 135))	('LEC10', 'Gene', (112, 117))	('mutant', 'Var', (136, 142))	('GlcNAcT-III', 'Gene', '17309', (66, 77))
80297	20805325	The deletion mutant Myc-GnT1IP-S-CD1 had no effect on GlcNAcT-I, GlcNAcT-III, or beta4GalT activity (Fig.	('GlcNAcT-III', 'Gene', '17309', (65, 76))	('GlcNAcT-III', 'Gene', (65, 76))	('CD1', 'Gene', (33, 36))	('CD1', 'Gene', '111334', (33, 36))	('GlcNAcT-I', 'MPA', (54, 63))	('deletion', 'Var', (4, 12))	('beta4GalT activity', 'MPA', (81, 99))
80300	20805325	Cells expressing either GnT1IP-L or Myc-GnT1IP-S produced markedly more of the Man5GlcNAc2 substrate of GlcNAcT-I than wild-type CHO cells, and synthesized very few complex N-glycans, consistent with a similar degree of inhibition of GlcNAcT-I activity.	('Man5GlcNAc2 substrate', 'MPA', (79, 100))	('more', 'PosReg', (67, 71))	('N-glycans', 'Chemical', '-', (173, 182))	('Man5GlcNAc2', 'Chemical', 'MESH:C058642', (79, 90))	('GnT1IP-L', 'Gene', (24, 32))	('rat', 'Species', '10116', (96, 99))	('Myc-GnT1IP-S', 'Var', (36, 48))	('GnT1IP-L', 'Gene', '67555', (24, 32))
80304	20805325	The stem-region deletion mutants of N-terminally tagged GnT1IP-L and -S were also localized to the ER, cis-Golgi, and probably the ERGIC compartment (Fig.	('tag', 'Gene', (49, 52))	('GnT1IP-L and -S', 'Gene', '67555', (56, 71))	('men', 'Species', '9606', (144, 147))	('deletion mutants', 'Var', (16, 32))	('mutants', 'Var', (25, 32))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('tag', 'Gene', '107423', (49, 52))
80319	20805325	Cells expressing both GlcNAcT-I-HA and Myc-GnT1IP-L had punctate costaining around the nucleus, typical of ERGIC localization, in addition to reticular costaining of the ER, whereas endogenous ManII localized only to the ER in the presence of Myc-GnT1IP-L and did not colocalize with GnT1IP-L at punctate ER exit sites after BFA treatment (Fig.	('GlcNAcT-I-HA', 'Var', (22, 34))	('men', 'Species', '9606', (334, 337))	('GnT1IP-L', 'Gene', (284, 292))	('GnT1IP-L', 'Gene', (43, 51))	('GnT1IP-L', 'Gene', '67555', (284, 292))	('GnT1IP-L', 'Gene', '67555', (43, 51))	('GnT1IP-L', 'Gene', '67555', (247, 255))	('GnT1IP-L', 'Gene', (247, 255))	('ManII', 'Gene', '17158', (193, 198))	('punctate', 'MPA', (56, 64))	('ManII', 'Gene', (193, 198))	('BFA', 'Chemical', 'MESH:D020126', (325, 328))
80323	20805325	Although endogenous ManII mislocalized to the ER with GlcNAcT-I-HA-KDEL in some cells (Fig.	('ManII', 'Gene', (20, 25))	('ManII', 'Gene', '17158', (20, 25))	('mislocalized', 'Var', (26, 38))
80337	20805325	Interestingly, secreted SP-HA-GnT1IP-S also interacted with GlcNAcT-I, the full-length GlcNAcT-III and ManIIx, but not the trans-Golgi sialyltransferase STX (Fig.	('STX', 'Gene', '20450', (153, 156))	('STX', 'Gene', (153, 156))	('SP-HA-GnT1IP-S', 'Var', (24, 38))	('GlcNAcT-III', 'Gene', '17309', (87, 98))	('GlcNAcT-III', 'Gene', (87, 98))	('ManIIx', 'Gene', '140481', (103, 109))	('SP-HA', 'Chemical', '-', (24, 29))	('ManIIx', 'Gene', (103, 109))	('interacted', 'Interaction', (44, 54))
80351	20805325	It was previously shown that truncated N-glycans occurring in the ManIIx knockout mouse inhibit the binding of germ cells to Sertoli cells.	('ManIIx', 'Gene', '140481', (66, 72))	('binding', 'Interaction', (100, 107))	('inhibit', 'NegReg', (88, 95))	('truncated', 'Var', (29, 38))	('N-glycans', 'Chemical', '-', (39, 48))	('Sertoli cell', 'Phenotype', 'HP:0100619', (125, 137))	('ManIIx', 'Gene', (66, 72))	('Sertoli cells', 'Phenotype', 'HP:0100619', (125, 138))	('mouse', 'Species', '10090', (82, 87))	('N-glycans', 'Protein', (39, 48))
80358	20805325	Cells highly expressing GlcNAcT-I-HA-KDEL in the ER either mislocalized endogenous ManII to the ER or led to its disappearance.	('ManII', 'Gene', '17158', (83, 88))	('GlcNAcT-I-HA-KDEL', 'Var', (24, 41))	('ManII', 'Gene', (83, 88))	('disappearance', 'NegReg', (113, 126))
80442	20805325	After washing with PBS, cells were fixed in 3% (wt/vol) paraformaldehyde, then incubated with blocking buffer supplemented with 0.2% Triton X-100, 1% FBS, and 0.5% (wt/vol) BSA in PBS with Ca2+ and Mg2+ as described previously.	('paraformaldehyde', 'Chemical', 'MESH:C003043', (56, 72))	('Ca2+', 'Var', (189, 193))	('Mg2+', 'Var', (198, 202))	('Ca2+', 'Chemical', 'MESH:D000069285', (189, 193))	('kin', 'Gene', (98, 101))	('PBS', 'Chemical', 'MESH:D007854', (19, 22))	('Mg2+', 'Chemical', '-', (198, 202))	('kin', 'Gene', '16588', (98, 101))	('Triton X-100', 'Chemical', 'MESH:D017830', (133, 145))	('men', 'Species', '9606', (116, 119))	('PBS', 'Chemical', 'MESH:D007854', (180, 183))
80451	20805325	Cells were then washed three times with cold PBS containing Ca2+ and Mg2+ and processed for immunofluorescence microscopy.	('Mg2+', 'Chemical', '-', (69, 73))	('PBS', 'Chemical', 'MESH:D007854', (45, 48))	('Ca2+', 'Var', (60, 64))	('Ca2+', 'Chemical', 'MESH:D000069285', (60, 64))	('Mg2+', 'Var', (69, 73))
80496	32961939	Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females.	('puberty', 'CPA', (37, 44))	('induce alterations', 'Reg', (15, 33))	('cancer', 'Disease', (97, 103))	('Phthalates', 'Var', (0, 10))	('testicular dysgenesis syndrome', 'Disease', (65, 95))	('Phthalates', 'Chemical', 'MESH:C032279', (0, 10))	('testicular dysgenesis syndrome', 'Disease', 'None', (65, 95))	('fertility disorders', 'Phenotype', 'HP:0000144', (109, 128))	('fertility disorders', 'Disease', 'MESH:D007246', (109, 128))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fertility disorders', 'Disease', (109, 128))	('men', 'Species', '9606', (57, 60))	('testicular dysgenesis', 'Phenotype', 'HP:0008715', (65, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
80596	32961939	Phthalates as EDs can impair the development of the genital system during prenatal as well as the postnatal period of ontogenesis.	('development of the genital system', 'Phenotype', 'HP:0000078', (33, 66))	('Phthalates', 'Var', (0, 10))	('development of the genital system', 'CPA', (33, 66))	('Phthalates', 'Chemical', 'MESH:C032279', (0, 10))	('men', 'Species', '9606', (40, 43))	('impair', 'NegReg', (22, 28))
80616	32961939	The level of mono-iso-nonyl phthalate (MiBP) was positively associated with sperm motility and negatively associated with total sperm count.	('mono-iso-nonyl', 'Var', (13, 27))	('MiBP', 'Gene', (39, 43))	('mono-iso-nonyl phthalate', 'Chemical', 'MESH:C471400', (13, 37))	('associated', 'Interaction', (60, 70))	('MiBP', 'Gene', '27231', (39, 43))	('negatively', 'NegReg', (95, 105))	('sperm motility', 'CPA', (76, 90))
80617	32961939	Urinary levels of monobutyl phthalate(MBP) and monoethyl phthalate (MEP) were associated with decreased sperm concentration and reduced sperm motility, respectively, in 125 Chinese men visiting an infertility clinic.	('monobutyl', 'Var', (18, 27))	('sperm concentration', 'CPA', (104, 123))	('monobutyl phthalate', 'Chemical', 'MESH:C028577', (18, 37))	('reduced', 'NegReg', (128, 135))	('sperm motility', 'CPA', (136, 150))	('monoethyl', 'Var', (47, 56))	('men', 'Species', '9606', (181, 184))	('infertility', 'Disease', 'MESH:D007247', (197, 208))	('decreased', 'NegReg', (94, 103))	('reduced sperm motility', 'Phenotype', 'HP:0012207', (128, 150))	('infertility', 'Phenotype', 'HP:0000789', (197, 208))	('MBP', 'Chemical', 'MESH:C028577', (38, 41))	('MEP', 'Chemical', 'MESH:C581825', (68, 71))	('infertility', 'Disease', (197, 208))	('monoethyl phthalate', 'Chemical', 'MESH:C581825', (47, 66))
80619	32961939	The semen levels of monobenzyl phthalate (MBzP), MEHP, MEHHP were associated with reduced sperm motility in 1247 Chinese men visiting an infertility clinic.	('infertility', 'Disease', (137, 148))	('reduced sperm motility', 'Phenotype', 'HP:0012207', (82, 104))	('men', 'Species', '9606', (121, 124))	('monobenzyl phthalate', 'Chemical', 'MESH:C103325', (20, 40))	('MEHP', 'Gene', (49, 53))	('MEHHP', 'Var', (55, 60))	('MBzP', 'Chemical', 'MESH:C103325', (42, 46))	('MEHHP', 'Chemical', 'MESH:C479069', (55, 60))	('infertility', 'Disease', 'MESH:D007247', (137, 148))	('reduced', 'NegReg', (82, 89))	('sperm motility', 'CPA', (90, 104))	('infertility', 'Phenotype', 'HP:0000789', (137, 148))	('MEHP', 'Chemical', 'MESH:C016599', (49, 53))	('men', 'Species', '9606', (6, 9))
80621	32961939	Moreover, DnBP disturbed the maturation and activation of human sperm before fertilization, which was associated with early motility response and acrosomal exocytosis.	('maturation', 'CPA', (29, 39))	('associated', 'Reg', (102, 112))	('DnBP', 'Var', (10, 14))	('human', 'Species', '9606', (58, 63))	('activation', 'CPA', (44, 54))	('acrosomal exocytosis', 'MPA', (146, 166))	('disturbed', 'Reg', (15, 24))	('DnBP', 'Chemical', 'MESH:D003993', (10, 14))
80651	32961939	For instance, higher levels of phthalate metabolites were observed in non-Hispanic blacks and Hispanics in comparison with non-Hispanic whites and Asians.	('higher levels of phthalate', 'Phenotype', 'HP:0000218', (14, 40))	('phthalate', 'Chemical', 'MESH:C032279', (31, 40))	('Hispanics', 'Var', (94, 103))	('phthalate metabolites', 'MPA', (31, 52))	('higher', 'PosReg', (14, 20))
80664	32961939	Any alternation in the functioning of these genes leads to uncontrolled cell division, which is known as tumorigenesis.	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('alternation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('uncontrolled cell division', 'CPA', (59, 85))	('leads to', 'Reg', (50, 58))
80685	32961939	EDs may induce the cancer of the prostate gland and testis.	('cancer of the prostate', 'Phenotype', 'HP:0012125', (19, 41))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('induce', 'Reg', (8, 14))	('testis', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('EDs', 'Var', (0, 3))
80704	32961939	In addition, DEHP disturbed the maturation and activation of oocytes before fertilization via meiotic maturation inhibition and oxidative stress.	('disturbed', 'Reg', (18, 27))	('maturation', 'CPA', (32, 42))	('activation', 'CPA', (47, 57))	('meiotic maturation inhibition', 'CPA', (94, 123))	('DEHP', 'Chemical', 'MESH:D004051', (13, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (128, 144))	('DEHP', 'Var', (13, 17))
80706	32961939	The imbalance of the hypothalamic-pituitary-ovarian axis furthermore negatively affected the development and function of the reproductive system of female progeny.	('men', 'Species', '9606', (100, 103))	('hypothalamic-pituitary-ovarian axis', 'Disease', 'MESH:C566610', (21, 56))	('negatively', 'NegReg', (69, 79))	('imbalance', 'Var', (4, 13))	('hypothalamic-pituitary-ovarian axis', 'Disease', (21, 56))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))	('development', 'CPA', (93, 104))	('affected', 'Reg', (80, 88))
80710	32961939	In conclusion, the data have shown that phthalates affect ovarian functions leading to full-spectrum disorders associated with reproduction.	('affect', 'Reg', (51, 57))	('phthalates', 'Var', (40, 50))	('ovarian functions', 'CPA', (58, 75))	('phthalates', 'Chemical', 'MESH:C032279', (40, 50))	('leading to', 'Reg', (76, 86))	('full-spectrum disorders', 'Disease', (87, 110))
80774	32961939	showed that MEHP at 10-7-10-9 M triggered the proliferation of human cervical cancer cell lines HeLa and SiHa.	('human', 'Species', '9606', (63, 68))	('MEHP', 'Chemical', 'MESH:C016599', (12, 16))	('proliferation', 'CPA', (46, 59))	('MEHP', 'Var', (12, 16))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('HeLa', 'CellLine', 'CVCL:0030', (96, 100))	('cervical cancer', 'Disease', (69, 84))	('SiHa', 'CellLine', 'CVCL:0032', (105, 109))
80787	32961939	After the analysis of nine original research articles, this systematic review reported that SigmaDEHP was positively associated with a risk of leiomyoma.	('leiomyoma', 'Disease', (143, 152))	('associated', 'Reg', (117, 127))	('leiomyoma', 'Disease', 'MESH:D007889', (143, 152))	('SigmaDEHP', 'Chemical', '-', (92, 101))	('SigmaDEHP', 'Var', (92, 101))
80790	32961939	In conclusion, the results from in vitro and epidemiological studies have shown that phthalate exposure is associated with an increased risk of cancer in female reproductive cells and organs.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('phthalate', 'Chemical', 'MESH:C032279', (85, 94))	('cancer', 'Disease', (144, 150))	('phthalate', 'Var', (85, 94))
80791	32961939	Taken together, the available data have suggested that phthalate exposure in females can lead to reproductive disorders, such as POF, decreased fecundity, adverse pregnancy outcomes, gynecological cancer, or a modulation of pubertal onset and pubertal symptoms in girls.	('adverse pregnancy outcomes', 'CPA', (155, 181))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('girls', 'Species', '9606', (264, 269))	('phthalate', 'Var', (55, 64))	('POF', 'Gene', (129, 132))	('fecundity', 'CPA', (144, 153))	('decreased', 'NegReg', (134, 143))	('phthalate', 'Chemical', 'MESH:C032279', (55, 64))	('reproductive disorder', 'Phenotype', 'HP:0000078', (97, 118))	('lead to', 'Reg', (89, 96))	('cancer', 'Disease', (197, 203))	('reproductive disorders', 'Phenotype', 'HP:0000078', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('modulation', 'Reg', (210, 220))	('reproductive disorders', 'Disease', (97, 119))	('pubertal symptoms', 'CPA', (243, 260))	('pubertal symptoms in girls', 'Phenotype', 'HP:0008647', (243, 269))	('pubertal onset', 'CPA', (224, 238))	('POF', 'Gene', '79983', (129, 132))
80886	32961939	Based on in vitro studies, DEP, DEHP, DiBP, DnBP are the anti-androgenic and DnBP, DEHP are anti-estrogenic xenobiotics, which means that they can bind to AR and ER to block the effect of androgens and estrogens on particular cells.	('ER', 'Gene', '2069', (162, 164))	('block', 'NegReg', (168, 173))	('DEHP', 'Var', (83, 87))	('DiBP', 'Chemical', 'MESH:C025605', (38, 42))	('DEHP', 'Chemical', 'MESH:D004051', (32, 36))	('DEP', 'Chemical', 'MESH:C007379', (27, 30))	('DnBP', 'Chemical', 'MESH:D003993', (44, 48))	('DnBP', 'Chemical', 'MESH:D003993', (77, 81))	('effect', 'MPA', (178, 184))	('bind', 'Interaction', (147, 151))	('DEHP', 'Chemical', 'MESH:D004051', (83, 87))	('AR', 'Gene', '367', (155, 157))
80887	32961939	Moreover, DEHP can bind to the PPAR and block its effects.	('DEHP', 'Var', (10, 14))	('PPAR', 'Gene', (31, 35))	('bind', 'Interaction', (19, 23))	('PPAR', 'Gene', '5465', (31, 35))	('DEHP', 'Chemical', 'MESH:D004051', (10, 14))	('block', 'NegReg', (40, 45))	('effects', 'MPA', (50, 57))
80892	32961939	DEP, DEHP, DiBP, DiNP, DnBP can significantly activate ER, DEHP, DiBP and DnBP can stimulate the activity of PPARs.	('ER', 'Gene', '2069', (55, 57))	('DiNP', 'Chemical', 'MESH:C012125', (17, 21))	('DiBP', 'Chemical', 'MESH:C025605', (65, 69))	('PPAR', 'Gene', (109, 113))	('activity', 'MPA', (97, 105))	('DEHP', 'Chemical', 'MESH:D004051', (5, 9))	('DEP', 'Chemical', 'MESH:C007379', (0, 3))	('DiBP', 'Chemical', 'MESH:C025605', (11, 15))	('DnBP', 'Chemical', 'MESH:D003993', (74, 78))	('stimulate', 'PosReg', (83, 92))	('DnBP', 'Chemical', 'MESH:D003993', (23, 27))	('activate', 'PosReg', (46, 54))	('DnBP', 'Var', (74, 78))	('DEHP', 'Chemical', 'MESH:D004051', (59, 63))	('PPAR', 'Gene', '5465', (109, 113))
80899	32961939	Besides, the phthalates modification of gene expression can also influence the onset of cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('influence', 'Reg', (65, 74))	('phthalates', 'Var', (13, 23))	('onset', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('phthalates', 'Chemical', 'MESH:C032279', (13, 23))
80904	32961939	Via epigenetic mechanisms, phthalates can affect the exposed individual as well as the first and second generation of progeny.	('affect', 'Reg', (42, 48))	('epigenetic', 'Var', (4, 14))	('phthalates', 'Chemical', 'MESH:C032279', (27, 37))
80905	32961939	This mechanism of toxicity is possible due to the epigenetic modulation of genes in germ cells.	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('epigenetic modulation', 'Var', (50, 71))	('toxicity', 'Disease', (18, 26))
80930	32961939	DnBP activated the sperm-specific CatSper channel and increased intracellular Ca2+ levels in vitro.	('DnBP', 'Var', (0, 4))	('sperm-specific', 'CPA', (19, 33))	('intracellular Ca2+ levels', 'MPA', (64, 89))	('activated', 'PosReg', (5, 14))	('increased', 'PosReg', (54, 63))	('CatSper channel', 'Pathway', (34, 49))	('increased intracellular Ca2+ levels', 'Phenotype', 'HP:0003575', (54, 89))	('Ca2+', 'Chemical', 'MESH:D000069285', (78, 82))	('DnBP', 'Chemical', 'MESH:D003993', (0, 4))
80946	32961939	The available data demonstrate that phthalate exposure is associated with male reproductive disorders, such as TDS, the modulation of pubertal onset, and the manifestation of pubertal symptoms.	('associated', 'Reg', (58, 68))	('phthalate', 'Chemical', 'MESH:C032279', (36, 45))	('reproductive disorder', 'Phenotype', 'HP:0000078', (79, 100))	('male reproductive disorders', 'Disease', (74, 101))	('reproductive disorders', 'Phenotype', 'HP:0000078', (79, 101))	('phthalate', 'Var', (36, 45))	('TDS', 'Disease', (111, 114))
80956	32961939	The available publications report that phthalates can either delay or induce precocious puberty onset.	('delay', 'NegReg', (61, 66))	('precocious puberty onset', 'CPA', (77, 101))	('phthalates', 'Var', (39, 49))	('induce', 'Reg', (70, 76))	('precocious puberty', 'Phenotype', 'HP:0000826', (77, 95))	('puberty onset', 'Phenotype', 'HP:0000826', (88, 101))	('phthalates', 'Chemical', 'MESH:C032279', (39, 49))
80984	31545448	In the present study, we selected three gene expression datasets (GSE15220, GSE1818 and GSE59520), which were downloaded from the Gene Expression Omnibus (GEO) database, to obtain differentially expressed genes (DEGs) and differentially expressed microRNAs (DEMs) between testicular seminoma tissues and normal tissue samples.	('DEG', 'Chemical', 'MESH:C042934', (212, 215))	('testicular seminoma', 'Phenotype', 'HP:0100617', (272, 291))	('GSE59520', 'Var', (88, 96))	('testicular seminoma', 'Disease', 'MESH:D018239', (272, 291))	('testicular seminoma', 'Disease', (272, 291))
81049	31545448	Compared with normal testis samples, 11 DEMs were acquired in GSE59520 in seminoma samples.	('GSE59520', 'Var', (62, 70))	('seminoma', 'Disease', (74, 82))	('seminoma', 'Disease', 'MESH:D018239', (74, 82))
81224	26366090	Any disorder of the hypothalamic-pituitary-testis axis might cause abnormal steroid secretion, which could result in oncogenesis.	('cause', 'Reg', (61, 66))	('hypothalamic-pituitary-testis axis', 'Disease', 'MESH:D007029', (20, 54))	('oncogenesis', 'CPA', (117, 128))	('disorder', 'Var', (4, 12))	('hypothalamic-pituitary-testis axis', 'Disease', (20, 54))	('abnormal steroid secretion', 'MPA', (67, 93))	('steroid', 'Chemical', 'MESH:D013256', (76, 83))	('disorder of the hypothalamic-pituitary-testis', 'Phenotype', 'HP:0000864', (4, 49))	('result in', 'Reg', (107, 116))
81240	26366090	The cleavage of caspases will further cleave poly ADP-ribose polymerase (PARP), resulting in cell death.	('cleavage', 'Var', (4, 12))	('caspases', 'Gene', (16, 24))	('cleave', 'Var', (38, 44))	('PARP', 'Gene', (73, 77))	('PARP', 'Gene', '11545', (73, 77))	('resulting in', 'Reg', (80, 92))	('poly ADP-ribose polymerase', 'Gene', (45, 71))	('cell death', 'CPA', (93, 103))	('caspases', 'Gene', '12368;12370;12371', (16, 24))	('poly ADP-ribose polymerase', 'Gene', '11545', (45, 71))
81276	26366090	Treatment for 24 hours with combinations of cisplatin + cordycepin, cisplatin + paclitaxel, cordycepin + paclitaxel, and cordycepin + cisplatin + paclitaxel resulted in more loss of cell attachment to the matrix, more membrane blebbing, and many more floating cells (Figure 1F-I).	('cordycepin', 'Chemical', 'MESH:C058120', (92, 102))	('cell attachment to the matrix', 'CPA', (182, 211))	('men', 'Species', '9606', (193, 196))	('cordycepin +', 'Var', (92, 104))	('cordycepin', 'Var', (121, 131))	('floating cells', 'CPA', (251, 265))	('membrane blebbing', 'CPA', (218, 235))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('cordycepin', 'Chemical', 'MESH:C058120', (121, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('more', 'PosReg', (246, 250))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('more', 'PosReg', (213, 217))	('cordycepin', 'Chemical', 'MESH:C058120', (56, 66))	('cisplatin + paclitaxel', 'Var', (68, 90))	('men', 'Species', '9606', (5, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('loss', 'NegReg', (174, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
81281	26366090	After 36 hours of treatment, cell viability was reduced to 66.63% by cordycepin, 68.52% by paclitaxel, 60.81% by cisplatin, 9.76% by cordycepin + cisplatin, 38.20% by cisplatin + paclitaxel, 9.34% by cordycepin + paclitaxel, and 13.20% by cordycepin + cisplatin + paclitaxel (Figure 1J).	('cordycepin', 'Chemical', 'MESH:C058120', (133, 143))	('cordycepin', 'Chemical', 'MESH:C058120', (239, 249))	('cordycepin', 'Var', (133, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('reduced', 'NegReg', (48, 55))	('paclitaxel', 'Chemical', 'MESH:D017239', (179, 189))	('cordycepin', 'Chemical', 'MESH:C058120', (69, 79))	('men', 'Species', '9606', (23, 26))	('cell viability', 'CPA', (29, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('cordycepin', 'Chemical', 'MESH:C058120', (200, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (213, 223))	('paclitaxel', 'Chemical', 'MESH:D017239', (264, 274))
81282	26366090	After 48 hours of treatment, cell viability was reduced to 46.12% by cordycepin; 51.75% at paclitaxel, 44.01% by cisplatin, 8.16% by cordycepin + cisplatin, 27.36% by cisplatin + paclitaxel, 6.59% by cordycepin + paclitaxel, and 11.50% by cordycepin + cisplatin + paclitaxel (Figure 1J).	('cordycepin', 'Chemical', 'MESH:C058120', (133, 143))	('cordycepin', 'Chemical', 'MESH:C058120', (239, 249))	('cisplatin', 'Var', (113, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('reduced', 'NegReg', (48, 55))	('paclitaxel', 'Chemical', 'MESH:D017239', (179, 189))	('cordycepin', 'Chemical', 'MESH:C058120', (69, 79))	('men', 'Species', '9606', (23, 26))	('cell viability', 'CPA', (29, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('cisplatin', 'Chemical', 'MESH:D002945', (252, 261))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('cordycepin', 'Chemical', 'MESH:C058120', (200, 210))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (213, 223))	('paclitaxel', 'Chemical', 'MESH:D017239', (264, 274))
81294	26366090	The combinations of cisplatin + cordycepin, cisplatin + paclitaxel, cordycepin + paclitaxel, and cisplatin + cordycepin + paclitaxel for 12 and 24 hours also induced significant caspase-8 cleavage (P<0.05, Figure 3A).	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('caspase-8', 'Gene', (178, 187))	('cleavage', 'MPA', (188, 196))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('cordycepin', 'Chemical', 'MESH:C058120', (109, 119))	('cordycepin', 'Chemical', 'MESH:C058120', (68, 78))	('cordycepin', 'Var', (68, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('caspase-8', 'Gene', '12370', (178, 187))	('cordycepin', 'Chemical', 'MESH:C058120', (32, 42))	('cisplatin', 'Var', (97, 106))
81297	26366090	Cordycepin (100 muM), paclitaxel (50 nM), cisplatin (100 muM), cisplatin + paclitaxel, cordycepin + paclitaxel, cisplatin + cordycepin, and cordycepin + cisplatin + paclitaxel, but not cisplatin alone, induced significant caspase-3 cleavage compared with control after 24 hours of treatment (P<0.05, Figure 3C).	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('paclitaxel', 'Chemical', 'MESH:D017239', (100, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('caspase-3', 'Gene', '12367', (222, 231))	('cordycepin', 'Chemical', 'MESH:C058120', (140, 150))	('men', 'Species', '9606', (286, 289))	('100 muM', 'Var', (53, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('caspase-3', 'Gene', (222, 231))	('paclitaxel', 'Chemical', 'MESH:D017239', (22, 32))	('paclitaxel', 'Chemical', 'MESH:D017239', (75, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('cordycepin', 'Chemical', 'MESH:C058120', (124, 134))	('Cordycepin', 'Chemical', 'MESH:C058120', (0, 10))	('cordycepin', 'Chemical', 'MESH:C058120', (87, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))
81306	26366090	To reconfirm whether phosphorylation of JNK, ERK, and p38 proteins could be induced by cordycepin + paclitaxel and/or cisplatin in MA-10 cells, inhibitors of JNK, ERK, and p38 (SP600125, PD98059, and SB203580, respectively) were used to abolish expression of phosphorylated JNK, ERK, and p38.	('p38', 'Gene', (172, 175))	('ERK', 'Gene', (45, 48))	('PD98059', 'Chemical', 'MESH:C093973', (187, 194))	('ERK', 'Gene', (163, 166))	('paclitaxel', 'Chemical', 'MESH:D017239', (100, 110))	('SP600125', 'Chemical', 'MESH:C432165', (177, 185))	('JNK', 'Gene', (40, 43))	('JNK', 'Gene', (158, 161))	('p38', 'Gene', '26416', (54, 57))	('JNK', 'Gene', '26419', (40, 43))	('p38', 'Gene', '26416', (172, 175))	('JNK', 'Gene', '26419', (158, 161))	('ERK', 'Gene', '26413', (45, 48))	('ERK', 'Gene', '26413', (163, 166))	('p38', 'Gene', (288, 291))	('expression', 'MPA', (245, 255))	('SB203580', 'Chemical', 'MESH:C093642', (200, 208))	('ERK', 'Gene', (279, 282))	('SP600125', 'Var', (177, 185))	('phosphorylation', 'MPA', (21, 36))	('JNK', 'Gene', (274, 277))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('p38', 'Gene', '26416', (288, 291))	('JNK', 'Gene', '26419', (274, 277))	('ERK', 'Gene', '26413', (279, 282))	('p38', 'Gene', (54, 57))	('cordycepin', 'Chemical', 'MESH:C058120', (87, 97))	('abolish', 'NegReg', (237, 244))
81307	26366090	SP600125 at 10, 50, and 100 muM significantly inhibited phosphorylation of JNK induced by cordycepin 100 muM (P<0.05, Figure 5A).	('JNK', 'Gene', '26419', (75, 78))	('JNK', 'Gene', (75, 78))	('phosphorylation', 'MPA', (56, 71))	('cordycepin', 'Chemical', 'MESH:C058120', (90, 100))	('SP600125', 'Chemical', 'MESH:C432165', (0, 8))	('SP600125', 'Var', (0, 8))	('inhibited', 'NegReg', (46, 55))
81308	26366090	In the combination experiments, SP600125 10 muM significantly reduced the expression of phosphorylated JNK after treatment with cisplatin + cordycepin, cordycepin + paclitaxel, and cordycepin + cisplatin + paclitaxel for 12 hours (P<0.05, Figure 5B).	('expression', 'MPA', (74, 84))	('paclitaxel', 'Chemical', 'MESH:D017239', (206, 216))	('cordycepin', 'Chemical', 'MESH:C058120', (181, 191))	('SP600125', 'Chemical', 'MESH:C432165', (32, 40))	('cordycepin', 'Chemical', 'MESH:C058120', (140, 150))	('men', 'Species', '9606', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('men', 'Species', '9606', (118, 121))	('phosphorylated', 'MPA', (88, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))	('JNK', 'Gene', '26419', (103, 106))	('SP600125 10', 'Var', (32, 43))	('cordycepin', 'Chemical', 'MESH:C058120', (152, 162))	('reduced', 'NegReg', (62, 69))	('JNK', 'Gene', (103, 106))
81309	26366090	PD98059 at 5, 10, 25, and 50 muM significantly inhibited phosphorylation of ERK induced by cordycepin 100 muM (P<0.05, Figure 6A).	('inhibited', 'NegReg', (47, 56))	('cordycepin', 'Chemical', 'MESH:C058120', (91, 101))	('ERK', 'Gene', (76, 79))	('PD98059', 'Var', (0, 7))	('PD98059', 'Chemical', 'MESH:C093973', (0, 7))	('ERK', 'Gene', '26413', (76, 79))	('phosphorylation', 'MPA', (57, 72))
81310	26366090	In the combination experiments, PD98059 5 muM significantly reduced the expression of phosphorylated ERK in the cisplatin + cordycepin, cordycepin + paclitaxel, and cordycepin + cisplatin + paclitaxel groups treated for 12 hours (P<0.05, Figure 6B).	('cordycepin', 'Chemical', 'MESH:C058120', (136, 146))	('paclitaxel', 'Chemical', 'MESH:D017239', (149, 159))	('ERK', 'Gene', (101, 104))	('paclitaxel', 'Chemical', 'MESH:D017239', (190, 200))	('cordycepin', 'Chemical', 'MESH:C058120', (165, 175))	('ERK', 'Gene', '26413', (101, 104))	('expression', 'MPA', (72, 82))	('reduced', 'NegReg', (60, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('cordycepin', 'Chemical', 'MESH:C058120', (124, 134))	('PD98059', 'Var', (32, 39))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))	('men', 'Species', '9606', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
81311	26366090	SB203580 at 1, 5, and 10 muM significantly inhibited the phosphorylation of p38 induced by 100 muM cordycepin (P<0.05, Figure 7A).	('inhibited', 'NegReg', (43, 52))	('p38', 'Gene', (76, 79))	('SB203580', 'Var', (0, 8))	('cordycepin', 'Chemical', 'MESH:C058120', (99, 109))	('SB203580', 'Chemical', 'MESH:C093642', (0, 8))	('p38', 'Gene', '26416', (76, 79))	('phosphorylation', 'MPA', (57, 72))
81312	26366090	In the combination experiments, SB203580 10 muM significantly reduced the expression of phosphorylated p38 in the cisplatin + cordycepin, cordycepin + paclitaxel, and cordycepin + cisplatin + paclitaxel groups (P<0.05, Figure 7A and B).	('expression', 'MPA', (74, 84))	('cordycepin', 'Chemical', 'MESH:C058120', (167, 177))	('p38', 'Gene', (103, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (151, 161))	('p38', 'Gene', '26416', (103, 106))	('cordycepin', 'Chemical', 'MESH:C058120', (126, 136))	('men', 'Species', '9606', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('paclitaxel', 'Chemical', 'MESH:D017239', (192, 202))	('cordycepin', 'Chemical', 'MESH:C058120', (138, 148))	('SB203580', 'Var', (32, 40))	('SB203580', 'Chemical', 'MESH:C093642', (32, 40))	('reduced', 'NegReg', (62, 69))
81314	26366090	The tumor suppressor p53 is the central player in a network protecting higher eukaryotic cells against various types of damage that might lead to genetic alterations.	('tumor', 'Disease', (4, 9))	('genetic alterations', 'Var', (146, 165))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('lead', 'Reg', (138, 142))
81320	26366090	These results indicate that cordycepin, but not paclitaxel or cisplatin, could activate the p53 pathway to induce apoptosis of MA-10 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('induce', 'PosReg', (107, 113))	('activate', 'PosReg', (79, 87))	('cordycepin', 'Chemical', 'MESH:C058120', (28, 38))	('cordycepin', 'Var', (28, 38))	('p53 pathway', 'Pathway', (92, 103))	('apoptosis', 'CPA', (114, 123))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
81324	26366090	However, coadministration of cisplatin + cordycepin, cisplatin + paclitaxel, cordycepin + paclitaxel, or cisplatin + cordycepin + paclitaxel induced much more rounding up of MA-10 cells with membrane blebbing.	('cordycepin', 'Chemical', 'MESH:C058120', (77, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (90, 100))	('paclitaxel', 'Chemical', 'MESH:D017239', (65, 75))	('cisplatin', 'Var', (105, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('cordycepin', 'Chemical', 'MESH:C058120', (41, 51))	('cordycepin', 'Chemical', 'MESH:C058120', (117, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (130, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('rounding up', 'CPA', (159, 170))
81325	26366090	Moreover, we found that coadministration of cisplatin + cordycepin, cisplatin + paclitaxel, cordycepin + paclitaxel, or cisplatin + cordycepin + paclitaxel reduced cell viability to a greater extent than each agent used alone.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('cordycepin', 'Chemical', 'MESH:C058120', (92, 102))	('cell viability', 'CPA', (164, 178))	('paclitaxel', 'Chemical', 'MESH:D017239', (145, 155))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('cisplatin', 'Var', (68, 77))	('reduced', 'NegReg', (156, 163))	('cordycepin', 'Chemical', 'MESH:C058120', (56, 66))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('cordycepin', 'Chemical', 'MESH:C058120', (132, 142))
81332	26366090	Moreover, studies have shown that paclitaxel, cisplatin, and cordycepin can induce cell cycle arrest at G2/M phase in some cell types, including human bladder cancer, breast cancer, and lung cancer cells, which then proceed to subG1 phase, ending up in apoptosis.	('apoptosis', 'CPA', (253, 262))	('breast cancer', 'Disease', (167, 180))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('human', 'Species', '9606', (145, 150))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cisplatin', 'Var', (46, 55))	('paclitaxel', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('cell cycle arrest at G2/M phase', 'CPA', (83, 114))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('bladder cancer', 'Disease', (151, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('lung cancer', 'Disease', (186, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('cordycepin', 'Chemical', 'MESH:C058120', (61, 71))
81338	26366090	Taken together, we observed that cell numbers accumulated in subG1 phase in response to the combination treatments, suggesting that double or triple agent combinations could work more effective to induce DNA fragmentation and apoptosis of MA-10 cells.	('apoptosis', 'CPA', (226, 235))	('combinations', 'Var', (155, 167))	('DNA fragmentation', 'CPA', (204, 221))	('men', 'Species', '9606', (109, 112))	('induce', 'PosReg', (197, 203))	('men', 'Species', '9606', (212, 215))
81346	26366090	Moreover, many studies have demonstrated that activation of MAPK can stimulate expression of caspase-3 and cleavage of PARP as well as decrease expression of Bcl-2, which mediates the cellular steps in apoptosis of some types of tumor cell.	('MAPK', 'Gene', (60, 64))	('caspase-3', 'Gene', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('expression', 'MPA', (79, 89))	('PARP', 'Gene', (119, 123))	('PARP', 'Gene', '11545', (119, 123))	('expression', 'MPA', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('stimulate', 'PosReg', (69, 78))	('tumor', 'Disease', (229, 234))	('caspase-3', 'Gene', '12367', (93, 102))	('activation', 'Var', (46, 56))	('cleavage', 'MPA', (107, 115))	('Bcl-2', 'Gene', '12043', (158, 163))	('decrease', 'NegReg', (135, 143))	('Bcl-2', 'Gene', (158, 163))
81347	26366090	In the present study, combined treatment for 12 hours with cisplatin + cordycepin, cordycepin + paclitaxel, or cisplatin + cordycepin + paclitaxel induced significantly more expression of phosphorylated ERK when compared with treatment using cisplatin, paclitaxel, or cordycepin alone.	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('cordycepin', 'Chemical', 'MESH:C058120', (71, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('ERK', 'Gene', '26413', (203, 206))	('expression', 'MPA', (174, 184))	('cordycepin', 'Chemical', 'MESH:C058120', (123, 133))	('cordycepin', 'Chemical', 'MESH:C058120', (83, 93))	('men', 'Species', '9606', (231, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (242, 251))	('men', 'Species', '9606', (36, 39))	('cordycepin', 'Chemical', 'MESH:C058120', (268, 278))	('paclitaxel', 'Chemical', 'MESH:D017239', (253, 263))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('cisplatin', 'Var', (111, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('more', 'PosReg', (169, 173))	('ERK', 'Gene', (203, 206))
81350	26366090	Further, SP600125, PD98059, and PD98059 could reverse the activation of JNK, ERK, and p38 in the combination treatment of cordycepin plus cisplatin and/or taxol, respectively.	('p38', 'Gene', (86, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('SP600125', 'Chemical', 'MESH:C432165', (9, 17))	('JNK', 'Gene', (72, 75))	('PD98059', 'Chemical', 'MESH:C093973', (19, 26))	('cordycepin', 'Chemical', 'MESH:C058120', (122, 132))	('JNK', 'Gene', '26419', (72, 75))	('p38', 'Gene', '26416', (86, 89))	('taxol', 'Chemical', 'MESH:D017239', (155, 160))	('SP600125', 'Var', (9, 17))	('men', 'Species', '9606', (114, 117))	('ERK', 'Gene', (77, 80))	('ERK', 'Gene', '26413', (77, 80))	('activation', 'PosReg', (58, 68))	('PD98059', 'Var', (32, 39))	('PD98059', 'Var', (19, 26))	('PD98059', 'Chemical', 'MESH:C093973', (32, 39))
81358	26366090	These results strongly suggest that the combination of cordycepin + paclitaxel and/or cisplatin might be more effective than when these agents are used as single agents for chemotherapy in testicular cancer.	('testicular cancer', 'Disease', (189, 206))	('testicular cancer', 'Disease', 'MESH:D013736', (189, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('testicular cancer', 'Phenotype', 'HP:0010788', (189, 206))	('cordycepin', 'Var', (55, 65))	('cordycepin', 'Chemical', 'MESH:C058120', (55, 65))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))
81368	25228819	In addition to effects on quality of life and functional impairment, CINV can lead to medical complications, including anorexia, nutrient depletion, and metabolic disturbances, or may lead to noncompliance or premature discontinuation of anticancer therapy.	('men', 'Species', '9606', (63, 66))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('CINV', 'Chemical', '-', (69, 73))	('lead to', 'Reg', (78, 85))	('noncompliance', 'Disease', (192, 205))	('metabolic disturbances', 'MPA', (153, 175))	('nutrient depletion', 'MPA', (129, 147))	('anorexia', 'Disease', 'MESH:D000855', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('CINV', 'Var', (69, 73))	('anorexia', 'Disease', (119, 127))	('anorexia', 'Phenotype', 'HP:0002039', (119, 127))	('lead to', 'Reg', (184, 191))
81374	25228819	Delayed CINV is more common with cisplatin, carboplatin, cyclophosphamide, and/or doxorubicin.	('carboplatin', 'Chemical', 'MESH:D016190', (44, 55))	('cisplatin', 'Var', (33, 42))	('Delayed CINV', 'Disease', (0, 12))	('Delayed CINV', 'Disease', 'MESH:D006968', (0, 12))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (57, 73))	('common', 'Reg', (21, 27))
81418	25228819	Palonosetron has a longer half-life and greater 5-HT3 receptor binding affinity compared with other 5-HT3 RAs.	('Palonosetron', 'Chemical', 'MESH:D000077924', (0, 12))	('Palonosetron', 'Var', (0, 12))	('RA', 'Chemical', '-', (106, 108))	('5-HT3', 'Gene', (48, 53))	('greater', 'PosReg', (40, 47))	('5-HT3', 'Gene', '3359', (48, 53))	('5-HT3', 'Gene', (100, 105))	('5-HT3', 'Gene', '3359', (100, 105))
81419	25228819	Palonosetron has a unique binding profile (allosteric binding and positive cooperativity) that differs from that of other 5-HT3 RAs and triggers receptor internalization, inducing prolonged inhibition of receptor functioning.	('RA', 'Chemical', '-', (128, 130))	('5-HT3', 'Gene', (122, 127))	('binding', 'Interaction', (26, 33))	('Palonosetron', 'Var', (0, 12))	('5-HT3', 'Gene', '3359', (122, 127))	('Palonosetron', 'Chemical', 'MESH:D000077924', (0, 12))	('triggers', 'Reg', (136, 144))	('inhibition', 'MPA', (190, 200))	('receptor functioning', 'MPA', (204, 224))	('internalization', 'MPA', (154, 169))
81420	25228819	Finally, palonosetron inhibits cross-talk between 5-HT3 and NK1 signaling pathways.	('NK1', 'Gene', '6863', (60, 63))	('palonosetron', 'Var', (9, 21))	('5-HT3', 'Gene', '3359', (50, 55))	('5-HT3', 'Gene', (50, 55))	('cross-talk', 'MPA', (31, 41))	('inhibits', 'NegReg', (22, 30))	('palonosetron', 'Chemical', 'MESH:D000077924', (9, 21))	('NK1', 'Gene', (60, 63))
81443	25228819	Quality of life survey results indicated that CINV did not significantly impact her daily functioning (eg, life enjoyment, social life, sleep).	('CINV', 'Var', (46, 50))	('social life', 'CPA', (123, 134))	('men', 'Species', '9606', (117, 120))	('CINV', 'Chemical', '-', (46, 50))	('life enjoyment', 'CPA', (107, 121))
81461	25228819	Palonosetron has also been found to reduce extreme CINV events (eg, hospitalizations and emergency room and outpatient visits due to CINV) and costs by up to 76% compared with other 5-HT3 RAs, and has reduced staff management work time by approximately 4 months.	('man', 'Species', '9606', (215, 218))	('costs', 'MPA', (143, 148))	('reduce', 'NegReg', (36, 42))	('CINV', 'Chemical', '-', (51, 55))	('men', 'Species', '9606', (221, 224))	('Palonosetron', 'Chemical', 'MESH:D000077924', (0, 12))	('Palonosetron', 'Var', (0, 12))	('RA', 'Chemical', '-', (188, 190))	('5-HT3', 'Gene', (182, 187))	('5-HT3', 'Gene', '3359', (182, 187))	('outpatient', 'Species', '9606', (108, 118))	('CINV', 'Chemical', '-', (133, 137))	('extreme CINV events', 'MPA', (43, 62))
81475	25228819	An 18-year-old Caucasian man with metastatic, nonseminomatous testicular cancer was admitted to the hospital for rehydration, treatment of nausea and emesis, and evaluation of weakness on day 9 of the first cycle of BEP chemotherapy, ie, bleomycin (20 units intravenously on days 1, 8, and 15), etoposide (100 mg/m2 intravenously on days 1-5), and cisplatin (20 mg/m2 intravenously on days 1-5).	('emesis', 'Disease', 'MESH:D014839', (150, 156))	('nonseminomatous testicular cancer', 'Disease', (46, 79))	('man', 'Species', '9606', (25, 28))	('men', 'Species', '9606', (131, 134))	('emesis', 'Phenotype', 'HP:0002013', (150, 156))	('weakness', 'Disease', 'MESH:D018908', (176, 184))	('emesis', 'Disease', (150, 156))	('nausea', 'Disease', 'MESH:D009325', (139, 145))	('nausea and emesis', 'Phenotype', 'HP:0002017', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('weakness', 'Disease', (176, 184))	('bleomycin', 'Chemical', 'MESH:D001761', (238, 247))	('nonseminomatous testicular cancer', 'Disease', 'MESH:D013736', (46, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (348, 357))	('nausea', 'Phenotype', 'HP:0002018', (139, 145))	('100 mg/m2', 'Var', (306, 315))	('BEP', 'Chemical', 'MESH:C038328', (216, 219))	('nausea', 'Disease', (139, 145))	('etoposide', 'Chemical', 'MESH:D005047', (295, 304))	('testicular cancer', 'Phenotype', 'HP:0010788', (62, 79))
81483	25228819	Alternate regimens considered for cycle 2 were the addition of olanzapine, changing to another antagonist backbone, including an alternate 5-HT3 RA such as a GTP or substitution of palonosetron on days 1, 3, and 5 of chemotherapy, and the addition of aprepitant to the regimen.	('5-HT3', 'Gene', '3359', (139, 144))	('men', 'Species', '9606', (14, 17))	('5-HT3', 'Gene', (139, 144))	('palonosetron', 'Chemical', 'MESH:D000077924', (181, 193))	('GTP', 'Chemical', 'MESH:D017829', (158, 161))	('olanzapine', 'Chemical', 'MESH:D000077152', (63, 73))	('substitution', 'Var', (165, 177))	('men', 'Species', '9606', (273, 276))	('RA', 'Chemical', '-', (145, 147))
81497	25228819	Although high-grade evidence supports the use of palonosetron in the single-dose chemotherapy setting, and small studies demonstrate some effectiveness during adjuvant multiple-day chemotherapy for glioma or during multiple-day treatment for testicular cancer, randomized trials should be conducted to determine its efficacy versus that of other antiemetics and the most effective dose and frequency.	('testicular cancer', 'Phenotype', 'HP:0010788', (242, 259))	('glioma', 'Disease', (198, 204))	('testicular cancer', 'Disease', 'MESH:D013736', (242, 259))	('palonosetron', 'Chemical', 'MESH:D000077924', (49, 61))	('testicular cancer', 'Disease', (242, 259))	('glioma', 'Phenotype', 'HP:0009733', (198, 204))	('palonosetron', 'Var', (49, 61))	('glioma', 'Disease', 'MESH:D005910', (198, 204))	('men', 'Species', '9606', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
81503	22314417	Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio 3.95; 95% CI, 1.67-9.34) after adjusting for other perinatal factors, family history of testicular cancer, and cryptorchidism.	('cryptorchidism', 'Disease', (206, 220))	('testicular cancer', 'Phenotype', 'HP:0010788', (183, 200))	('testicular cancer', 'Disease', 'MESH:D013736', (183, 200))	('testicular cancer', 'Disease', (63, 80))	('cryptorchidism', 'Phenotype', 'HP:0000028', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('testicular cancer', 'Disease', (183, 200))	('preterm birth', 'Phenotype', 'HP:0001622', (8, 21))	('testicular cancer', 'Phenotype', 'HP:0010788', (63, 80))	('testicular cancer', 'Disease', 'MESH:D013736', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Extreme preterm', 'Var', (0, 15))
81511	22314417	Preterm birth is associated with altered sex hormone levels prenatally and postnatally in the offspring, and therefore has been hypothesized to be a potential risk factor for testicular cancer.	('testicular cancer', 'Disease', (175, 192))	('Preterm birth', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('testicular cancer', 'Phenotype', 'HP:0010788', (175, 192))	('testicular cancer', 'Disease', 'MESH:D013736', (175, 192))	('altered', 'Reg', (33, 40))	('sex hormone levels', 'MPA', (41, 59))	('Preterm birth', 'Phenotype', 'HP:0001622', (0, 13))
81515	22314417	We conducted a national cohort study in Sweden to examine whether low gestational age at birth, independent of fetal growth, is associated with testicular cancer in later life.	('testicular cancer', 'Disease', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('low gestational', 'Var', (66, 81))	('testicular cancer', 'Phenotype', 'HP:0010788', (144, 161))	('associated', 'Reg', (128, 138))	('low gestational age', 'Phenotype', 'HP:0001518', (66, 85))	('testicular cancer', 'Disease', 'MESH:D013736', (144, 161))
81517	22314417	We hypothesized that low gestational age at birth is independently associated with an increased risk of testicular cancer in later life.	('testicular cancer', 'Phenotype', 'HP:0010788', (104, 121))	('testicular cancer', 'Disease', 'MESH:D013736', (104, 121))	('low gestational age', 'Var', (21, 40))	('low gestational age', 'Phenotype', 'HP:0001518', (21, 40))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('testicular cancer', 'Disease', (104, 121))
81525	22314417	Included because twinning is associated with preterm birth and low fetal growth, and may be associated with an increased risk of testicular cancer in the male offspring.	('testicular cancer', 'Phenotype', 'HP:0010788', (129, 146))	('testicular cancer', 'Disease', 'MESH:D013736', (129, 146))	('preterm birth', 'Phenotype', 'HP:0001622', (45, 58))	('low fetal growth', 'CPA', (63, 79))	('testicular cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('twinning', 'Var', (17, 25))	('associated', 'Reg', (92, 102))
81546	22314417	Neither low nor high fetal growth was associated with testicular cancer, with or without adjustment for gestational age at birth and the other covariates.	('low', 'Var', (8, 11))	('testicular cancer', 'Phenotype', 'HP:0010788', (54, 71))	('high fetal growth', 'CPA', (16, 33))	('testicular cancer', 'Disease', 'MESH:D013736', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('testicular cancer', 'Disease', (54, 71))	('men', 'Species', '9606', (95, 98))
81554	22314417	A recent meta-analysis reported an overall odds ratio of 1.31 (95% CI, 1.07-1.59) for the association between low gestational age at birth and testicular cancer, and 1.34 (95% CI, 1.08-1.67) for the association between low birth weight and testicular cancer.	('low birth weight', 'Disease', 'MESH:C537577', (219, 235))	('low birth weight', 'Phenotype', 'HP:0001518', (219, 235))	('testicular cancer', 'Disease', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('low gestational age', 'Phenotype', 'HP:0001518', (110, 129))	('testicular cancer', 'Phenotype', 'HP:0010788', (143, 160))	('association', 'Interaction', (90, 101))	('testicular cancer', 'Disease', 'MESH:D013736', (143, 160))	('low gestational age', 'Var', (110, 129))	('low birth weight', 'Disease', (219, 235))	('testicular cancer', 'Phenotype', 'HP:0010788', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('birth and testicular cancer', 'Disease', 'MESH:D013736', (133, 160))	('testicular cancer', 'Disease', 'MESH:D013736', (240, 257))	('testicular cancer', 'Disease', (143, 160))
81557	22314417	In contrast to some earlier studies, we found that testicular cancer was not associated with twinning, low birth order, low maternal or paternal age, or high maternal age.	('testicular cancer', 'Disease', 'MESH:D013736', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('testicular cancer', 'Disease', (51, 68))	('low', 'Var', (120, 123))	('testicular cancer', 'Phenotype', 'HP:0010788', (51, 68))	('low birth order', 'Phenotype', 'HP:0001518', (103, 118))
81592	20535291	Gene analysis studies have also revealed that linkage to the Xq27 locus and duplication or amplification of the short arm of chromosome 12 are also associated with the development of testicular cancer.	('testicular cancer', 'Phenotype', 'HP:0010788', (183, 200))	('testicular cancer', 'Disease', 'MESH:D013736', (183, 200))	('linkage', 'Var', (46, 53))	('short arm', 'Phenotype', 'HP:0009824', (112, 121))	('amplification', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('testicular cancer', 'Disease', (183, 200))	('associated with', 'Reg', (148, 163))	('duplication', 'Var', (76, 87))	('Xq27', 'Gene', (61, 65))	('men', 'Species', '9606', (175, 178))
81730	30446455	Treatment options for patients with clinical stage IIA and small unifocal (<3cm) IIB NSGCT include RPLND with adjuvant chemotherapy in select cases, or induction chemotherapy with or without PC- RPLND.	('NSGCT', 'Disease', 'MESH:C537844', (85, 90))	('GCT', 'Phenotype', 'HP:0100728', (87, 90))	('patients', 'Species', '9606', (22, 30))	('RPLND', 'Var', (99, 104))	('men', 'Species', '9606', (5, 8))	('NSGCT', 'Disease', (85, 90))
81736	30446455	When analyzed by primary treatment intervention, induction chemotherapy followed by PC-RPLND was associated with a significantly improved 5-year recurrence free survival compared to primary RPLND (98% vs. 79%, P<0.001, respectively).	('improved', 'PosReg', (129, 137))	('PC-RPLND', 'Var', (84, 92))	('men', 'Species', '9606', (30, 33))
81824	30446455	PC-RPLND was associated with higher complication and open conversion rates and longer operative times, however, the estimated blood loss, lymph node yield and length of hospital stay were not significantly different.	('higher', 'PosReg', (29, 35))	('PC-RPLND', 'Var', (0, 8))	('open conversion', 'CPA', (53, 68))	('blood loss', 'Disease', 'MESH:D006473', (126, 136))	('complication', 'CPA', (36, 48))	('blood loss', 'Disease', (126, 136))
81861	24781282	Testicular germ cell tumours are considered to be sustained in vivo through a relatively frequent mutation in the KIT tyrosine kinase receptor that renders it constitutively active or through autocrine production of the KIT ligand, KITL (reviewed in).	('KITL', 'Gene', '4254', (232, 236))	('KIT ligand', 'Gene', (220, 230))	('mutation', 'Var', (98, 106))	('KIT ligand', 'Gene', '4254', (220, 230))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('it constitutively', 'MPA', (156, 173))	('Testicular germ cell tumours', 'Disease', 'MESH:C563236', (0, 28))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('Testicular germ cell tumours', 'Disease', (0, 28))	('KITL', 'Gene', (232, 236))
81920	24781282	The signals corresponding to PLAP, AP2gamma and KIT were much more intense in seminoma samples compared with normal testis and samples with CIS (Supplementary Figure 1).	('men', 'Species', '9606', (151, 154))	('more intense', 'PosReg', (62, 74))	('PLAP', 'Var', (29, 33))	('AP2gamma', 'Gene', '7022', (35, 43))	('seminoma', 'Disease', (78, 86))	('AP2gamma', 'Gene', (35, 43))	('CIS', 'Phenotype', 'HP:0030075', (140, 143))	('seminoma', 'Disease', 'MESH:D018239', (78, 86))
81929	24781282	In seminoma fragments cultured in media containing 10% FBS, a decrease in survival was observed from 7 days of culture, whereas overall cell viability loss was already evident from 5 days of culture for samples cultured in 0.1% BSA (Table 2).	('survival', 'CPA', (74, 82))	('seminoma', 'Disease', 'MESH:D018239', (3, 11))	('FBS', 'Var', (55, 58))	('men', 'Species', '9606', (16, 19))	('seminoma', 'Disease', (3, 11))	('decrease', 'NegReg', (62, 70))
81989	33923635	In the current study, Cis reduced the sperm count, plasma testosterone level, the testicular activity of alkaline phosphatase beside a marked inhabitation of succinate dehydrogenase activity.	('plasma testosterone level', 'MPA', (51, 76))	('Cis', 'Var', (22, 25))	('succinate dehydrogenase activity', 'MPA', (158, 190))	('testosterone', 'Chemical', 'MESH:D013739', (58, 70))	('reduced', 'NegReg', (26, 33))	('succinate', 'Chemical', 'MESH:D019802', (158, 167))	('sperm count', 'CPA', (38, 49))	('testicular activity of alkaline phosphatase', 'MPA', (82, 125))
81998	33923635	In the current study, Cis reduced sperm count, serum testosterone level, and testicular activity of alkaline phosphatase (AKP), besides a marked inhibition of succinate dehydrogenase (SDH) activity.	('testosterone', 'Chemical', 'MESH:D013739', (53, 65))	('Cis', 'Var', (22, 25))	('testicular', 'CPA', (77, 87))	('succinate', 'Chemical', 'MESH:D019802', (159, 168))	('Cis reduced sperm count', 'Phenotype', 'HP:0000798', (22, 45))	('reduced sperm', 'Phenotype', 'HP:0012207', (26, 39))	('alkaline', 'MPA', (100, 108))	('sperm count', 'CPA', (34, 45))	('reduced', 'NegReg', (26, 33))	('serum testosterone level', 'MPA', (47, 71))	('succinate', 'MPA', (159, 168))	('activity', 'MPA', (189, 197))	('inhibition', 'NegReg', (145, 155))
82008	33923635	stated that Cis triggers oxidative stress by generating reactive oxygen species (ROS) that stimulates cell destruction and necrosis through lipid peroxidation of tissues, protein denaturation, and DNA lesions.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (56, 79))	('Cis', 'Var', (12, 15))	('lipid', 'Chemical', 'MESH:D008055', (140, 145))	('necrosis', 'Disease', 'MESH:D009336', (123, 131))	('cell destruction', 'CPA', (102, 118))	('stimulates', 'PosReg', (91, 101))	('rat', 'Species', '10116', (49, 52))	('oxidative stress', 'Phenotype', 'HP:0025464', (25, 41))	('lipid peroxidation', 'MPA', (140, 158))	('reactive oxygen species', 'MPA', (56, 79))	('protein denaturation', 'MPA', (171, 191))	('oxidative stress', 'MPA', (25, 41))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('necrosis', 'Disease', (123, 131))	('rat', 'Species', '10116', (185, 188))
82090	33923635	Treatment with Cis resulted in significant (p <= 0.05) decrease in sperm count (3.33 +- 1.45) relative to the control group (48.07 +- 1.79).	('Cis', 'Var', (15, 18))	('decrease', 'NegReg', (55, 63))	('sperm count', 'CPA', (67, 78))	('men', 'Species', '9606', (5, 8))
82093	33923635	Table 2 revealed that animals treated with cisplatin had significant reduction in the serum level of testosterone hormone (0.39 +- 0.1 ng/mL), compared to the control group (1.89 +- 0.07 ng/mL).	('cisplatin', 'Var', (43, 52))	('testosterone', 'Chemical', 'MESH:D013739', (101, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('reduction', 'NegReg', (69, 78))	('serum level of testosterone hormone', 'MPA', (86, 121))
82100	33923635	The levels of pro-inflammatory (IL-6) cytokines (Table 4) revealed significant increase (p <= 0.05) in the Cis-treated group (392.7 +- 17.19 pg/mL), as compared to the control group (95.43 +- 4.28 pg/mL).	('increase', 'PosReg', (79, 87))	('IL-6', 'Gene', (32, 36))	('Cis-treated', 'Var', (107, 118))	('IL-6', 'Gene', '24498', (32, 36))
82101	33923635	However, IL-6 was significantly decreased (p <= 0.05) in the Cis group treated with BM-MSCs only (293.33 +- 10.1 pg/mL) or beetroot only (327.4 +- 17.92 pg/mL).	('beet', 'Species', '161934', (123, 127))	('MSC', 'Gene', (87, 90))	('IL-6', 'Gene', (9, 13))	('IL-6', 'Gene', '24498', (9, 13))	('MSC', 'Gene', '312897', (87, 90))	('293.33', 'Var', (98, 104))	('decreased', 'NegReg', (32, 41))
82222	33923635	Inactivation of caspase-3 dramatically reduces apoptosis in diverse settings, including activation-induced cell death (AICD).	('death', 'Disease', 'MESH:D003643', (112, 117))	('caspase-3', 'Gene', '25402', (16, 25))	('death', 'Disease', (112, 117))	('AICD', 'Disease', 'None', (119, 123))	('apoptosis', 'CPA', (47, 56))	('caspase-3', 'Gene', (16, 25))	('AICD', 'Disease', (119, 123))	('reduces', 'NegReg', (39, 46))	('Inactivation', 'Var', (0, 12))
82232	33923635	; writing:original draft preparation: M.T.H., H.K.M., M.M.M., N.A., R.A.E.	('M.T.H.', 'Var', (38, 44))	('H.K.M.', 'Var', (46, 52))	('M.M.M.', 'Var', (54, 60))	('rat', 'Species', '10116', (30, 33))
82290	30002831	In our review, there is no clear evidence showing that TML associated with cryptorchidism is a risk factor for testicular tumor.	('testicular tumor', 'Disease', 'MESH:D013736', (111, 127))	('testicular tumor', 'Phenotype', 'HP:0010788', (111, 127))	('TML', 'Phenotype', 'HP:0012215', (55, 58))	('testicular tumor', 'Disease', (111, 127))	('TML', 'Var', (55, 58))	('cryptorchidism', 'Disease', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cryptorchidism', 'Phenotype', 'HP:0000028', (75, 89))
82359	29727140	Oligozoospermic specimens were further sorted into groups based on severity (mild: 10-15x106/mL, moderate: 5-10x106/mL; and severe: less than 5x106/mL) and their sperm parameters before and after cryopreservation were compared and recovery rates calculated accordingly (Table 3).	('less', 'NegReg', (132, 136))	('men', 'Species', '9606', (21, 24))	('5-10x106/mL', 'Var', (107, 118))
82532	28630588	One of the brothers was diagnosed with right testicular teratoblastoma, staged T3N3M0 in January 1991, and died in December 1991, after unsuccessful treatment with resection and radiotherapy, followed by palliative care and analgesic treatment.	('right testicular teratoblastoma', 'Disease', 'MESH:D013733', (39, 70))	('right testicular teratoblastoma', 'Disease', (39, 70))	('men', 'Species', '9606', (154, 157))	('men', 'Species', '9606', (239, 242))	('T3N3M0', 'Var', (79, 85))
82559	28630588	Nevertheless, mutations in fibroblast growth factor receptor 3 gene FGFR3 and HRAS, found exclusively in spermatocytic seminomas, suggest a different tumorogenesis pathway associated with the accumulation of mutations during the adult life span (31).	('FGFR3', 'Gene', '2261', (68, 73))	('fibroblast growth factor receptor 3', 'Gene', '2261', (27, 62))	('fibroblast growth factor receptor 3', 'Gene', (27, 62))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (105, 128))	('tumorogenesis', 'CPA', (150, 163))	('FGFR3', 'Gene', (68, 73))	('mutations', 'Var', (208, 217))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (105, 128))	('HRAS', 'Gene', '3265', (78, 82))	('spermatocytic seminomas', 'Disease', (105, 128))	('mutations', 'Var', (14, 23))	('HRAS', 'Gene', (78, 82))
82644	25882629	In general, our current understanding of TGCT genetics supports this interpretation in that most identified variants are of low penetrance, and many (though not all) are located in or near genes known to influence primordial germ cell maturation and differentiation and are therefore less likely to be associated with other cancer types.	('cancer', 'Disease', (324, 330))	('associated', 'Reg', (302, 312))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('variants', 'Var', (108, 116))	('primordial germ cell maturation', 'CPA', (214, 245))	('differentiation', 'CPA', (250, 265))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('influence', 'Reg', (204, 213))
82699	24586462	In this study, we observed that CMTM3 was frequently down-regulated in testicular cancer tissues via methylation at a specific, single CpG site located within the Sp1/Sp3-responsive region of the promoter.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CMTM3', 'Gene', (32, 37))	('testicular cancer', 'Phenotype', 'HP:0010788', (71, 88))	('Sp3', 'Gene', '6670', (167, 170))	('testicular cancer', 'Disease', 'MESH:D013736', (71, 88))	('CMTM3', 'Gene', '123920', (32, 37))	('Sp3', 'Gene', (167, 170))	('testicular cancer', 'Disease', (71, 88))	('methylation', 'Var', (101, 112))	('down-regulated', 'NegReg', (53, 67))
82734	24586462	The expression of CMTM3, based on calculating a total immunostaining score (TIS) as the product of a proportion score (PS) and an intensity score (IS), was quantified under microscope and classified into four subgroups: no expression (0-4); weak expression (+:5,6,8); moderate expression (++: 9,10,12); intense expression (+++: 15).	('CMTM3', 'Gene', '123920', (18, 23))	('++', 'Var', (289, 291))	('CMTM3', 'Gene', (18, 23))
82737	24586462	Cells were infected with Ad-CMTM3 or Ad-null.	('CMTM3', 'Gene', (28, 33))	('Ad-null', 'Var', (37, 44))	('CMTM3', 'Gene', '123920', (28, 33))
82740	24586462	For the in vitro wound-healing assay, cells infected with Ad-CMTM3 or Ad-null were cultured in six-well plates until confluent.	('CMTM3', 'Gene', (61, 66))	('Ad-null', 'Var', (70, 77))	('CMTM3', 'Gene', '123920', (61, 66))
82746	24586462	Forty-eight hours after cells were infected with Ad-CMTM3 or Ad-null, cells were harvested, and total RNA was isolated and purified with the RNeasy RNA Isolation Kit (Qiagen).	('CMTM3', 'Gene', '123920', (52, 57))	('CMTM3', 'Gene', (52, 57))	('Ad-null', 'Var', (61, 68))
82751	24586462	Forty-eight hours after cells were infected with Ad-CMTM3 or Ad-null, the cells were trypsinized, washed twice, resuspended in phosphate-buffered saline (PBS), and fixed in ice-cold 70% ethanol.	('phosphate-buffered saline', 'Chemical', '-', (127, 152))	('CMTM3', 'Gene', '123920', (52, 57))	('PBS', 'Chemical', '-', (154, 157))	('Ad-null', 'Var', (61, 68))	('ethanol', 'Chemical', 'MESH:D000431', (186, 193))	('CMTM3', 'Gene', (52, 57))
82766	24586462	The silencing of CMTM3 in testicular cancer indicated that CMTM3 might be a functional tumor suppressor in testicular carcinogenesis.	('testicular carcinogenesis', 'Disease', 'MESH:D063646', (107, 132))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CMTM3', 'Gene', '123920', (17, 22))	('testicular carcinogenesis', 'Disease', (107, 132))	('tumor', 'Disease', (87, 92))	('testicular cancer', 'Phenotype', 'HP:0010788', (26, 43))	('testicular cancer', 'Disease', 'MESH:D013736', (26, 43))	('CMTM3', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CMTM3', 'Gene', (17, 22))	('silencing', 'Var', (4, 13))	('testicular cancer', 'Disease', (26, 43))	('CMTM3', 'Gene', '123920', (59, 64))
82775	24586462	Representative results of the cell-cycle distribution in Ad-null- or Ad-CMTM3-infected NCCIT cells are shown in Figure 3A.	('Ad-null-', 'Var', (57, 65))	('CMTM3', 'Gene', '123920', (72, 77))	('CMTM3', 'Gene', (72, 77))
82792	24586462	To confirm whether the relevant cis-acting elements, Sp1 and Sp3, are involved in the regulation of CMTM3 gene expression, 293FT and PC3 cells were co-transfected with the construct pGL3-PD and pCMV-Sp1 or pCMV-Sp3.	('pGL3', 'Gene', (182, 186))	('CMTM3', 'Gene', '123920', (100, 105))	('Sp3', 'Gene', '6670', (211, 214))	('293FT', 'CellLine', 'CVCL:6911', (123, 128))	('pCMV-Sp1', 'Var', (194, 202))	('PC3', 'Gene', (133, 136))	('pGL3', 'Gene', '6391', (182, 186))	('Sp3', 'Gene', '6670', (61, 64))	('men', 'Species', '9606', (46, 49))	('Sp3', 'Gene', (211, 214))	('Sp3', 'Gene', (61, 64))	('PC3', 'Gene', '3853', (133, 136))	('CMTM3', 'Gene', (100, 105))
82793	24586462	Luciferase reporter gene assays showed that the overexpression of Sp1 or Sp3 could significantly increase CMTM3 promoter activity (Figure 4B).	('increase', 'PosReg', (97, 105))	('Sp3', 'Gene', (73, 76))	('CMTM3', 'Gene', (106, 111))	('overexpression', 'PosReg', (48, 62))	('CMTM3', 'Gene', '123920', (106, 111))	('Sp1', 'Var', (66, 69))	('Sp3', 'Gene', '6670', (73, 76))
82794	24586462	Moreover, CMTM3 promoter activity was reduced dramatically after methylation (Figure 4C).	('CMTM3', 'Gene', '123920', (10, 15))	('methylation', 'Var', (65, 76))	('CMTM3', 'Gene', (10, 15))	('reduced', 'NegReg', (38, 45))
82795	24586462	We next performed the bisulfite sequencing of 53 CpG sites including the CMTM3 core promoter region (-353 to +126 bp from start the codon site) in 13 paired primary testis tumor samples (Figure 5A).	('testis tumor', 'Phenotype', 'HP:0010788', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('-353', 'Var', (101, 105))	('testis tumor', 'Disease', (165, 177))	('CMTM3', 'Gene', (73, 78))	('bisulfite', 'Chemical', 'MESH:C042345', (22, 31))	('testis tumor', 'Disease', 'MESH:D013736', (165, 177))	('CMTM3', 'Gene', '123920', (73, 78))
82801	24586462	We found that the re-expression of CMTM3 strongly impaired NCCIT cell motility and suppressed colony formation (Figure 2), which was consistent with previous reports in other cancers.	('CMTM3', 'Gene', (35, 40))	('colony formation', 'CPA', (94, 110))	('CMTM3', 'Gene', '123920', (35, 40))	('impaired', 'NegReg', (50, 58))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('NCCIT cell motility', 'CPA', (59, 78))	('cancers', 'Disease', (175, 182))	('suppressed', 'NegReg', (83, 93))	('re-expression', 'Var', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
82809	24586462	The down-regulation of tumor suppressors is associated with transcriptional inhibition through the induction of repressive epigenetic modifications in the promoter, including DNA methylation and histone modification.	('inhibition', 'NegReg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('histone modification', 'MPA', (195, 215))	('DNA', 'MPA', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('epigenetic', 'Var', (123, 133))	('transcriptional', 'MPA', (60, 75))	('tumor', 'Disease', (23, 28))	('down-regulation', 'NegReg', (4, 19))
82810	24586462	Previous studies showed that CMTM family genes CMTM3 and CMTM5 are silenced or down-regulated by promoter CpG methylation in several carcinoma cell lines and primary tumors.	('carcinoma cell lines', 'Disease', 'MESH:C538614', (133, 153))	('CMTM5', 'Gene', (57, 62))	('primary tumors', 'Disease', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CMTM3', 'Gene', (47, 52))	('carcinoma cell lines', 'Disease', (133, 153))	('down-regulated', 'NegReg', (79, 93))	('primary tumors', 'Disease', 'MESH:D009369', (158, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('silenced', 'NegReg', (67, 75))	('methylation', 'Var', (110, 121))	('CMTM3', 'Gene', '123920', (47, 52))	('CMTM5', 'Gene', '116173', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
82811	24586462	Our present study shows that the CpG sites near the core promoter of the CMTM3 gene are nearly devoid of methylation in TGCTs (Figure 5A, 5B), which supports the notion that the aberrant de novo methylation of tumor suppressor genes or tumor-related genes is a rare event in TGCTs.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CMTM3', 'Gene', (73, 78))	('methylation', 'Var', (195, 206))	('CMTM3', 'Gene', '123920', (73, 78))	('tumor', 'Disease', (210, 215))	('devoid', 'NegReg', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('TGCTs', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
82818	24586462	The transcriptional repression of CMTM3 in TGCTs may be mediated by the methylation of a single CpG site, even if the overall methylation of the genes is very limited, which would suggest that the underlying epigenetic mechanisms are different between TGCTs and cancer cells of somatic tissue origin.	('transcriptional', 'MPA', (4, 19))	('cancer', 'Disease', (262, 268))	('mediated by', 'Reg', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('methylation', 'Var', (72, 83))	('CMTM3', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('CMTM3', 'Gene', '123920', (34, 39))
82912	28235028	Risk factors for the type of thyroid cancer that occurs most frequently in teens:papillary thyroid carcinoma:, include ionizing radiation, a mutation to the RET proto-oncogene, and family history.	('thyroid cancer', 'Disease', (29, 43))	('RET', 'Gene', (157, 160))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (91, 108))	('thyroid cancer', 'Phenotype', 'HP:0002890', (29, 43))	('thyroid cancer', 'Disease', 'MESH:D013964', (29, 43))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (91, 108))	('thyroid carcinoma', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (81, 108))	('mutation', 'Var', (141, 149))	('RET', 'Gene', '5979', (157, 160))
82970	22754236	Bruce et al., demonstrated BRCA 1 mutation in a patient with ovarian dysgerminoma.	('BRCA 1', 'Gene', (27, 33))	('BRCA 1', 'Gene', '672', (27, 33))	('ovarian dysgerminoma', 'Disease', (61, 81))	('dysgerminoma', 'Phenotype', 'HP:0100621', (69, 81))	('mutation', 'Var', (34, 42))	('patient', 'Species', '9606', (48, 55))	('ovarian dysgerminoma', 'Disease', 'MESH:D004407', (61, 81))
83068	21232125	Consequently, de-differentiation of Sertoli cells in adult testis may reactivate this niche potential and promote SSC proliferation and neoplastic transformation towards CIS and seminoma.	('rat', 'Species', '10116', (125, 128))	('CIS', 'Phenotype', 'HP:0030075', (170, 173))	('Sertoli cells', 'Phenotype', 'HP:0100619', (36, 49))	('CIS', 'Disease', (170, 173))	('de-differentiation', 'Var', (14, 32))	('promote', 'PosReg', (106, 113))	('seminoma', 'Disease', (178, 186))	('Sertoli cell', 'Phenotype', 'HP:0100619', (36, 48))	('neoplastic transformation', 'CPA', (136, 161))	('seminoma', 'Disease', 'MESH:D018239', (178, 186))	('SSC proliferation', 'CPA', (114, 131))
83122	30203047	Pancan-meQTL: a database to systematically evaluate the effects of genetic variants on methylation in human cancer DNA methylation is an important epigenetic mechanism for regulating gene expression.	('methylation', 'Var', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('human', 'Species', '9606', (102, 107))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
83123	30203047	Aberrant DNA methylation has been observed in various human diseases, including cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DNA', 'Protein', (9, 12))	('observed', 'Reg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (54, 59))	('cancer', 'Disease', (80, 86))
83124	30203047	Single-nucleotide polymorphisms can contribute to tumor initiation, progression and prognosis by influencing DNA methylation, and DNA methylation quantitative trait loci (meQTL) have been identified in physiological and pathological contexts.	('DNA methylation', 'MPA', (109, 124))	('contribute', 'Reg', (36, 46))	('tumor initiation', 'Disease', 'MESH:D009369', (50, 66))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('influencing', 'Reg', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor initiation', 'Disease', (50, 66))
83131	30203047	Aberrant DNA methylation is frequently observed in various cancers and represents an attractive biomarker and therapeutic target.	('Aberrant', 'Var', (0, 8))	('observed', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('DNA', 'Protein', (9, 12))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
83132	30203047	Increasing evidence indicates that single-nucleotide polymorphisms (SNPs) contribute to tumor initiation, progression and prognosis by influencing DNA methylation levels.	('DNA methylation levels', 'MPA', (147, 169))	('contribute', 'Reg', (74, 84))	('progression', 'CPA', (106, 117))	('tumor initiation', 'Disease', 'MESH:D009369', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('influencing', 'Reg', (135, 146))	('tumor initiation', 'Disease', (88, 104))	('single-nucleotide polymorphisms', 'Var', (35, 66))
83140	30203047	In each cancer type, probes were filtered by the following criteria: (i) methylation beta value missing rate > 0.05, (ii) mapping to multiple locations on the genome  and (iii) containing known SNP (1000 Genome Phase3, MAF > 0.01) at CpG sites (Figure 1B).	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('methylation', 'Var', (73, 84))	('SNP', 'Var', (194, 197))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
83160	30203047	In trans-meQTL analysis, we identified 3 044 224 meQTL-CpG pairs at FDR < 0.05 and  r  >=0.3 in 23 cancer types, which corresponded to a median of P-value < 1 x 10-9.	('FDR < 0.05', 'Var', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('meQTL-CpG', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
83164	30203047	Enrichment analyses showed that meQTLs are significant enriched in most of TFBSs, such as CTCF, SIN3AK20 and NRSF (Supplementary Figure S1) and GWAS loci (Supplementary Table S1).	('SIN3AK20', 'Var', (96, 104))	('CTCF', 'Disease', (90, 94))	('NRSF', 'Gene', (109, 113))	('TFBSs', 'Disease', (75, 80))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (115, 138))	('NRSF', 'Gene', '5978', (109, 113))	('Supplementary Figure S1', 'Disease', (115, 138))
83168	30203047	For example, with inputs of 'rs11047888' and 'rs4975682', our results show that rs11044788 has significant correlations with cg11559192 and cg25763538 in 17 and 16 cancer types, respectively; whereas rs4975682 correlates with cg14565270 and cg03265642 in two and six cancer types, respectively (Figure 2D).	('rs11044788', 'Mutation', 'rs11044788', (80, 90))	('cancer', 'Disease', (267, 273))	('cg11559192', 'Var', (125, 135))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cg03265642', 'Var', (241, 251))	('rs4975682', 'Var', (200, 209))	('cg25763538', 'Var', (140, 150))	('cg14565270', 'Var', (226, 236))	('rs4975682', 'Mutation', 'rs4975682', (200, 209))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('rs4975682', 'Mutation', 'rs4975682', (46, 55))	('rs11044788', 'Var', (80, 90))	('correlations', 'Interaction', (107, 119))	('rs11047888', 'Mutation', 'rs11047888', (29, 39))
83171	30203047	Search boxes are designed for retrieving specific cancer types, SNP, methylation probe and gene.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('methylation', 'Var', (69, 80))
83201	30386652	Mutation in the SLC34A2 gene (4p15) has been found to occur in patients with pulmonary alveolar microliths.	('SLC34A2', 'Gene', '10568', (16, 23))	('Mutation', 'Var', (0, 8))	('pulmonary alveolar microliths', 'Disease', 'MESH:D011649', (77, 106))	('SLC34A2', 'Gene', (16, 23))	('pulmonary alveolar microliths', 'Disease', (77, 106))	('patients', 'Species', '9606', (63, 71))	('occur', 'Reg', (54, 59))
83228	30386652	The obstruction of seminiferous tubules may cause secondary inflammation, increased intraseminiferous pressure and change the blood supply of testicles.	('cause', 'Reg', (44, 49))	('inflammation', 'Disease', 'MESH:D007249', (60, 72))	('intraseminiferous pressure', 'MPA', (84, 110))	('obstruction', 'Var', (4, 15))	('increased', 'PosReg', (74, 83))	('inflammation', 'Disease', (60, 72))	('change', 'Reg', (115, 121))	('blood supply', 'MPA', (126, 138))
83249	30386652	Patients with small or atrophic testes with microliths are at increased risk of CIS.	('microliths', 'Var', (44, 54))	('atrophic testes', 'Disease', (23, 38))	('CIS', 'Disease', (80, 83))	('Patients', 'Species', '9606', (0, 8))	('small or atrophic testes', 'Phenotype', 'HP:0010468', (14, 38))	('atrophic testes', 'Phenotype', 'HP:0000029', (23, 38))	('atrophic testes', 'Disease', 'MESH:D013736', (23, 38))
83256	23473982	Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds.	('Dmrt1', 'Gene', (8, 13))	('Dmrt1', 'Gene', (191, 196))	('testicular teratomas', 'Disease', 'MESH:C562472', (66, 86))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('teratomas', 'Phenotype', 'HP:0009792', (77, 86))	('mice', 'Species', '10090', (30, 34))	('testicular teratomas', 'Disease', (66, 86))	('129Sv', 'Species', '10090', (17, 22))	('Loss', 'NegReg', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('teratoma', 'Phenotype', 'HP:0009792', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (156, 162))	('testicular teratomas', 'Phenotype', 'HP:0100616', (66, 86))	('mutants', 'Var', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
83257	23473982	To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis.	('mutant', 'Var', (127, 133))	('129Sv', 'Species', '10090', (150, 155))	('Dmrt1', 'Gene', (121, 126))	('mRNA expression', 'MPA', (88, 103))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mice', 'Species', '10090', (163, 167))	('tumor', 'Disease', (214, 219))
83258	23473982	In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes.	('silence regulators of pluripotency', 'MPA', (77, 111))	('Dmrt1', 'Gene', (23, 28))	('loss', 'Var', (15, 19))	('129Sv', 'Species', '10090', (32, 37))	('failure', 'NegReg', (66, 73))
83259	23473982	A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('human', 'Species', '9606', (79, 84))	('mouse', 'Species', '10090', (178, 183))	('129Sv', 'Species', '10090', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('germ cell tumors', 'Phenotype', 'HP:0100728', (158, 174))	('man', 'Species', '9606', (188, 191))	('germ cell tumors', 'Phenotype', 'HP:0100728', (96, 112))	('germ cell tumor', 'Phenotype', 'HP:0100728', (158, 173))	('germ cell tumor', 'Phenotype', 'HP:0100728', (96, 111))	('129Sv mutant', 'Var', (34, 46))	('cell tumors', 'Disease', (163, 174))	('cell tumors', 'Disease', 'MESH:D005935', (163, 174))	('cell tumors', 'Disease', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cell tumors', 'Disease', 'MESH:D005935', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('man', 'Species', '9606', (81, 84))
83260	23473982	Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas.	('teratoma', 'Phenotype', 'HP:0009792', (138, 146))	('regulates', 'Reg', (44, 53))	('mutant', 'Var', (108, 114))	('teratomas', 'Phenotype', 'HP:0009792', (138, 147))	('teratomas', 'Disease', (138, 147))	('teratomas', 'Disease', 'MESH:D013724', (138, 147))	('Dmrt1', 'Gene', (102, 107))	('pluripotency genes', 'MPA', (54, 72))
83261	23473982	Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF.	('disruption', 'Reg', (27, 37))	('Dmrt1', 'Gene', (71, 76))	('signaling pathways', 'Pathway', (49, 67))	('GDNF', 'Gene', '14573', (126, 130))	('mutant', 'Var', (77, 83))	('GDNF', 'Gene', (126, 130))
83271	23473982	Misregulation of pluripotency plays an important role in testicular germ cell tumors, the most common malignancy of young men.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('germ cell tumor', 'Phenotype', 'HP:0100728', (68, 83))	('malignancy', 'Disease', (102, 112))	('pluripotency', 'MPA', (17, 29))	('cell tumors', 'Disease', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Misregulation', 'Var', (0, 13))	('cell tumors', 'Disease', 'MESH:D005935', (73, 84))	('malignancy', 'Disease', 'MESH:D009369', (102, 112))	('germ cell tumors', 'Phenotype', 'HP:0100728', (68, 84))	('men', 'Species', '9606', (122, 125))
83275	23473982	Most mouse strains do not develop teratomas, but they occur spontaneously at a low incidence in mice of the 129Sv inbred strain and can occur at higher incidence in mice mutant for germ cell developmental regulators including the RNA binding protein Dnd1 or the transcription factor Dmrt1, or mutant for the tumor suppressor Pten.	('mice', 'Species', '10090', (165, 169))	('teratomas', 'Disease', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('mutant', 'Var', (170, 176))	('Dmrt1', 'Gene', (283, 288))	('mouse', 'Species', '10090', (5, 10))	('teratomas', 'Phenotype', 'HP:0009792', (34, 43))	('mice', 'Species', '10090', (96, 100))	('Dnd1', 'Gene', (250, 254))	('Dnd1', 'Gene', '213236', (250, 254))	('mutant', 'Var', (293, 299))	('teratoma', 'Phenotype', 'HP:0009792', (34, 42))	('men', 'Species', '9606', (198, 201))	('tumor', 'Disease', (308, 313))	('teratomas', 'Disease', 'MESH:D013724', (34, 43))	('Pten', 'Gene', (325, 329))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('129Sv', 'Species', '10090', (108, 113))	('Pten', 'Gene', '19211', (325, 329))
83281	23473982	Linkage analysis in the mouse confirms the genetic component and suggests that 100 or more loci may significantly affect TGCT susceptibility.	('affect', 'Reg', (114, 120))	('mouse', 'Species', '10090', (24, 29))	('TGCT', 'Disease', (121, 125))	('loci', 'Var', (91, 95))
83284	23473982	In addition, in the mouse the availability of single gene mutations that dramatically elevate TGCT incidence, such as Dnd1 and Dmrt1, has provided an entry point to explore the role of genetic background and to define the genetic architecture involved in TGCT formation.	('mutations', 'Var', (58, 67))	('mouse', 'Species', '10090', (20, 25))	('Dnd1', 'Gene', (118, 122))	('Dnd1', 'Gene', '213236', (118, 122))	('elevate', 'PosReg', (86, 93))	('TGCT', 'Disease', (94, 98))	('incidence', 'MPA', (99, 108))	('Dmrt1', 'Gene', (127, 132))
83286	23473982	We found previously that loss of Dmrt1 in mice of the 129Sv genetic background results in a very high incidence of teratoma formation, whereas Dmrt1-/- mice of the C57BL/6J or mixed strain backgrounds do not develop teratomas.	('129Sv', 'Species', '10090', (54, 59))	('teratomas', 'Phenotype', 'HP:0009792', (216, 225))	('teratomas', 'Disease', (216, 225))	('loss', 'Var', (25, 29))	('teratomas', 'Disease', 'MESH:D013724', (216, 225))	('teratoma', 'Phenotype', 'HP:0009792', (115, 123))	('teratoma', 'Disease', 'MESH:D013724', (115, 123))	('mice', 'Species', '10090', (42, 46))	('teratoma', 'Disease', 'MESH:D013724', (216, 224))	('teratoma', 'Disease', (216, 224))	('Dmrt1', 'Gene', (33, 38))	('mice', 'Species', '10090', (152, 156))	('teratoma', 'Phenotype', 'HP:0009792', (216, 224))	('teratoma', 'Disease', (115, 123))
83287	23473982	Mutations in Dnd1 also cause teratomas only in 129Sv mice, and this is due to a strain-dependent difference in apoptotic response; genetic suppression of apoptosis allows loss of Dnd1 to cause teratomas in B6/129Sv mixed background mice as well.	('129Sv', 'Species', '10090', (209, 214))	('Dnd1', 'Gene', (13, 17))	('Dnd1', 'Gene', '213236', (13, 17))	('teratomas', 'Phenotype', 'HP:0009792', (29, 38))	('teratomas only', 'Disease', (29, 43))	('teratomas', 'Disease', (193, 202))	('mice', 'Species', '10090', (53, 57))	('cause', 'Reg', (23, 28))	('teratoma', 'Phenotype', 'HP:0009792', (29, 37))	('Dnd1', 'Gene', (179, 183))	('Mutations', 'Var', (0, 9))	('Dnd1', 'Gene', '213236', (179, 183))	('teratomas', 'Disease', 'MESH:D013724', (29, 38))	('129Sv', 'Species', '10090', (47, 52))	('loss', 'Var', (171, 175))	('teratoma', 'Phenotype', 'HP:0009792', (193, 201))	('teratomas only', 'Disease', 'MESH:D013724', (29, 43))	('teratomas', 'Phenotype', 'HP:0009792', (193, 202))	('cause', 'Reg', (187, 192))	('teratomas', 'Disease', (29, 38))	('mice', 'Species', '10090', (232, 236))	('teratomas', 'Disease', 'MESH:D013724', (193, 202))
83288	23473982	By contrast, Dmrt1 mutant mice of B6, 129Sv or mixed background do not undergo elevated fetal germ cell apoptosis, but loss of Dmrt1 nevertheless causes teratomas only in 129Sv mice.	('129Sv', 'Species', '10090', (171, 176))	('129Sv', 'Species', '10090', (38, 43))	('teratomas only', 'Disease', 'MESH:D013724', (153, 167))	('mice', 'Species', '10090', (26, 30))	('teratoma', 'Phenotype', 'HP:0009792', (153, 161))	('teratomas', 'Phenotype', 'HP:0009792', (153, 162))	('teratomas only', 'Disease', (153, 167))	('mice', 'Species', '10090', (177, 181))	('loss', 'Var', (119, 123))	('causes', 'Reg', (146, 152))	('Dmrt1', 'Gene', (127, 132))
83291	23473982	In particular, loss of Dmrt1 more severely deregulates pluripotency gene repression in 129Sv than in B6 mice.	('pluripotency gene repression', 'MPA', (55, 83))	('mice', 'Species', '10090', (104, 108))	('129Sv', 'Species', '10090', (87, 92))	('Dmrt1', 'Gene', (23, 28))	('loss', 'Var', (15, 19))	('deregulates', 'Reg', (43, 54))
83292	23473982	The TGF family ligand GDNF and its tyrosine kinase coreceptors Gfra1 and Ret were underexpressed in Dmrt1 mutant testes, suggesting that GDNF signaling pathway might regulate fetal germ cell proliferation and/or pluripotency (this paper and).	('mutant', 'Var', (106, 112))	('fetal germ cell proliferation', 'CPA', (175, 204))	('Dmrt1', 'Gene', (100, 105))	('Gfra1', 'Gene', (63, 68))	('TGF', 'Gene', '7040', (4, 7))	('TGF', 'Gene', (4, 7))	('Gfra1', 'Gene', '14585', (63, 68))	('pluripotency', 'MPA', (212, 224))	('GDNF', 'Gene', '14573', (22, 26))	('GDNF', 'Gene', '14573', (137, 141))	('GDNF', 'Gene', (22, 26))	('Ret', 'Gene', (73, 76))	('GDNF', 'Gene', (137, 141))	('regulate', 'Reg', (166, 174))	('Ret', 'Gene', '19713', (73, 76))
83293	23473982	We conditionally deleted each GDNF coreceptor in fetal germ cells using a Nanos3-cre knockin allele and found that loss Gfra1 caused elevated teratoma susceptibility.	('Gfra1', 'Gene', '14585', (120, 125))	('teratoma', 'Phenotype', 'HP:0009792', (142, 150))	('Gfra1', 'Gene', (120, 125))	('elevated teratoma', 'Disease', 'MESH:D013724', (133, 150))	('loss', 'Var', (115, 119))	('elevated teratoma', 'Disease', (133, 150))	('Nanos3', 'Gene', (74, 80))	('GDNF', 'Gene', '14573', (30, 34))	('Nanos3', 'Gene', '244551', (74, 80))	('GDNF', 'Gene', (30, 34))
83300	23473982	The mix of 129S1 and 129S6 substrains is presumed to cause the elevated teratoma background seen in Dmrt1fl/+ animals (Fig.	('teratoma', 'Phenotype', 'HP:0009792', (72, 80))	('elevated teratoma', 'Disease', 'MESH:D013724', (63, 80))	('129S6', 'Var', (21, 26))	('129S1', 'Var', (11, 16))	('Dmrt1fl/+', 'Var', (100, 109))	('elevated teratoma', 'Disease', (63, 80))
83314	23473982	We chose E15.5 as the developmental time for this analysis in part because previous mRNA profiling at E13.5 identified very few misexpressed genes in Dmrt1 mutant 129Sv testes.	('men', 'Species', '9606', (29, 32))	('129Sv', 'Species', '10090', (163, 168))	('Dmrt1', 'Gene', (150, 155))	('mutant 129Sv', 'Var', (156, 168))
83320	23473982	A Dmrt1 null mutation in B6 or mixed background mice causes postnatal defects in germ cell and Sertoli cell development and eventually leads to male-to-female transdifferentiation of Sertoli cells.	('male-to-female transdifferentiation', 'CPA', (144, 179))	('mutation', 'Var', (13, 21))	('mice', 'Species', '10090', (48, 52))	('postnatal defects', 'Disease', (60, 77))	('men', 'Species', '9606', (115, 118))	('Dmrt1', 'Gene', (2, 7))	('postnatal defects', 'Disease', 'MESH:D019052', (60, 77))	('Sertoli cell', 'Phenotype', 'HP:0100619', (183, 195))	('leads to', 'Reg', (135, 143))	('Sertoli cells', 'Phenotype', 'HP:0100619', (183, 196))	('Sertoli cell', 'Phenotype', 'HP:0100619', (95, 107))
83322	23473982	From these results we conclude that loss of Dmrt1 in B6 mice impairs fetal testicular differentiation by E15.5.	('impairs', 'NegReg', (61, 68))	('loss', 'Var', (36, 40))	('mice', 'Species', '10090', (56, 60))	('Dmrt1', 'Gene', (44, 49))	('fetal testicular differentiation', 'CPA', (69, 101))
83323	23473982	In 129Sv mice, loss of Dmrt1 disrupted expression of 632 mRNAs (>2-fold change; P < 0.05) (Fig.	('disrupted', 'NegReg', (29, 38))	('129Sv', 'Species', '10090', (3, 8))	('Dmrt1', 'Gene', (23, 28))	('loss', 'Var', (15, 19))	('expression', 'MPA', (39, 49))	('mice', 'Species', '10090', (9, 13))
83324	23473982	As in B6 mutants, some of these mRNAs normally are developmentally regulated; however a greater proportion of affected mRNAs in 129Sv mutants were not developmentally regulated (Fig.	('men', 'Species', '9606', (158, 161))	('mutants', 'Var', (9, 16))	('mutants', 'Var', (134, 141))	('129Sv', 'Species', '10090', (128, 133))	('men', 'Species', '9606', (58, 61))	('129Sv mutants', 'Var', (128, 141))
83325	23473982	In addition, while the affected mRNAs in mutants of either strain mainly showed reduced expression, the proportion with elevated expression was higher in 129Sv mutants (17% elevated in B6, versus 42% in 129Sv).	('expression', 'MPA', (129, 139))	('elevated', 'PosReg', (173, 181))	('129Sv', 'Species', '10090', (203, 208))	('reduced', 'NegReg', (80, 87))	('higher', 'PosReg', (144, 150))	('129Sv', 'Var', (154, 159))	('expression', 'MPA', (88, 98))	('129Sv', 'Species', '10090', (154, 159))
83326	23473982	We conclude that loss of Dmrt1 in the 129Sv testis compromises testicular differentiation as it does in B6, but also is likely to disrupt other functions, and these presumably contribute to the highly elevated incidence of teratoma formation in mutants of this strain.	('Dmrt1', 'Gene', (25, 30))	('teratoma', 'Phenotype', 'HP:0009792', (223, 231))	('129Sv', 'Species', '10090', (38, 43))	('compromises', 'NegReg', (51, 62))	('teratoma', 'Disease', 'MESH:D013724', (223, 231))	('testicular differentiation', 'CPA', (63, 89))	('mutants', 'Var', (245, 252))	('teratoma', 'Disease', (223, 231))	('disrupt', 'NegReg', (130, 137))	('loss', 'Var', (17, 21))	('functions', 'MPA', (144, 153))
83327	23473982	167 germ line enriched mRNAs differed significantly (p < 0.05) between wild type testes of the two strains, with an average elevation of 1.33-fold in 129Sv versus B6.	('elevation', 'PosReg', (124, 133))	('129Sv', 'Species', '10090', (150, 155))	('129Sv', 'Var', (150, 155))
83328	23473982	These data suggest that germ cell numbers are slightly higher in 129Sv than B6 testes and that B6 mutant testes have approximately normal germ cell numbers relative to wild type.	('129Sv', 'Var', (65, 70))	('B6 mutant', 'Var', (95, 104))	('129Sv', 'Species', '10090', (65, 70))	('germ cell numbers', 'CPA', (24, 41))	('higher', 'PosReg', (55, 61))	('mutant', 'Var', (98, 104))
83329	23473982	In 129Sv testes 136 mRNAs differed significantly between wild type and mutant, averaging 1.66-fold higher in the mutant.	('mutant', 'Var', (113, 119))	('129Sv', 'Species', '10090', (3, 8))	('higher', 'PosReg', (99, 105))
83330	23473982	This difference was strongly affected by a small number of highly elevated mRNAs (eg, >40-fold higher expression of L1td1 and Otx2) but it remained possible that 129Sv mutants also have an increase in germ cell numbers relative to wild type.	('129Sv mutants', 'Var', (162, 175))	('germ cell numbers', 'CPA', (201, 218))	('expression', 'MPA', (102, 112))	('higher', 'PosReg', (95, 101))	('L1td1', 'Gene', (116, 121))	('129Sv', 'Species', '10090', (162, 167))	('increase', 'PosReg', (189, 197))	('mutants', 'Var', (168, 175))
83332	23473982	We could not exclude a modest increase in germ cells in 129Sv mutant testes, but a major difference was not apparent at E15.5, consistent with the previous conclusion that germ cell numbers are normal in 129Sv mutant gonads at E13.5 and at birth.	('129Sv', 'Species', '10090', (204, 209))	('129Sv', 'Species', '10090', (56, 61))	('129Sv mutant', 'Var', (204, 216))	('129Sv mutant', 'Var', (56, 68))
83333	23473982	In particular, loss of Dmrt1 in 129Sv testes affected many mRNAs that were not affected by loss in B6: of 894 mRNAs affected in the two strains, 262 were significantly affected only in testes of B6 mutants, 404 only in 129Sv mutants, and 228 in both (>2-fold change; P < 0.05).	('man', 'Species', '9606', (54, 57))	('129Sv', 'Var', (219, 224))	('129Sv', 'Species', '10090', (219, 224))	('affected', 'Reg', (168, 176))	('mutants', 'Var', (198, 205))	('129Sv', 'Species', '10090', (32, 37))
83334	23473982	Most of the mRNAs that were affected in both strains normally are developmentally regulated but had failed to increase or decrease in expression appropriately, further indicating that loss of Dmrt1 disrupts testicular differentiation in both strains (Fig.	('men', 'Species', '9606', (73, 76))	('loss', 'Var', (184, 188))	('Dmrt1', 'Gene', (192, 197))	('disrupts', 'NegReg', (198, 206))	('testicular differentiation', 'CPA', (207, 233))
83335	23473982	However, among the mRNAs selectively affected in 129Sv mutant testes about half were overexpressed and were not normally subject to temporal regulation in the fetal testis (Fig.	('129Sv mutant', 'Var', (49, 61))	('129Sv', 'Species', '10090', (49, 54))	('overexpressed', 'PosReg', (85, 98))
83337	23473982	Indeed, among mRNAs more strongly overexpressed in 129Sv than B6 mutant testis were a number already implicated in human testicular germ cell tumors, including the three most highly over-expressed (L1td1, Otx2, and Zic3; Table S5).	('cell tumors', 'Disease', (137, 148))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('over-expressed', 'PosReg', (182, 196))	('129Sv', 'Var', (51, 56))	('cell tumors', 'Disease', 'MESH:D005935', (137, 148))	('Zic3', 'Gene', (215, 219))	('B6 mutant', 'Var', (62, 71))	('human', 'Species', '9606', (115, 120))	('germ cell tumors', 'Phenotype', 'HP:0100728', (132, 148))	('129Sv', 'Species', '10090', (51, 56))	('Zic3', 'Gene', '7547', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('germ cell tumor', 'Phenotype', 'HP:0100728', (132, 147))	('overexpressed', 'PosReg', (34, 47))
83339	23473982	Expression profiling indicated distinct transcriptional responses to loss of Dmrt1 in 129Sv and B6 fetal testes.	('loss', 'Var', (69, 73))	('Dmrt1', 'Gene', (77, 82))	('transcriptional', 'MPA', (40, 55))	('129Sv', 'Species', '10090', (86, 91))
83340	23473982	Disrupted functions specific to 129Sv mutants included organogenesis, cell morphology, infertility, cellular homeostasis, and morphology of gonadal cells.	('129Sv', 'Species', '10090', (32, 37))	('mutants', 'Var', (38, 45))	('infertility', 'Phenotype', 'HP:0000789', (87, 98))	('infertility', 'Disease', 'MESH:D007247', (87, 98))	('cellular homeostasis', 'CPA', (100, 120))	('infertility', 'Disease', (87, 98))	('129Sv', 'Gene', (32, 37))
83341	23473982	Pathway analysis highlighted pluripotency regulation as affected in both strains, but with more genes affected in 129Sv mutant testes (Table S6).	('pluripotency regulation', 'MPA', (29, 52))	('129Sv mutant', 'Var', (114, 126))	('affected', 'Reg', (56, 64))	('129Sv', 'Species', '10090', (114, 119))
83342	23473982	We confirmed the differential effect on pluripotency gene expression in the two strains using quantitative RT-PCR (qRT-PCR), which showed that loss of Dmrt1 caused a more severe failure to silence pluripotency genes in 129Sv than in B6 (Fig.	('Dmrt1', 'Gene', (151, 156))	('129Sv', 'Species', '10090', (219, 224))	('silence', 'MPA', (189, 196))	('failure', 'NegReg', (178, 185))	('loss', 'Var', (143, 147))	('pluripotency genes', 'Gene', (197, 215))
83343	23473982	Based on target gene expression, a larger number of transcriptional networks appeared to be misregulated in mutants of both strains including targets of CTNNB1/ -catenin, which was predicted to be activated; however, many more networks were specifically affected in 129Sv mutants (17 with p<0.001 in 129Sv, versus 3 in B6).	('129Sv', 'Species', '10090', (266, 271))	('129Sv', 'Var', (300, 305))	('mutants', 'Var', (272, 279))	('mutants', 'Var', (108, 115))	('129Sv mutants', 'Var', (266, 279))	('129Sv', 'Species', '10090', (300, 305))	('CTNNB1', 'Gene', '12387', (153, 159))	('man', 'Species', '9606', (217, 220))	('affected', 'Reg', (254, 262))	('CTNNB1', 'Gene', (153, 159))
83344	23473982	These results suggest that while loss of Dmrt1 affects expression of similar numbers of mRNAs in the two strains (490 in B6 versus 632 in 129Sv), the consequences for transcriptional regulatory networks are substantially more severe in 129Sv mice.	('transcriptional regulatory networks', 'MPA', (167, 202))	('Dmrt1', 'Gene', (41, 46))	('129Sv', 'Species', '10090', (138, 143))	('expression', 'MPA', (55, 65))	('loss', 'Var', (33, 37))	('severe', 'Reg', (226, 232))	('129Sv', 'Species', '10090', (236, 241))	('mice', 'Species', '10090', (242, 246))
83345	23473982	IPA analysis suggested that a number of other regulatory genes and pathways relevant to germ cell identity or cancer were affected in mutant testes, including some affected selectively in 129Sv mutants.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('129Sv', 'Species', '10090', (188, 193))	('129Sv mutants', 'Var', (188, 201))	('affected', 'Reg', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('affected', 'Reg', (164, 172))	('regulatory genes', 'Gene', (46, 62))	('mutant', 'Var', (134, 140))
83347	23473982	Expression profiling detected elevated expression of mRNAs encoding the TGF -family signaling proteins NODAL (2.6-fold in B6, 6.2-fold in 129Sv) and GDF3, which potentiates NODAL signaling (unchanged in B6, 2.7-fold in 129Sv), as well as the NODAL receptor TDGF1 (Teratocarcinoma-derived growth factor 1)/CRIPTO (2.3-fold in B6, 11-fold in 129Sv) and the Nodal target LEFTY1 (3.4-fold in B6, 5.2-fold in 129Sv).	('Teratocarcinoma-derived growth factor 1', 'Gene', '21667', (264, 303))	('NODAL signaling', 'MPA', (173, 188))	('129Sv', 'Species', '10090', (340, 345))	('129Sv', 'Species', '10090', (138, 143))	('129Sv', 'Species', '10090', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('TGF', 'Gene', '7040', (72, 75))	('mRNAs', 'Var', (53, 58))	('TGF', 'Gene', (72, 75))	('elevated', 'PosReg', (30, 38))	('expression', 'MPA', (39, 49))	('129Sv', 'Species', '10090', (404, 409))	('potentiates', 'PosReg', (161, 172))	('Teratocarcinoma-derived growth factor 1', 'Gene', (264, 303))	('GDF3', 'Gene', '14562', (149, 153))	('GDF3', 'Gene', (149, 153))
83348	23473982	Quantitative RT-PCR (qRT-PCR) for several of these components confirmed their elevated expression and stronger misregulation in 129Sv mutants (Fig.	('misregulation', 'MPA', (111, 124))	('elevated', 'PosReg', (78, 86))	('expression', 'MPA', (87, 97))	('129Sv', 'Species', '10090', (128, 133))	('129Sv mutants', 'Var', (128, 141))
83349	23473982	One goal of profiling mRNA expression changes in Dmrt1 mutant testes is to identify regulatory pathways whose disruption might contribute to teratoma susceptibility.	('Dmrt1', 'Gene', (49, 54))	('teratoma', 'Phenotype', 'HP:0009792', (141, 149))	('teratoma', 'Disease', 'MESH:D013724', (141, 149))	('mutant', 'Var', (55, 61))	('contribute', 'Reg', (127, 137))	('teratoma', 'Disease', (141, 149))
83351	23473982	Our previous mRNA profiling at E13.5 identified 18 mRNAs misexpressed more than two-fold (p<0.05) in 129Sv Dmrt1 null mutant versus wild-type testes.	('Dmrt1', 'Gene', (107, 112))	('129Sv', 'Var', (101, 106))	('mRNAs', 'MPA', (51, 56))	('129Sv', 'Species', '10090', (101, 106))	('misexpressed', 'Reg', (57, 69))
83352	23473982	Among these was Ret, whose protein depletion in germ cells at E13.5 was confirmed by immunofluorescence.	('Ret', 'Gene', (16, 19))	('E13.5', 'Var', (62, 67))	('fl', 'Chemical', '-', (91, 93))	('Ret', 'Gene', '19713', (16, 19))
83354	23473982	In addition, loss of Ret, but not Gdnf, compromises germ cell survival in the fetal testis.	('Ret', 'Gene', (21, 24))	('compromises', 'NegReg', (40, 51))	('Gdnf', 'Gene', (34, 38))	('Ret', 'Gene', '19713', (21, 24))	('germ cell survival in the fetal testis', 'CPA', (52, 90))	('Gdnf', 'Gene', '14573', (34, 38))	('loss', 'Var', (13, 17))
83355	23473982	At E15.5 expression profiling detected misregulation of both Ret (down 2.3-fold in B6 and 2.6-fold in 129Sv) and Gdnf (down 1.8-fold in B6 and 2.4-fold in 129Sv Dmrt1 mutants).	('129Sv', 'Species', '10090', (102, 107))	('Ret', 'Gene', (61, 64))	('129Sv', 'Var', (155, 160))	('Gdnf', 'Gene', '14573', (113, 117))	('misregulation', 'MPA', (39, 52))	('Ret', 'Gene', '19713', (61, 64))	('129Sv', 'Species', '10090', (155, 160))	('Dmrt1', 'Gene', (161, 166))	('mutants', 'Var', (167, 174))	('Gdnf', 'Gene', (113, 117))
83356	23473982	We therefore tested the possibility that DMRT1 is required for proper GDNF signaling in the embryo and that loss of GDNF signaling may cause germ cells to differentiate into teratomas in 129Sv mice.	('teratomas', 'Phenotype', 'HP:0009792', (174, 183))	('loss', 'Var', (108, 112))	('GDNF', 'Gene', (70, 74))	('teratomas', 'Disease', (174, 183))	('teratomas', 'Disease', 'MESH:D013724', (174, 183))	('GDNF', 'Gene', '14573', (116, 120))	('tested', 'Reg', (13, 19))	('mice', 'Species', '10090', (193, 197))	('teratoma', 'Phenotype', 'HP:0009792', (174, 182))	('cause', 'Reg', (135, 140))	('129Sv', 'Species', '10090', (187, 192))	('GDNF', 'Gene', (116, 120))	('GDNF', 'Gene', '14573', (70, 74))
83357	23473982	Because Ret and Gfra1 null mutations are lethal, we bred conditional alleles of each gene onto the 129Sv genetic background and conditionally deleted each gene in fetal germ cells using a "knock-in" allele in which Cre is expressed from the Nanos3 locus (Nanos3Cre).	('mutations', 'Var', (27, 36))	('Nanos3', 'Gene', '244551', (255, 261))	('Nanos3', 'Gene', '244551', (241, 247))	('Gfra1', 'Gene', '14585', (16, 21))	('129Sv', 'Species', '10090', (99, 104))	('deleted', 'NegReg', (142, 149))	('Ret', 'Gene', (8, 11))	('Nanos3', 'Gene', (255, 261))	('Nanos3', 'Gene', (241, 247))	('Gfra1', 'Gene', (16, 21))	('Ret', 'Gene', '19713', (8, 11))
83358	23473982	Conditional deletion of Ret did not affect teratoma formation (0/18 Retfl/fl;Nanos3Cre/+ 129Sv testes had tumors), but loss of Gfra1 in germ cells resulted in teratoma formation in 16% of mutant testes (7/44; Fig.	('fl', 'Chemical', '-', (71, 73))	('teratoma', 'Disease', 'MESH:D013724', (159, 167))	('tumors', 'Disease', (106, 112))	('Retfl', 'Chemical', '-', (68, 73))	('Nanos3', 'Gene', (77, 83))	('129Sv', 'Species', '10090', (89, 94))	('teratoma', 'Disease', (43, 51))	('Gfra1', 'Gene', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Ret', 'Gene', (24, 27))	('resulted in', 'Reg', (147, 158))	('Ret', 'Gene', '19713', (24, 27))	('Nanos3', 'Gene', '244551', (77, 83))	('teratoma', 'Disease', (159, 167))	('teratoma', 'Phenotype', 'HP:0009792', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('teratoma', 'Phenotype', 'HP:0009792', (159, 167))	('mutant', 'Var', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Ret', 'Gene', (68, 71))	('fl', 'Chemical', '-', (74, 76))	('Ret', 'Gene', '19713', (68, 71))	('Gfra1', 'Gene', '14585', (127, 132))	('teratoma', 'Disease', 'MESH:D013724', (43, 51))	('loss', 'Var', (119, 123))
83360	23473982	Comparison of tumor incidence in Gfra1fl/fl;Nanos3Cre/+ versus Gfra1fl/fl controls indicated that homozygous deletion of the conditional allele of Gfra1 causes a significant increase in tumor incidence (P = 0.025, Fisher's exact test; Fig.	('fl', 'Chemical', '-', (71, 73))	('Gfra1', 'Gene', (63, 68))	('tumor', 'Disease', (186, 191))	('fl', 'Chemical', '-', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('deletion', 'Var', (109, 117))	('Gfra1', 'Gene', '14585', (147, 152))	('Nanos3', 'Gene', (44, 50))	('Gfra1', 'Gene', '14585', (33, 38))	('fl', 'Chemical', '-', (68, 70))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('Gfra1', 'Gene', '14585', (63, 68))	('Nanos3', 'Gene', '244551', (44, 50))	('tumor', 'Disease', (14, 19))	('Gfra1', 'Gene', (147, 152))	('increase', 'PosReg', (174, 182))	('Gfra1', 'Gene', (33, 38))	('fl', 'Chemical', '-', (41, 43))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
83364	23473982	We previously found that heterozygosity of Dmrt1 alone did not significantly increase teratoma formation in 129Sv males.	('teratoma', 'Phenotype', 'HP:0009792', (86, 94))	('teratoma', 'Disease', 'MESH:D013724', (86, 94))	('129Sv', 'Species', '10090', (108, 113))	('heterozygosity', 'Var', (25, 39))	('Dmrt1', 'Gene', (43, 48))	('increase', 'PosReg', (77, 85))	('teratoma', 'Disease', (86, 94))
83365	23473982	By contrast, 129Sv males doubly heterozygous for Dmrt1fl and Nanos3cre had highly elevated teratoma formation (21/29 testes) relative to either Dmrt1fl/+ (2/12; P = 0.002, Fisher's exact test) or Nanos3Cre/+ (0/22; P < 0.001, Fisher's exact test) (Fig 4A,B).	('Nanos3', 'Gene', '244551', (196, 202))	('Dmrt1fl', 'Var', (49, 56))	('elevated teratoma', 'Disease', 'MESH:D013724', (82, 99))	('fl', 'Chemical', '-', (54, 56))	('129Sv', 'Species', '10090', (13, 18))	('teratoma', 'Phenotype', 'HP:0009792', (91, 99))	('Nanos3', 'Gene', (61, 67))	('elevated teratoma', 'Disease', (82, 99))	('Nanos3', 'Gene', (196, 202))	('fl', 'Chemical', '-', (149, 151))	('Nanos3', 'Gene', '244551', (61, 67))
83370	23473982	Of these potential direct target genes, 23 were misexpressed specifically in 129Sv Dmrt1-/- testes, 14 were misexpressed in B6 Dmrt1-/- testes, and 16 were misexpressed in mutants on both genetic backgrounds.	('Dmrt1-/-', 'Var', (83, 91))	('misexpressed', 'Var', (48, 60))	('129Sv', 'Species', '10090', (77, 82))	('129Sv Dmrt1-/-', 'Var', (77, 91))
83372	23473982	Two putative direct targets elevated in mutant testes are involved in Wnt signaling: one is Wnt inhibitory factor 1 (Wif1) and the other is Rnf43, a stem cell E3 ubiquitin ligase that can block Wnt responsiveness in a variety of cancer cells by inducing Wnt receptor endocytosis.	('Wnt inhibitory factor 1', 'Gene', '24117', (92, 115))	('Rnf43', 'Gene', '207742', (140, 145))	('Wnt inhibitory factor 1', 'Gene', (92, 115))	('Wif1', 'Gene', (117, 121))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Wif1', 'Gene', '24117', (117, 121))	('Wnt responsiveness', 'MPA', (194, 212))	('Wnt receptor endocytosis', 'MPA', (254, 278))	('inducing', 'Reg', (245, 253))	('mutant', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('Rnf43', 'Gene', (140, 145))	('block', 'NegReg', (188, 193))
83373	23473982	Pmaip1/Noxa is a putative direct target elevated in mutant testes that is linked to cisplatin sensitivity in embryonal carcinoma cells.	('mutant', 'Var', (52, 58))	('Noxa', 'Gene', '58801', (7, 11))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (109, 128))	('Pmaip1', 'Gene', (0, 6))	('Pmaip1', 'Gene', '58801', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Noxa', 'Gene', (7, 11))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (109, 128))	('embryonal carcinoma', 'Disease', (109, 128))
83374	23473982	Among putative direct targets reduced in mutant testes, Rrad acts as a tumor suppressor in nasopharyngeal carcinoma, Prdm16 is an H3K9me1 histone methyltransferase involved in maintaining integrity of heterochromatin, and Nedd4l is an E3 ubiquitin ligase that is reduced during development of prostate cancer and whose reduced expression is associated with aggressiveness and poor prognosis in other cancers.	('cancers', 'Phenotype', 'HP:0002664', (400, 407))	('cancers', 'Disease', (400, 407))	('Rrad', 'Gene', (56, 60))	('Prdm16', 'Gene', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (91, 115))	('reduced', 'NegReg', (319, 326))	('mutant', 'Var', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('expression', 'MPA', (327, 337))	('cancers', 'Disease', 'MESH:D009369', (400, 407))	('men', 'Species', '9606', (285, 288))	('prostate cancer', 'Disease', 'MESH:D011471', (293, 308))	('aggressiveness', 'Disease', (357, 371))	('Rrad', 'Gene', '56437', (56, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (293, 308))	('nasopharyngeal carcinoma', 'Disease', (91, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (357, 371))	('Prdm16', 'Gene', '70673', (117, 123))	('tumor', 'Disease', (71, 76))	('prostate cancer', 'Disease', (293, 308))	('aggressiveness', 'Disease', 'MESH:D001523', (357, 371))	('Nedd4l', 'Gene', '83814', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Nedd4l', 'Gene', (222, 228))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (91, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))
83376	23473982	Epigenetic reprogramming is a major germ cell-specific event that occurs around the time when teratomas form in Dmrt1 mutant mice.	('teratoma', 'Phenotype', 'HP:0009792', (94, 102))	('teratomas', 'Phenotype', 'HP:0009792', (94, 103))	('mice', 'Species', '10090', (125, 129))	('teratomas', 'Disease', 'MESH:D013724', (94, 103))	('mutant', 'Var', (118, 124))	('Dmrt1', 'Gene', (112, 117))	('teratomas', 'Disease', (94, 103))
83377	23473982	Two important DNA methylases were misregulated in Dmrt1 mutant testes, suggesting that epigenetic defects may contribute to the mutant phenotype.	('mutant', 'Var', (56, 62))	('Dmrt1', 'Gene', (50, 55))	('genetic defects', 'Disease', 'MESH:D030342', (90, 105))	('genetic defects', 'Disease', (90, 105))	('DNA methylases', 'Enzyme', (14, 28))	('contribute', 'Reg', (110, 120))
83381	23473982	Another important germ cell DNA methylase, Dnmt3b, was elevated 4-fold in 129Sv mutant testes but unchanged in B6 mutants (Table S4) and appeared to be indirectly regulated.	('129Sv mutant', 'Var', (74, 86))	('Dnmt3b', 'Gene', '13436', (43, 49))	('Dnmt3b', 'Gene', (43, 49))	('elevated', 'PosReg', (55, 63))	('129Sv', 'Species', '10090', (74, 79))
83382	23473982	DNMT3L is expressed in human TGCTs and knockdown of DNMT3L in EC cell lines suppressed their growth and induced apoptosis, suggesting a role in human TGCT formation.	('apoptosis', 'CPA', (112, 121))	('human', 'Species', '9606', (144, 149))	('DNMT3L', 'Gene', (52, 58))	('knockdown', 'Var', (39, 48))	('DNMT3L', 'Gene', (0, 6))	('growth', 'CPA', (93, 99))	('suppressed', 'NegReg', (76, 86))	('DNMT3L', 'Gene', '29947', (0, 6))	('DNMT3L', 'Gene', '29947', (52, 58))	('human', 'Species', '9606', (23, 28))	('induced', 'Reg', (104, 111))
83383	23473982	We speculate that abnormal DNA methylation resulting from misregulated methylase expression may affect teratoma sensitivity.	('affect', 'Reg', (96, 102))	('teratoma', 'Phenotype', 'HP:0009792', (103, 111))	('abnormal', 'Var', (18, 26))	('teratoma', 'Disease', 'MESH:D013724', (103, 111))	('misregulated', 'Var', (58, 70))	('DNA methylation', 'MPA', (27, 42))	('teratoma', 'Disease', (103, 111))	('methylase', 'Protein', (71, 80))
83384	23473982	For example, the nearly complete elimination of Dnmt3l expression in B6 mutant germ cells may help block their ability to differentiate into teratomas, whereas overexpression of Dnmt3b may enhance teratoma formation in 129Sv mutant testes.	('Dnmt3b', 'Gene', (178, 184))	('Dnmt3l', 'Gene', '54427', (48, 54))	('teratoma', 'Phenotype', 'HP:0009792', (197, 205))	('teratomas', 'Phenotype', 'HP:0009792', (141, 150))	('Dnmt3l', 'Gene', (48, 54))	('mutant', 'Var', (72, 78))	('teratoma', 'Phenotype', 'HP:0009792', (141, 149))	('teratoma', 'Disease', 'MESH:D013724', (197, 205))	('enhance', 'PosReg', (189, 196))	('teratomas', 'Disease', 'MESH:D013724', (141, 150))	('elimination', 'NegReg', (33, 44))	('block', 'NegReg', (99, 104))	('teratoma', 'Disease', 'MESH:D013724', (141, 149))	('expression', 'MPA', (55, 65))	('teratomas', 'Disease', (141, 150))	('129Sv mutant', 'Var', (219, 231))	('teratoma', 'Disease', (197, 205))	('129Sv', 'Species', '10090', (219, 224))	('teratoma', 'Disease', (141, 149))	('Dnmt3b', 'Gene', '13436', (178, 184))
83385	23473982	At E13.5, only eight mRNAs were misexpressed two-fold or more in mutant ovaries, including the meiotic regulator Stra8.	('Stra8', 'Gene', (113, 118))	('mutant', 'Var', (65, 71))	('Stra8', 'Gene', '20899', (113, 118))
83387	23473982	However, as in males, the overexpressed mRNAs in Dmrt1 mutant females included a number that are associated with pluripotency (eg, Sall4, Sox2, Dppa2, Dppa3/Stella, Dppa4, Dppa5, and Lin28).	('Dmrt1', 'Gene', (49, 54))	('Lin28', 'Gene', (183, 188))	('Sall4', 'Gene', '99377', (131, 136))	('Dppa4', 'Gene', (165, 170))	('Lin28', 'Gene', '83557', (183, 188))	('associated', 'Reg', (97, 107))	('Dppa4', 'Gene', '73693', (165, 170))	('overexpressed', 'PosReg', (26, 39))	('Dppa3', 'Gene', (151, 156))	('Stella', 'Gene', (157, 163))	('Dppa5', 'Gene', '434423', (172, 177))	('pluripotency', 'MPA', (113, 125))	('Sox2', 'Gene', (138, 142))	('mutant', 'Var', (55, 61))	('Dppa2', 'Gene', '73703', (144, 149))	('Dppa5', 'Gene', (172, 177))	('Sox2', 'Gene', '20674', (138, 142))	('Sall4', 'Gene', (131, 136))	('Stella', 'Gene', '73708', (157, 163))	('Dppa3', 'Gene', '73708', (151, 156))	('Dppa2', 'Gene', (144, 149))
83392	23473982	DMRT1 was unable to bind this C-rich element in vitro (Figure 6C), suggesting either that its association with DMRT1 in vivo is indirect or that the association requires a modification of DMRT1 that is lacking in the in vitro translated protein.	('DMRT1', 'Gene', (111, 116))	('association', 'Interaction', (149, 160))	('association', 'Interaction', (94, 105))	('modification', 'Var', (172, 184))	('men', 'Species', '9606', (40, 43))	('DMRT1', 'Gene', (188, 193))
83397	23473982	Many were overexpressed in mutants of both strains, but the number of genes affected and the magnitude of overexpression both were higher in 129Sv mutants.	('mutants', 'Var', (27, 34))	('129Sv', 'Species', '10090', (141, 146))	('mutants', 'Var', (147, 154))	('129Sv mutants', 'Var', (141, 154))	('higher', 'PosReg', (131, 137))
83401	23473982	Previously we found by analysis of candidate genes that a number of pluripotency genes were upregulated in Dmrt1 mutant fetal testes and that DMRT1 binds to Sox2 in the fetal testis.	('pluripotency genes', 'MPA', (68, 86))	('upregulated', 'PosReg', (92, 103))	('Dmrt1', 'Gene', (107, 112))	('binds', 'Interaction', (148, 153))	('Sox2', 'Gene', '20674', (157, 161))	('mutant', 'Var', (113, 119))	('Sox2', 'Gene', (157, 161))
83409	23473982	Several of the pluripotency regulators misexpressed in Dmrt1 mutant testes (for example Nanog, Klf4, Nr5a2/Lrh1, Oct4) can help to reprogram differentiated somatic cells into pluripotent stem cells.	('Klf4', 'Gene', (95, 99))	('Lrh1', 'Gene', (107, 111))	('Dmrt1', 'Gene', (55, 60))	('Nanog', 'Gene', '71950', (88, 93))	('help', 'Reg', (123, 127))	('Oct4', 'Gene', '18999', (113, 117))	('Nanog', 'Gene', (88, 93))	('Lrh1', 'Gene', '26424', (107, 111))	('Nr5a2', 'Gene', (101, 106))	('mutant', 'Var', (61, 67))	('Klf4', 'Gene', '16600', (95, 99))	('Oct4', 'Gene', (113, 117))	('Nr5a2', 'Gene', '26424', (101, 106))	('reprogram differentiated somatic cells', 'CPA', (131, 169))
83412	23473982	In postnatal Dmrt1 mutant testes, which undergo Sertoli-to-granulosa cell (male to female) reprogramming, Nr5a2/Lrh1 also is highly expressed.	('Nr5a2', 'Gene', (106, 111))	('Nr5a2', 'Gene', '26424', (106, 111))	('Lrh1', 'Gene', (112, 116))	('mutant', 'Var', (19, 25))	('Dmrt1', 'Gene', (13, 18))	('Lrh1', 'Gene', '26424', (112, 116))
83414	23473982	We found that loss of Dmrt1 also causes elevated pluripotency gene expression in fetal ovaries, and yet wild type and Dmrt1 mutant females of the 129Sv strain do not develop ovarian teratomas.	('teratoma', 'Phenotype', 'HP:0009792', (182, 190))	('loss', 'Var', (14, 18))	('ovarian teratomas', 'Disease', (174, 191))	('fetal ovaries', 'Disease', (81, 94))	('fetal ovaries', 'Disease', 'MESH:D005315', (81, 94))	('mutant', 'Var', (124, 130))	('129Sv', 'Species', '10090', (146, 151))	('teratomas', 'Phenotype', 'HP:0009792', (182, 191))	('ovarian teratomas', 'Phenotype', 'HP:0012226', (174, 191))	('elevated pluripotency', 'Disease', 'MESH:D006937', (40, 61))	('Dmrt1', 'Gene', (118, 123))	('elevated pluripotency', 'Disease', (40, 61))	('Dmrt1', 'Gene', (22, 27))	('ovarian teratomas', 'Disease', 'MESH:C562731', (174, 191))
83416	23473982	One possibility is that the testicular but not the ovarian somatic microenvironment is conducive to teratoma formation and thus germ cells in a fetal testis must suppress pluripotency by E15.5 to prevent aberrant differentiation in response to that environment.	('men', 'Species', '9606', (79, 82))	('teratoma', 'Disease', 'MESH:D013724', (100, 108))	('suppress', 'NegReg', (162, 170))	('pluripotency', 'MPA', (171, 183))	('aberrant', 'CPA', (204, 212))	('men', 'Species', '9606', (256, 259))	('teratoma', 'Disease', (100, 108))	('teratoma', 'Phenotype', 'HP:0009792', (100, 108))	('E15.5', 'Var', (187, 192))
83417	23473982	Recent studies have shown an association between ectopic meiotic initiation and teratoma formation in fetal germ cells, and mutation of the meiotic regulator Stra8 reduced teratoma incidence in 129Sv mice.	('teratoma', 'Disease', (80, 88))	('Stra8', 'Gene', (158, 163))	('teratoma', 'Phenotype', 'HP:0009792', (172, 180))	('teratoma', 'Disease', 'MESH:D013724', (172, 180))	('ectopic', 'MPA', (49, 56))	('teratoma', 'Phenotype', 'HP:0009792', (80, 88))	('teratoma', 'Disease', 'MESH:D013724', (80, 88))	('Stra8', 'Gene', '20899', (158, 163))	('teratoma', 'Disease', (172, 180))	('mutation', 'Var', (124, 132))	('129Sv', 'Species', '10090', (194, 199))	('mice', 'Species', '10090', (200, 204))	('reduced', 'NegReg', (164, 171))
83420	23473982	We confirmed the low expression by qRT-PCR (not shown), and antibody staining did not detect STRA8 in wild type or Dmrt1 mutant fetal male germ cells of either strain and unpublished results).	('Dmrt1', 'Gene', (115, 120))	('STRA8', 'Gene', '20899', (93, 98))	('STRA8', 'Gene', (93, 98))	('mutant', 'Var', (121, 127))
83421	23473982	These results suggest that teratoma formation in Dmrt1 mutants is likely independent of Stra8 In addition to pluripotency genes, a number of the mRNAs misregulated in Dmrt1 mutant 129Sv testes also are known to be associated with human TGCT formation (Table S5).	('Stra8', 'Gene', '20899', (88, 93))	('mutants', 'Var', (55, 62))	('misregulated', 'Var', (151, 163))	('teratoma', 'Disease', (27, 35))	('129Sv', 'Species', '10090', (180, 185))	('mutant', 'Var', (173, 179))	('Dmrt1', 'Gene', (167, 172))	('associated', 'Reg', (214, 224))	('Stra8', 'Gene', (88, 93))	('teratoma', 'Phenotype', 'HP:0009792', (27, 35))	('human', 'Species', '9606', (230, 235))	('teratoma', 'Disease', 'MESH:D013724', (27, 35))
83423	23473982	Loss of Dmrt1 caused elevated expression of several Nodal pathway components including the TGF family ligands Nodal and Gdf3, the receptor Tdgf1/Cripto, and the downstream target Lefty1, all with stronger misregulation in 129Sv than B6 mutant testes.	('Lefty1', 'Gene', '13590', (179, 185))	('expression', 'MPA', (30, 40))	('Cripto', 'Gene', '21667', (145, 151))	('Cripto', 'Gene', (145, 151))	('Nodal pathway', 'Pathway', (52, 65))	('Tdgf1', 'Gene', (139, 144))	('Tdgf1', 'Gene', '21667', (139, 144))	('Dmrt1', 'Gene', (8, 13))	('Gdf3', 'Gene', (120, 124))	('elevated', 'PosReg', (21, 29))	('Gdf3', 'Gene', '14562', (120, 124))	('TGF', 'Gene', '7040', (91, 94))	('TGF', 'Gene', (91, 94))	('Loss', 'Var', (0, 4))	('129Sv', 'Species', '10090', (222, 227))	('Lefty1', 'Gene', (179, 185))
83430	23473982	It will be of interest to test whether activated Nodal signaling in fetal germ cells is sufficient to cause teratoma formation and whether loss of Nodal signaling is sufficient to suppress teratomas in 129Sv mice.	('teratoma', 'Disease', 'MESH:D013724', (189, 197))	('suppress', 'NegReg', (180, 188))	('teratoma', 'Phenotype', 'HP:0009792', (108, 116))	('cause', 'Reg', (102, 107))	('teratoma', 'Disease', 'MESH:D013724', (108, 116))	('teratomas', 'Phenotype', 'HP:0009792', (189, 198))	('teratomas', 'Disease', (189, 198))	('teratomas', 'Disease', 'MESH:D013724', (189, 198))	('129Sv', 'Species', '10090', (202, 207))	('loss', 'Var', (139, 143))	('teratoma', 'Disease', (108, 116))	('teratoma', 'Disease', (189, 197))	('mice', 'Species', '10090', (208, 212))	('teratoma', 'Phenotype', 'HP:0009792', (189, 197))
83435	23473982	Dmrt1 mutant 129Sv germ cells have reduced RET expression (this study and, suggesting a possible role for GDNF signaling in teratoma formation.	('teratoma', 'Phenotype', 'HP:0009792', (124, 132))	('mutant', 'Var', (6, 12))	('teratoma', 'Disease', 'MESH:D013724', (124, 132))	('RET', 'Gene', (43, 46))	('reduced', 'NegReg', (35, 42))	('129Sv', 'Species', '10090', (13, 18))	('RET', 'Gene', '19713', (43, 46))	('GDNF', 'Gene', '14573', (106, 110))	('GDNF', 'Gene', (106, 110))	('teratoma', 'Disease', (124, 132))	('Dmrt1', 'Gene', (0, 5))
83437	23473982	Deletion of Ret using Nanos3Cre had no affect on teratoma incidence, but deletion of Gfra1 caused a modest increase in teratomas from 2% to 16%.	('Gfra1', 'Gene', (85, 90))	('teratoma', 'Phenotype', 'HP:0009792', (49, 57))	('teratoma', 'Disease', 'MESH:D013724', (49, 57))	('Gfra1', 'Gene', '14585', (85, 90))	('teratoma', 'Disease', (119, 127))	('teratomas', 'Phenotype', 'HP:0009792', (119, 128))	('teratomas', 'Disease', (119, 128))	('teratomas', 'Disease', 'MESH:D013724', (119, 128))	('Nanos3', 'Gene', (22, 28))	('Nanos3', 'Gene', '244551', (22, 28))	('teratoma', 'Disease', (49, 57))	('Ret', 'Gene', (12, 15))	('teratoma', 'Phenotype', 'HP:0009792', (119, 127))	('teratoma', 'Disease', 'MESH:D013724', (119, 127))	('deletion', 'Var', (73, 81))	('Ret', 'Gene', '19713', (12, 15))
83440	23473982	The relatively low incidence of teratomas in Gfra1 mutants compared to Dmrt1 mutants may indicate that other pathways act in parallel downstream of Dmrt1.	('teratomas', 'Disease', (32, 41))	('mutants', 'Var', (51, 58))	('teratoma', 'Phenotype', 'HP:0009792', (32, 40))	('Dmrt1', 'Gene', (71, 76))	('Gfra1', 'Gene', (45, 50))	('Gfra1', 'Gene', '14585', (45, 50))	('teratomas', 'Phenotype', 'HP:0009792', (32, 41))	('teratomas', 'Disease', 'MESH:D013724', (32, 41))
83441	23473982	There are a number of possible explanations for the lack of teratomas in conditional Ret mutants.	('teratomas', 'Phenotype', 'HP:0009792', (60, 69))	('teratomas', 'Disease', 'MESH:D013724', (60, 69))	('teratomas', 'Disease', (60, 69))	('Ret', 'Gene', (85, 88))	('Ret', 'Gene', '19713', (85, 88))	('teratoma', 'Phenotype', 'HP:0009792', (60, 68))	('mutants', 'Var', (89, 96))
83443	23473982	However it also is possible that deletion of Ret by Nanos3Cre does not deplete RET protein early enough to reveal a function or that Ret mutant EC cells arrest or die before they can form teratomas.	('Nanos3', 'Gene', '244551', (52, 58))	('Ret', 'Gene', '19713', (133, 136))	('teratomas', 'Phenotype', 'HP:0009792', (188, 197))	('arrest', 'CPA', (153, 159))	('teratomas', 'Disease', (188, 197))	('teratomas', 'Disease', 'MESH:D013724', (188, 197))	('deletion', 'Var', (33, 41))	('Ret', 'Gene', (45, 48))	('RET', 'Gene', (79, 82))	('teratoma', 'Phenotype', 'HP:0009792', (188, 196))	('Ret', 'Gene', '19713', (45, 48))	('die', 'CPA', (163, 166))	('RET', 'Gene', '19713', (79, 82))	('Nanos3', 'Gene', (52, 58))	('mutant', 'Var', (137, 143))	('Ret', 'Gene', (133, 136))
83455	23473982	In Drosophila Nanos represses the expression of somatic cell markers and loss of Nanos causes some germ cells to adopt somatic fates.	('somatic fates', 'CPA', (119, 132))	('Nanos', 'Gene', (81, 86))	('loss', 'Var', (73, 77))	('expression', 'MPA', (34, 44))	('represses', 'NegReg', (20, 29))	('Nanos', 'Gene', '42297', (81, 86))	('Nanos', 'Gene', (14, 19))	('adopt', 'Reg', (113, 118))	('Drosophila', 'Species', '7227', (3, 13))	('Nanos', 'Gene', '42297', (14, 19))
83457	23473982	The data presented here have allowed us to identify genes and gene networks that differ between testes of TGCT-resistant and TGCT-prone mice as well as those that respond differently to loss of Dmrt1 in the two strains.	('loss', 'Var', (186, 190))	('mice', 'Species', '10090', (136, 140))	('Dmrt1', 'Gene', (194, 199))	('TGCT-resistant', 'Disease', (106, 120))
83460	23473982	Dmrt1 mutant mice develop testicular teratomas only on the 129Sv strain background.	('mice', 'Species', '10090', (13, 17))	('mutant', 'Var', (6, 12))	('129Sv', 'Species', '10090', (59, 64))	('testicular teratomas', 'Disease', (26, 46))	('testicular teratomas', 'Phenotype', 'HP:0100616', (26, 46))	('teratomas only', 'Disease', 'MESH:D013724', (37, 51))	('teratoma', 'Phenotype', 'HP:0009792', (37, 45))	('develop', 'Reg', (18, 25))	('testicular teratomas', 'Disease', 'MESH:C562472', (26, 46))	('teratomas only', 'Disease', (37, 51))	('Dmrt1', 'Gene', (0, 5))	('teratomas', 'Phenotype', 'HP:0009792', (37, 46))
83480	22691563	Radiotherapy and chemotherapy for TGCT have been reported to be associated with decreased testosterone production, vascular damage and thereby decreasing semen counts and possibly causing erectile dysfunction.	('erectile dysfunction', 'Disease', 'MESH:D007172', (188, 208))	('decreased testosterone', 'Phenotype', 'HP:0040171', (80, 102))	('vascular damage', 'Disease', (115, 130))	('erectile dysfunction', 'Phenotype', 'HP:0000802', (188, 208))	('Radiotherapy', 'Var', (0, 12))	('men', 'Species', '9606', (156, 159))	('decreasing', 'NegReg', (143, 153))	('decreased', 'NegReg', (80, 89))	('testosterone production', 'MPA', (90, 113))	('erectile dysfunction', 'Disease', (188, 208))	('causing', 'Reg', (180, 187))	('testosterone', 'Chemical', 'MESH:D013739', (90, 102))	('semen counts', 'MPA', (154, 166))	('vascular damage', 'Disease', 'MESH:D000783', (115, 130))	('TGCT', 'Gene', (34, 38))
83535	32422572	MK2206 Enhances Cisplatin-Induced Cytotoxicity and Apoptosis in Testicular Cancer Through Akt Signaling Pathway Inhibition OBJECTIVE: To improve conventional chemotherapeutic efficacy, it is significant to identify novel molecular markers for chemosensitivity as well as possible molecules accelerating cell-killing mechanisms.	('Enhances', 'PosReg', (7, 15))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Cytotoxicity and Apoptosis in Testicular Cancer', 'Disease', 'MESH:D064420', (34, 81))	('Akt', 'Gene', (90, 93))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('Cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('Testicular Cancer', 'Phenotype', 'HP:0010788', (64, 81))	('MK2206', 'Var', (0, 6))	('Akt', 'Gene', '207', (90, 93))
83536	32422572	In this study, we attempted to elucidate how MK2206, an allosteric Akt inhibitor, enhances the cisplatin (CDDP)-induced cytotoxicity and apoptosis in testicular cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('apoptosis', 'CPA', (137, 146))	('MK2206', 'Chemical', 'MESH:C548887', (45, 51))	('cisplatin', 'MPA', (95, 104))	('cytotoxicity', 'Disease', (120, 132))	('enhances', 'PosReg', (82, 90))	('MK2206', 'Var', (45, 51))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (150, 167))	('testicular cancer', 'Phenotype', 'HP:0010788', (150, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('testicular cancer', 'Disease', (150, 167))	('CDDP', 'Chemical', 'MESH:D002945', (106, 110))
83541	32422572	Combined with CDDP, MK2206 potentiated CDDP-induced cytotoxicity and apoptosis, with repressed expression of p-Akt and its downstream targets.	('MK2206', 'Chemical', 'MESH:C548887', (20, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (52, 64))	('CDDP', 'Chemical', 'MESH:D002945', (14, 18))	('p-Akt', 'Protein', (109, 114))	('CDDP-induced', 'Disease', (39, 51))	('MK2206', 'Var', (20, 26))	('apoptosis', 'CPA', (69, 78))	('cytotoxicity', 'Disease', (52, 64))	('CDDP', 'Chemical', 'MESH:D002945', (39, 43))	('potentiated', 'PosReg', (27, 38))	('expression', 'MPA', (95, 105))
83543	32422572	CONCLUSION: These results suggested that the concomitant use of MK2206 could enhance the CDDP-induced cytotoxicity and apoptosis in testicular cancer with the suppressed expression of Akt pathway.	('CDDP', 'Chemical', 'MESH:D002945', (89, 93))	('testicular cancer', 'Disease', 'MESH:D013736', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Akt pathway', 'Pathway', (184, 195))	('cytotoxicity', 'Disease', (102, 114))	('testicular cancer', 'Disease', (132, 149))	('MK2206', 'Var', (64, 70))	('apoptosis', 'CPA', (119, 128))	('suppressed', 'NegReg', (159, 169))	('cytotoxicity', 'Disease', 'MESH:D064420', (102, 114))	('enhance', 'PosReg', (77, 84))	('testicular cancer', 'Phenotype', 'HP:0010788', (132, 149))	('expression', 'MPA', (170, 180))	('MK2206', 'Chemical', 'MESH:C548887', (64, 70))
83550	32422572	Dominant-negative mutants of Akt enhance the cytotoxicity of chemotherapeutic agents, suggesting an important role of Akt in drug resistance.	('cytotoxicity', 'Disease', 'MESH:D064420', (45, 57))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('mutants', 'Var', (18, 25))	('Akt', 'Gene', (29, 32))	('cytotoxicity', 'Disease', (45, 57))	('enhance', 'PosReg', (33, 40))
83552	32422572	MK2206 is a highly potent and selective allosteric Akt inhibitor which is under development for the treatment of solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('men', 'Species', '9606', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('men', 'Species', '9606', (105, 108))	('MK2206', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
83553	32422572	Previous reports have demonstrated that MK2206 has antitumor activity alone and enhanced anti-tumor efficacy in combination use with chemotherapeutic agents in solid tumors, but there were no reports about the anti-tumor effects of MK2206 combined with chemotherapeutic agents in testicular cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MK2206', 'Var', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('testicular cancer', 'Disease', (280, 297))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('testicular cancer', 'Phenotype', 'HP:0010788', (280, 297))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('enhanced', 'PosReg', (80, 88))	('tumors', 'Disease', (166, 172))	('MK2206', 'Chemical', 'MESH:C548887', (232, 238))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (215, 220))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('MK2206', 'Chemical', 'MESH:C548887', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('testicular cancer', 'Disease', 'MESH:D013736', (280, 297))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (55, 60))
83554	32422572	In the present study, we investigated the effectiveness of MK2206 to enhance CDDP-induced cytotoxicity and apoptosis through the suppression of phospho(p)-Akt expression and its downstream molecules.	('CDDP-induced', 'Disease', (77, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (90, 102))	('enhance', 'PosReg', (69, 76))	('MK2206', 'Chemical', 'MESH:C548887', (59, 65))	('apoptosis', 'CPA', (107, 116))	('phospho', 'Protein', (144, 151))	('expression', 'MPA', (159, 169))	('CDDP', 'Chemical', 'MESH:D002945', (77, 81))	('MK2206', 'Var', (59, 65))	('cytotoxicity', 'Disease', (90, 102))	('suppression', 'NegReg', (129, 140))
83566	32422572	For analysis of Akt pathway, cells were treated with CDDP at the concentration corresponding to IC30 with or without treatment of 600 nM MK2206.	('MK2206', 'Chemical', 'MESH:C548887', (137, 143))	('Akt pathway', 'Pathway', (16, 27))	('IC30', 'Var', (96, 100))	('CDDP', 'Chemical', 'MESH:D002945', (53, 57))	('men', 'Species', '9606', (122, 125))
83576	32422572	After growing for 7 days, mice with tumor xenograft were divided into four groups (5 mice each group) and treated for 2 weeks as follows: (a) vehicle alone (DMSO); (b) CDDP at 6 mg/kg weekly; (c) MK2206 at 50 mg/kg weekly; (d) combination of (b) and (c).	('mice', 'Species', '10090', (85, 89))	('MK2206', 'Chemical', 'MESH:C548887', (196, 202))	('CDDP', 'Chemical', 'MESH:D002945', (168, 172))	('DMSO', 'Chemical', 'MESH:D004121', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('MK2206', 'Var', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('mice', 'Species', '10090', (26, 30))
83584	32422572	Three testicular cancer cell lines had overexpression of p-Akt (Ser473), p-Akt (Thr308), and downstream targets, including p-4EBP1, p-GSK3beta, p-mTOR, and the cell line P19 had the strongest expression of those molecules (Figure 1).	('p-Akt (Thr308', 'Var', (73, 86))	('overexpression', 'PosReg', (39, 53))	('mTOR', 'Gene', '2475', (146, 150))	('testicular cancer', 'Disease', (6, 23))	('4EBP1', 'Gene', '1978', (125, 130))	('4EBP1', 'Gene', (125, 130))	('mTOR', 'Gene', (146, 150))	('p-Akt', 'Var', (57, 62))	('Thr308', 'Chemical', '-', (80, 86))	('testicular cancer', 'Disease', 'MESH:D013736', (6, 23))	('GSK3beta', 'Gene', (134, 142))	('Ser473', 'Chemical', '-', (64, 70))	('GSK3beta', 'Gene', '2931', (134, 142))	('testicular cancer', 'Phenotype', 'HP:0010788', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
83587	32422572	The cell viability rates after exposure to 600 nM of MK2206 were 74.67+-2.54, 77.74+-2.90, 78.93+-3.03% in TCAM-2, NCCIT and P19, respectively (Figure 2B).	('MK2206', 'Chemical', 'MESH:C548887', (53, 59))	('TCAM-', 'Chemical', '-', (107, 112))	('MK2206', 'Var', (53, 59))	('cell viability', 'CPA', (4, 18))
83588	32422572	In this study, we used the concentration (600 nM) at which MK2206 alone successfully suppressed p-Akt expression, but repressed cell viability only slightly and did not induce significant apoptosis (Figure 2, A and B, and 4A).	('p-Akt', 'Protein', (96, 101))	('MK2206', 'Var', (59, 65))	('MK2206', 'Chemical', 'MESH:C548887', (59, 65))	('suppressed', 'NegReg', (85, 95))
83589	32422572	The effects of MK2206 on cell proliferation were elucidated by Matrigel invasion chamber assay (MTT), corresponding to the same concentrations as those of WB.	('MK2206', 'Var', (15, 21))	('MTT', 'Chemical', 'MESH:C070243', (96, 99))	('MK2206', 'Chemical', 'MESH:C548887', (15, 21))	('cell proliferation', 'CPA', (25, 43))
83591	32422572	Invasion capability of TCAM-2 and P19 treated with MK2206 were decreased significantly compared with the control group (Figure 2, C and D, and 2, F and G).	('decreased', 'NegReg', (63, 72))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('TCAM-', 'Chemical', '-', (23, 28))	('Invasion capability', 'CPA', (0, 19))	('MK2206', 'Var', (51, 57))
83592	32422572	The invasion assay result was influenced by decreased cell proliferation because cell proliferation was repressed approximately to 20% by MK2206 at 600 nM, which could inhibit cell invasion rate approximately to 50% in TCAM-2 cells, and the invasion assay result of P19 was similar with TCAM-2 (Figure 2, D and G).	('cell proliferation', 'CPA', (81, 99))	('TCAM-', 'Chemical', '-', (219, 224))	('cell proliferation', 'CPA', (54, 72))	('MK2206', 'Chemical', 'MESH:C548887', (138, 144))	('inhibit', 'NegReg', (168, 175))	('TCAM-', 'Chemical', '-', (287, 292))	('cell invasion rate', 'CPA', (176, 194))	('MK2206', 'Var', (138, 144))
83594	32422572	The WB results demonstrated that pretreatment with MK2206 for 24 hours inhibited the expression of Snail, Slug, and ZEB1 (Figure 2E).	('expression', 'MPA', (85, 95))	('Slug', 'Gene', (106, 110))	('inhibited', 'NegReg', (71, 80))	('Snail', 'Gene', '6615', (99, 104))	('Snail', 'Gene', (99, 104))	('MK2206', 'Chemical', 'MESH:C548887', (51, 57))	('ZEB1', 'Gene', '6935', (116, 120))	('ZEB1', 'Gene', (116, 120))	('MK2206', 'Var', (51, 57))	('men', 'Species', '9606', (41, 44))	('Slug', 'Gene', '6591', (106, 110))
83595	32422572	Meanwhile, Akt phosphorylation expression was also decreased when exposed to MK2206 (600 nM) for 24 hours in TCAM-2 (Figure 2A).	('TCAM-', 'Chemical', '-', (109, 114))	('decreased', 'NegReg', (51, 60))	('MK2206 (600 nM', 'Var', (77, 91))	('Akt', 'Protein', (11, 14))	('MK2206', 'Chemical', 'MESH:C548887', (77, 83))
83596	32422572	We also tried invasion assay in P19, and the observation that MK2206 had an inhibited effect on invasion in P19 was similar with TCAM-2 (Figure 2H).	('MK2206', 'Chemical', 'MESH:C548887', (62, 68))	('TCAM-', 'Chemical', '-', (129, 134))	('invasion', 'CPA', (96, 104))	('MK2206', 'Var', (62, 68))	('inhibited', 'NegReg', (76, 85))
83599	32422572	Combination with MK2206 (600 nM) significantly enhanced sensitivity to CDDP in a dose-dependent manner.	('enhanced', 'PosReg', (47, 55))	('MK2206', 'Chemical', 'MESH:C548887', (17, 23))	('sensitivity to CDDP', 'MPA', (56, 75))	('MK2206', 'Var', (17, 23))	('CDDP', 'Chemical', 'MESH:D002945', (71, 75))
83600	32422572	Significant differences in cell viability rates were observed, statistical differences between CDDP and CDDP+MK2206 were P < .05, P < .05, and P < .05 in TCAM-2, NCCIT and P19, respectively (Figure 3B).	('CDDP', 'Chemical', 'MESH:D002945', (104, 108))	('differences', 'Reg', (12, 23))	('CDDP+MK2206', 'Var', (104, 115))	('TCAM-', 'Chemical', '-', (154, 159))	('TCAM-2', 'Gene', (154, 160))	('MK2206', 'Chemical', 'MESH:C548887', (109, 115))	('cell viability rates', 'CPA', (27, 47))	('CDDP', 'Chemical', 'MESH:D002945', (95, 99))
83601	32422572	To explore the molecular mechanisms underlying the effects of MK2206 in CDDP-induced apoptosis, p-Akt, p-GSK3beta, p-4EBP1, p-mTOR, survivin, Bax, and caspases were examined after treatment with CDDP, MK2206, and CDDP+MK2206 in a time-dependent manner in P19 (Figure 4, A and B).	('4EBP1', 'Gene', (117, 122))	('GSK3beta', 'Gene', (105, 113))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('MK2206', 'Chemical', 'MESH:C548887', (218, 224))	('men', 'Species', '9606', (185, 188))	('CDDP', 'Chemical', 'MESH:D002945', (213, 217))	('MK2206', 'Chemical', 'MESH:C548887', (201, 207))	('4EBP1', 'Gene', '1978', (117, 122))	('Bax', 'Gene', (142, 145))	('CDDP', 'Chemical', 'MESH:D002945', (195, 199))	('Bax', 'Gene', '581', (142, 145))	('GSK3beta', 'Gene', '2931', (105, 113))	('CDDP+MK2206', 'Var', (213, 224))	('mTOR', 'Gene', (126, 130))	('MK2206', 'Var', (201, 207))	('MK2206', 'Chemical', 'MESH:C548887', (62, 68))	('caspases', 'Gene', (151, 159))	('mTOR', 'Gene', '2475', (126, 130))	('caspases', 'Gene', '841;842', (151, 159))
83603	32422572	Concomitant use of CDDP (130 muM) and MK2206 (600 nM) did not change the expression of Akt, but it suppressed p-Akt, p-GSK3beta from 3 hours, p-mTOR from 9 hours, and p-4EBP1 from 12 hours.	('muM', 'Gene', (29, 32))	('MK2206', 'Chemical', 'MESH:C548887', (38, 44))	('suppressed', 'NegReg', (99, 109))	('4EBP1', 'Gene', '1978', (169, 174))	('p-Akt', 'Pathway', (110, 115))	('GSK3beta', 'Gene', (119, 127))	('4EBP1', 'Gene', (169, 174))	('CDDP', 'Chemical', 'MESH:D002945', (19, 23))	('GSK3beta', 'Gene', '2931', (119, 127))	('muM', 'Gene', '56925', (29, 32))	('MK2206', 'Var', (38, 44))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
83605	32422572	The downregulation of survivin, as an antiapoptotic protein, was observed in 9 hours after treatment with CDDP combined with MK2206, but there was no obvious change in bax, an apoptotic protein, when treated with CDDP+MK2206 in time course (Figure 4B).	('men', 'Species', '9606', (96, 99))	('CDDP', 'Chemical', 'MESH:D002945', (213, 217))	('MK2206', 'Chemical', 'MESH:C548887', (125, 131))	('bax', 'Gene', '581', (168, 171))	('downregulation', 'NegReg', (4, 18))	('MK2206', 'Chemical', 'MESH:C548887', (218, 224))	('MK2206', 'Var', (125, 131))	('survivin', 'Protein', (22, 30))	('CDDP', 'Chemical', 'MESH:D002945', (106, 110))	('bax', 'Gene', (168, 171))
83609	32422572	CDDP combined with MK2206 induced significant suppression of p-Akt, p-4EBP1, p-mTOR, survivin, and activated caspases in the cell line, contrary to MK2206 or CDDP single treatment.	('mTOR', 'Gene', (79, 83))	('p-Akt', 'Protein', (61, 66))	('caspases', 'Gene', (109, 117))	('mTOR', 'Gene', '2475', (79, 83))	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('4EBP1', 'Gene', (70, 75))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))	('MK2206', 'Var', (19, 25))	('caspases', 'Gene', '841;842', (109, 117))	('activated', 'PosReg', (99, 108))	('suppression', 'NegReg', (46, 57))	('MK2206', 'Chemical', 'MESH:C548887', (148, 154))	('survivin', 'MPA', (85, 93))	('men', 'Species', '9606', (175, 178))	('4EBP1', 'Gene', '1978', (70, 75))	('CDDP', 'Chemical', 'MESH:D002945', (158, 162))
83611	32422572	For the clinical use of MK2206 for testicular cancer, we examined the effects of MK2206 alone or in combination with CDDP to the in vivo growth of P19 cells, using a subcutaneous xenograft model.	('MK2206', 'Chemical', 'MESH:C548887', (81, 87))	('MK2206', 'Chemical', 'MESH:C548887', (24, 30))	('testicular cancer', 'Disease', (35, 52))	('MK2206', 'Var', (81, 87))	('CDDP', 'Chemical', 'MESH:D002945', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('testicular cancer', 'Phenotype', 'HP:0010788', (35, 52))	('testicular cancer', 'Disease', 'MESH:D013736', (35, 52))
83616	32422572	Ki-67 immunostaining of tumors demonstrated that CDDP/MK2206 combination therapy of could reduce tumor cells proliferation significantly when compared with CDDP treatment alone (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CDDP', 'Chemical', 'MESH:D002945', (49, 53))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CDDP', 'Chemical', 'MESH:D002945', (156, 160))	('men', 'Species', '9606', (166, 169))	('tumor', 'Disease', (97, 102))	('CDDP/MK2206', 'Var', (49, 60))	('reduce', 'NegReg', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MK2206', 'Chemical', 'MESH:C548887', (54, 60))
83617	32422572	These results indicated that MK2206 could enhance CDDP-induced cytotoxicity in vivo as well as in vitro.	('MK2206', 'Var', (29, 35))	('enhance', 'PosReg', (42, 49))	('CDDP-induced', 'Disease', (50, 62))	('cytotoxicity', 'Disease', (63, 75))	('CDDP', 'Chemical', 'MESH:D002945', (50, 54))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
83618	32422572	This study has shown that MK2206, an Akt inhibitor, specifically enhanced the CDDP-induced cytotoxicity and apoptosis with suppression of the Akt pathway in testicular cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('MK2206', 'Chemical', 'MESH:C548887', (26, 32))	('MK2206', 'Var', (26, 32))	('Akt pathway', 'Pathway', (142, 153))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('testicular cancer', 'Phenotype', 'HP:0010788', (157, 174))	('enhanced', 'PosReg', (65, 73))	('testicular cancer', 'Disease', 'MESH:D013736', (157, 174))	('CDDP', 'Chemical', 'MESH:D002945', (78, 82))	('CDDP-induced', 'Disease', (78, 90))	('suppression', 'NegReg', (123, 134))	('apoptosis', 'CPA', (108, 117))	('cytotoxicity', 'Disease', (91, 103))	('testicular cancer', 'Disease', (157, 174))
83619	32422572	We demonstrated that MK2206 sensitized those cancer cells to CDDP via the inhibition of phosphorylated Akt (p-Akt) and its downstream molecules in the Akt signaling pathway.	('sensitized', 'Reg', (28, 38))	('CDDP', 'Chemical', 'MESH:D002945', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MK2206', 'Chemical', 'MESH:C548887', (21, 27))	('inhibition', 'NegReg', (74, 84))	('phosphorylated', 'MPA', (88, 102))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('MK2206', 'Var', (21, 27))	('Akt signaling pathway', 'Pathway', (151, 172))	('cancer', 'Disease', (45, 51))
83622	32422572	Overactivation of Akt can influence many downstream effectors and mediate multiple pathways that favor tumorigenesis, and correlate with tumor progression and reduced survival in human cancer.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('human', 'Species', '9606', (179, 184))	('Akt', 'Gene', (18, 21))	('tumor', 'Disease', (137, 142))	('favor', 'PosReg', (97, 102))	('influence', 'Reg', (26, 35))	('survival', 'CPA', (167, 175))	('mediate', 'Reg', (66, 73))	('reduced', 'NegReg', (159, 166))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Disease', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Overactivation', 'Var', (0, 14))
83623	32422572	Meanwhile, the finding of PI3K/Akt mutations is notable, as prior studies in several tumor types have identified mutational activation of the PI3K-Akt pathway as a potential mechanism of resistance to cytotoxic chemotherapy, including cisplatin.	('tumor', 'Disease', (85, 90))	('activation', 'PosReg', (124, 134))	('PI3K-Akt pathway', 'Pathway', (142, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutational', 'Var', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
83630	32422572	MK2206, a highly selective allosteric inhibitor of Akt, is being tested in both preclinical settings and clinical trials as an anticancer agent.	('cancer', 'Disease', (131, 137))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MK2206', 'Var', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
83631	32422572	MK2206 by itself causes cell proliferation inhibition of cell lines, including breast cancer lines, hepatocellular cancer lines, nasopharyngeal carcinoma cell lines, and so on.	('carcinoma', 'Disease', (144, 153))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (100, 121))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (100, 121))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('breast cancer', 'Disease', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('carcinoma', 'Disease', 'MESH:D009369', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cell proliferation inhibition', 'CPA', (24, 53))	('MK2206', 'Var', (0, 6))	('hepatocellular cancer', 'Disease', (100, 121))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (129, 153))
83632	32422572	Meanwhile, MK2206 could synergistically enhance antitumor efficacy with some chemotherapeutic agents, and suppress cell invasion coincided with decreased Akt phosphorylation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('decreased', 'NegReg', (144, 153))	('tumor', 'Disease', (52, 57))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('cell invasion', 'CPA', (115, 128))	('Akt phosphorylation', 'CPA', (154, 173))	('enhance', 'PosReg', (40, 47))	('MK2206', 'Var', (11, 17))	('suppress', 'NegReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
83633	32422572	In the current study, MK2206 (600 nM) alone inhibited Akt phosphorylation effectively using the concentration that could inhibit cell proliferation slightly, but cell invasion rate was suppressed significantly by MK2206 (600 nM) with the inhibition of Snail, Slug and ZEB1, which were transcription factors related with epithelial to mesenchymal transition (EMT).	('Slug', 'Gene', (259, 263))	('cell proliferation', 'CPA', (129, 147))	('inhibit', 'NegReg', (121, 128))	('Snail', 'Gene', (252, 257))	('ZEB1', 'Gene', '6935', (268, 272))	('Snail', 'Gene', '6615', (252, 257))	('MK2206', 'Chemical', 'MESH:C548887', (213, 219))	('inhibited', 'NegReg', (44, 53))	('suppressed', 'NegReg', (185, 195))	('ZEB1', 'Gene', (268, 272))	('Akt', 'Pathway', (54, 57))	('Slug', 'Gene', '6591', (259, 263))	('cell invasion rate', 'CPA', (162, 180))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('MK2206 (600 nM', 'Var', (213, 227))
83634	32422572	In addition, it has been reported that the expression of EMT pathways including Snail, Slug and ZEB1 were responsible for tumor invasion, metastasis, and decreased chemosensitivity, and inhibition of those targets increased the chemosensitivity.	('decreased', 'NegReg', (154, 163))	('chemosensitivity', 'CPA', (164, 180))	('metastasis', 'CPA', (138, 148))	('Slug', 'Gene', '6591', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('ZEB1', 'Gene', (96, 100))	('increased', 'PosReg', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('chemosensitivity', 'CPA', (228, 244))	('Slug', 'Gene', (87, 91))	('Snail', 'Gene', '6615', (80, 85))	('Snail', 'Gene', (80, 85))	('inhibition', 'Var', (186, 196))	('ZEB1', 'Gene', '6935', (96, 100))	('EMT', 'Gene', (57, 60))	('tumor', 'Disease', (122, 127))
83637	32422572	CDDP combined with MK2206 clearly inhibited cell viability in comparison with single use of CDDP.	('CDDP', 'Chemical', 'MESH:D002945', (0, 4))	('MK2206', 'Var', (19, 25))	('inhibited', 'NegReg', (34, 43))	('CDDP', 'Chemical', 'MESH:D002945', (92, 96))	('cell viability', 'CPA', (44, 58))	('MK2206', 'Chemical', 'MESH:C548887', (19, 25))
83640	32422572	We found the contribution of Akt pathway inhibition to apoptosis using MK2206 by showing the enhancement of CDDP-induced apoptosis in CDDP+MK2206.	('CDDP', 'Chemical', 'MESH:D002945', (134, 138))	('men', 'Species', '9606', (100, 103))	('enhancement', 'PosReg', (93, 104))	('Akt pathway', 'Pathway', (29, 40))	('CDDP+MK2206', 'Var', (134, 145))	('CDDP-induced', 'MPA', (108, 120))	('CDDP', 'Chemical', 'MESH:D002945', (108, 112))	('MK2206', 'Chemical', 'MESH:C548887', (139, 145))	('MK2206', 'Chemical', 'MESH:C548887', (71, 77))
83645	32422572	SGK1 inhibition exhibits significant antitumor effects against prostate cancer by inducing autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('inhibition', 'Var', (5, 15))	('Foxo3a', 'Gene', (134, 140))	('tumor', 'Disease', (41, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('mTOR', 'Gene', '2475', (129, 133))	('SGK1', 'Gene', (0, 4))	('mTOR', 'Gene', (129, 133))	('inducing', 'PosReg', (82, 90))	('prostate cancer', 'Disease', (63, 78))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('autophagy-dependent apoptosis', 'CPA', (91, 120))	('SGK1', 'Gene', '6446', (0, 4))	('Foxo3a', 'Gene', '2309', (134, 140))
83646	32422572	NSCLC cells treated with cryptotanshinone reduced cell growth, and induced G0/G1 cell cycle arrest and the activation of apoptosis through PI3K/Akt/GSK3beta pathway inhibition.	('GSK3beta', 'Gene', (148, 156))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('reduced', 'NegReg', (42, 49))	('cryptotanshinone', 'Chemical', 'MESH:C037886', (25, 41))	('GSK3beta', 'Gene', '2931', (148, 156))	('cell growth', 'CPA', (50, 61))	('apoptosis', 'CPA', (121, 130))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('cryptotanshinone', 'Var', (25, 41))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('arrest', 'Disease', (92, 98))	('NSCLC', 'Disease', (0, 5))
83647	32422572	From our data, considerable apoptosis and increased chemosensitivity to CDDP were detected in combination use of CDDP and MK2206, depending on the suppression of the Akt signaling pathway, including reduction of p-4EBP1, p-mTOR and p-GSK3beta.	('increased', 'PosReg', (42, 51))	('mTOR', 'Gene', '2475', (223, 227))	('Akt signaling pathway', 'Pathway', (166, 187))	('4EBP1', 'Gene', '1978', (214, 219))	('CDDP', 'Gene', (113, 117))	('MK2206', 'Var', (122, 128))	('CDDP', 'Chemical', 'MESH:D002945', (72, 76))	('CDDP', 'Chemical', 'MESH:D002945', (113, 117))	('MK2206', 'Chemical', 'MESH:C548887', (122, 128))	('4EBP1', 'Gene', (214, 219))	('reduction', 'NegReg', (199, 208))	('chemosensitivity', 'MPA', (52, 68))	('GSK3beta', 'Gene', (234, 242))	('GSK3beta', 'Gene', '2931', (234, 242))	('mTOR', 'Gene', (223, 227))	('suppression', 'NegReg', (147, 158))
83649	32422572	In addition, our findings suggested that MK2206 might inhibit the molecular targets of Akt pathway, leading to acceleration of CDDP-induced apoptosis and enhancement of chemosensitivity.	('Akt pathway', 'Pathway', (87, 98))	('molecular targets', 'Pathway', (66, 83))	('inhibit', 'NegReg', (54, 61))	('acceleration', 'PosReg', (111, 123))	('MK2206', 'Chemical', 'MESH:C548887', (41, 47))	('chemosensitivity', 'CPA', (169, 185))	('enhancement', 'PosReg', (154, 165))	('MK2206', 'Var', (41, 47))	('CDDP-induced', 'Disease', (127, 139))	('men', 'Species', '9606', (161, 164))	('CDDP', 'Chemical', 'MESH:D002945', (127, 131))
83658	32422572	When we consider the clinical application of MK2206 at a low concentration with CDDP, which is one of the most frequently used agents for testicular cancer, is a very attractive choice.	('testicular cancer', 'Disease', (138, 155))	('MK2206', 'Chemical', 'MESH:C548887', (45, 51))	('CDDP', 'Chemical', 'MESH:D002945', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('testicular cancer', 'Phenotype', 'HP:0010788', (138, 155))	('MK2206', 'Var', (45, 51))	('testicular cancer', 'Disease', 'MESH:D013736', (138, 155))
83659	32422572	In summary, we identified that MK2206 could promote CDDP-induced cytotoxicity and apoptosis in testicular cancer cells by the repression of Akt activation and its downstream molecular targets.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('promote', 'PosReg', (44, 51))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('apoptosis', 'CPA', (82, 91))	('CDDP-induced', 'Disease', (52, 64))	('repression', 'NegReg', (126, 136))	('testicular cancer', 'Phenotype', 'HP:0010788', (95, 112))	('testicular cancer', 'Disease', 'MESH:D013736', (95, 112))	('CDDP', 'Chemical', 'MESH:D002945', (52, 56))	('activation', 'PosReg', (144, 154))	('cytotoxicity', 'Disease', (65, 77))	('MK2206', 'Var', (31, 37))	('testicular cancer', 'Disease', (95, 112))	('Akt', 'Gene', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
83660	32422572	Akt target therapy using MK2206 will develop as a promising strategy applied to enhance chemosensitivity to CDDP in testicular cancer.	('testicular cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('CDDP', 'Chemical', 'MESH:D002945', (108, 112))	('testicular cancer', 'Phenotype', 'HP:0010788', (116, 133))	('testicular cancer', 'Disease', 'MESH:D013736', (116, 133))	('MK2206', 'Var', (25, 31))
83767	28903372	After knocking-down the expression of myosin Va by RNAi, a decrease of cell migration velocity is clearly observed in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cell migration velocity', 'CPA', (71, 94))	('expression', 'MPA', (24, 34))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('RNAi', 'Gene', (51, 55))	('decrease', 'NegReg', (59, 67))	('knocking-down', 'Var', (6, 19))	('lung cancer', 'Disease', (118, 129))	('myosin Va', 'Protein', (38, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))
83823	28903372	To investigate whether knock-down of myosin Va changes the mitosis of normal cells, Hela cells were stained for nucleus, actin and myosin Va (Figure 9).	('myosin Va changes the mitosis', 'Disease', (37, 66))	('myosin Va changes the mitosis', 'Disease', 'MESH:C564253', (37, 66))	('knock-down', 'Var', (23, 33))	('Hela cells', 'CellLine', 'CVCL:0030', (84, 94))
83847	28903372	CCK-8 assay showed a strong relationship between myosin Va knock down and the inhibition of tumor cell proliferation.	('knock down', 'Var', (59, 69))	('myosin Va', 'Protein', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('inhibition', 'NegReg', (78, 88))	('tumor', 'Disease', (92, 97))
83905	28903372	Opposite to myosin Va, myosin Vb is another member of the class V of unconventional, dimeric nonfilamentous myosins, whose inactivation accelerates tumor cell migration and invasion.	('inactivation', 'Var', (123, 135))	('invasion', 'CPA', (173, 181))	('men', 'Species', '9606', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('accelerates', 'PosReg', (136, 147))	('tumor', 'Disease', (148, 153))	('myosin Vb', 'Gene', '4645', (23, 32))	('myosin Vb', 'Gene', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
83906	28903372	The mutation of myosin Vb could induce diseases related to microvillus inclusion and disrupt epithelial cell polarity.	('diseases', 'Disease', (39, 47))	('mutation', 'Var', (4, 12))	('myosin Vb', 'Gene', '4645', (16, 25))	('induce', 'Reg', (32, 38))	('disrupt', 'NegReg', (85, 92))	('epithelial cell polarity', 'CPA', (93, 117))	('microvillus inclusion', 'Disease', (59, 80))	('myosin Vb', 'Gene', (16, 25))
83911	28903372	When myosin Vb is down-regulated; the inactivation of myosin Va may inhibit proliferation, invasion, and motility of tumor cells, whereas myosin Vb could promote these activities.	('myosin Vb', 'Gene', '4645', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('invasion', 'CPA', (91, 99))	('tumor', 'Disease', (117, 122))	('inactivation', 'Var', (38, 50))	('inhibit', 'NegReg', (68, 75))	('myosin', 'Protein', (54, 60))	('proliferation', 'CPA', (76, 89))	('myosin Vb', 'Gene', '4645', (5, 14))	('myosin Vb', 'Gene', (138, 147))	('myosin Vb', 'Gene', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
83972	26517592	The development of genome-wide chromatin-state maps using chromatin immunoprecipitation followed by sequencing (ChIP-seq) revealed that known genes actively transcribed by RNA polymerase II carried specific histone 3 (H3) lysine methylation marks: H3K4me3 (trimethylation on lysine 4) at the promoter and H3K36me3 (trimethylation on lysine 36) across the transcribed region.	('lysine', 'Chemical', 'MESH:D008239', (275, 281))	('H3K36me3', 'Var', (305, 313))	('H3', 'Chemical', '-', (305, 307))	('H3', 'Chemical', '-', (218, 220))	('lysine', 'Chemical', 'MESH:D008239', (222, 228))	('lysine', 'Chemical', 'MESH:D008239', (333, 339))	('H3K4me3', 'Var', (248, 255))	('H3', 'Chemical', '-', (248, 250))	('men', 'Species', '9606', (11, 14))
84010	26517592	Alternatively, lncRNAs might maintain chromatin or expression states, once they are established, as is the case for the lncRNA FIRRE (Firre intergenic repeating RNA element), which is required to maintain previously established H3K27me3 on the inactive X-chromosome.	('FIRRE', 'Gene', (127, 132))	('maintain', 'Reg', (29, 37))	('chromatin', 'MPA', (38, 47))	('H3K27me3', 'Var', (228, 236))	('Firre', 'Gene', (134, 139))	('FIRRE', 'Gene', '286467', (127, 132))	('expression', 'MPA', (51, 61))	('Firre', 'Gene', '286467', (134, 139))	('men', 'Species', '9606', (168, 171))	('H3', 'Chemical', '-', (228, 230))
84011	26517592	In addition to its role in maintaining H3K27me3 on the inactive X-chromosome, FIRRE is required for nucleolar localization of the inactive X-chromosome in mammals.	('H3', 'Chemical', '-', (39, 41))	('FIRRE', 'Gene', '286467', (78, 83))	('FIRRE', 'Gene', (78, 83))	('H3K27me3', 'Var', (39, 47))
84019	26517592	Interestingly, this lncRNA exerts its translational control through sequences with similarity to the SINEB2 (short interspersed nuclear element B2) repetitive element.	('men', 'Species', '9606', (139, 142))	('men', 'Species', '9606', (162, 165))	('sequences', 'Var', (68, 77))	('translational control', 'MPA', (38, 59))
84025	26517592	miR-9 can also target the lncRNA MALAT1 for degradation.	('miR-9', 'Var', (0, 5))	('target', 'Reg', (15, 21))	('MALAT1', 'Gene', '378938', (33, 39))	('degradation', 'MPA', (44, 55))	('MALAT1', 'Gene', (33, 39))
84056	26517592	Overexpressing Dmr in primary Sertoli cell cultures increased the abundance of this altered form of DMRT1 protein, reduced the abundance of the cannonical DMRT1 isoform, and led to impaired expression of DMRT1 targetgenes, mimicking the Dmrt1 loss-of-function phenotype.	('protein', 'Protein', (106, 113))	('Sertoli cell', 'Phenotype', 'HP:0100619', (30, 42))	('increased', 'PosReg', (52, 61))	('DMRT1', 'Gene', (100, 105))	('abundance', 'MPA', (66, 75))	('DMRT1', 'Gene', (155, 160))	('reduced', 'NegReg', (115, 122))	('DMRT1', 'Gene', '1761', (100, 105))	('Dmr', 'Var', (15, 18))	('DMRT1', 'Gene', (204, 209))	('DMRT1', 'Gene', '1761', (155, 160))	('impaired', 'NegReg', (181, 189))	('expression', 'MPA', (190, 200))	('DMRT1', 'Gene', '1761', (204, 209))	('abundance', 'MPA', (127, 136))
84062	26517592	Loss of the enhancer RNAs, by siRNA knockdown, reduced transcription of targetgenes without affecting ESR1 recruitment; moreover, tethering specific enhancer RNAs to a reporter gene enabled reporter activation.	('ESR1', 'Gene', (102, 106))	('reporter activation', 'MPA', (190, 209))	('transcription of targetgenes', 'MPA', (55, 83))	('men', 'Species', '9606', (114, 117))	('Loss', 'NegReg', (0, 4))	('tethering', 'Var', (130, 139))	('ESR1', 'Gene', '2099', (102, 106))	('reduced', 'NegReg', (47, 54))
84086	26517592	Indeed, many RNAs with IME4-dependent m6A modifications have been described, and meiosis-specific lncRNAs beyond RMA2 have been described in S. cerevisiae, raising the likelihood that additional lncRNA-dependent mechanisms exist that regulate meiosis.	('m6A', 'Gene', (38, 41))	('modifications', 'Var', (42, 55))	('S. cerevisiae', 'Species', '4932', (141, 154))	('RMA2', 'Gene', (113, 117))	('RMA2', 'Gene', '852408', (113, 117))
84100	26517592	Male mice lacking MOV10L1, or carrying a point mutation in the ATP-binding domain of the helicase, exhibit meiotic arrest in prophase I; on the other hand, females deficient for the protein are fertile.	('meiotic arrest', 'Disease', 'MESH:D006323', (107, 121))	('helicase', 'Protein', (89, 97))	('ATP', 'Chemical', 'MESH:D000255', (63, 66))	('meiotic arrest', 'Disease', (107, 121))	('point mutation in', 'Var', (41, 58))	('MOV10L1', 'Gene', (18, 25))	('mice', 'Species', '10090', (5, 9))
84116	26517592	AIkbh5-knockout mice exhibit decreased testis size, sterility, more m6A-modified mRNAs, altered RNA localization, and significant changes in gene expression.	('m6A-modified', 'Var', (68, 80))	('decreased testis size', 'Phenotype', 'HP:0008734', (29, 50))	('sterility', 'CPA', (52, 61))	('changes', 'Reg', (130, 137))	('mice', 'Species', '10090', (16, 20))	('gene expression', 'MPA', (141, 156))	('decreased', 'NegReg', (29, 38))	('more', 'PosReg', (63, 67))	('altered', 'Reg', (88, 95))	('testis size', 'CPA', (39, 50))	('RNA localization', 'MPA', (96, 112))	('AIkbh5-knockout', 'Gene', (0, 15))
84117	26517592	The increased half-life of demethylated RNAs at this stage may contribute to the increased expression and overall abundance of lncRNAs in spermatocytes, which could potentially affect recruitment of other chromatin readers/writers such as PRC2 to specific loci.	('half-life', 'MPA', (14, 23))	('expression', 'MPA', (91, 101))	('demethylated', 'Var', (27, 39))	('recruitment', 'MPA', (184, 195))	('abundance', 'MPA', (114, 123))	('men', 'Species', '9606', (191, 194))	('affect', 'Reg', (177, 183))	('increased', 'PosReg', (81, 90))	('RNAs', 'Protein', (40, 44))	('increased', 'PosReg', (4, 13))
84119	26517592	Transcription of Tbca13 in a spermatocyte cell line is regulated by a pseudogene, Tbca16, which originated from a duplication of Tbca13 with both sense and antisense transcription on chromosome 16.	('regulated', 'Reg', (55, 64))	('Tbca13', 'Gene', (129, 135))	('Tbca13', 'Gene', '21371', (129, 135))	('Tbca13', 'Gene', (17, 23))	('Tbca13', 'Gene', '21371', (17, 23))	('Tbca16', 'Gene', (82, 88))	('Transcription', 'MPA', (0, 13))	('duplication', 'Var', (114, 125))
84125	26517592	Yet Malat1 knockouts do not exhibit defects in fertility, underlining the fact that its function at this stage is unclear.	('knockouts', 'Var', (11, 20))	('Malat1', 'Gene', '378938', (4, 10))	('fertility', 'CPA', (47, 56))	('defects in fertility', 'Phenotype', 'HP:0000144', (36, 56))	('Malat1', 'Gene', (4, 10))
84132	26517592	Loss of the oskar protein causes defects in oocyte polarity, embryonic germ line specification, and abdominal development; the loss of the oskar RNA, however, caused early arrest in oogenesis.	('oogenesis', 'CPA', (182, 191))	('embryonic germ line specification', 'CPA', (61, 94))	('oocyte polarity', 'CPA', (44, 59))	('men', 'Species', '9606', (117, 120))	('Loss', 'NegReg', (0, 4))	('oskar', 'Gene', (139, 144))	('oskar', 'Gene', (12, 17))	('oskar', 'Gene', '41066', (139, 144))	('oskar', 'Gene', '41066', (12, 17))	('abdominal development', 'CPA', (100, 121))	('loss', 'Var', (127, 131))
84140	26517592	A point mutation in LDMAR increased DNA methylation of the locus, reduced LDMAR expression under long daylight conditions, and caused premature apoptosis of developing anthers.	('reduced', 'NegReg', (66, 73))	('DNA methylation', 'MPA', (36, 51))	('AR', 'Gene', '367', (77, 79))	('apoptosis', 'CPA', (144, 153))	('AR', 'Gene', '367', (23, 25))	('point mutation', 'Var', (2, 16))	('increased', 'PosReg', (26, 35))	('expression', 'MPA', (80, 90))	('caused', 'Reg', (127, 133))
84160	26517592	For instance, elimination of the miRNA pathway by Drosha knockout or the piRNA pathway by Mov10I1 knockout increased the penetrance of the Kit phenotype, suggesting that miRNAs and piRNAs act as suppressors rather than activators of paramutation.	('Mov10', 'Gene', '4343', (90, 95))	('rat', 'Species', '10116', (207, 210))	('Drosha', 'Gene', (50, 56))	('elimination', 'NegReg', (14, 25))	('increased', 'PosReg', (107, 116))	('miRNA pathway', 'Pathway', (33, 46))	('knockout', 'Var', (57, 65))	('penetrance', 'MPA', (121, 131))	('piRNA', 'Gene', (73, 78))	('knockout', 'Var', (98, 106))	('Mov10', 'Gene', (90, 95))
84172	26517592	A study of nineteen men with idiopathic infertility and histologically confirmed meiotic arrest revealed copy-number variants of three genes, including the lncRNA LOC100507205, that are unique to the meiotic-arrest patients as compared to 95 fertile controls.	('patients', 'Species', '9606', (215, 223))	('idiopathic infertility', 'Disease', (29, 51))	('idiopathic infertility', 'Disease', 'MESH:D007247', (29, 51))	('meiotic arrest', 'Disease', (81, 95))	('copy-number variants', 'Var', (105, 125))	('meiotic arrest', 'Disease', 'MESH:D006323', (81, 95))	('infertility', 'Phenotype', 'HP:0000789', (40, 51))	('meiotic-arrest', 'Disease', (200, 214))	('meiotic-arrest', 'Disease', 'MESH:D006323', (200, 214))	('men', 'Species', '9606', (20, 23))
84179	26517592	Two related genital malformation syndromes are associated with epigenetic alterations at H19, which is methylated on the paternal allele and thereby silenced.	('malformation syndromes', 'Disease', (20, 42))	('malformation syndromes', 'Disease', 'MESH:D000014', (20, 42))	('rat', 'Species', '10116', (78, 81))	('genital malformation', 'Phenotype', 'HP:0000078', (12, 32))	('H19', 'Gene', '283120', (89, 92))	('associated', 'Reg', (47, 57))	('H19', 'Gene', (89, 92))	('epigenetic alterations', 'Var', (63, 85))
84181	26517592	Silver-Russell syndrome is clinically and genetically heterogeneous, with some patients exhibiting hypomethylation of H19.	('hypomethylation', 'Var', (99, 114))	('Silver-Russell syndrome', 'Disease', (0, 23))	('H19', 'Gene', '283120', (118, 121))	('H19', 'Gene', (118, 121))	('patients', 'Species', '9606', (79, 87))
84183	26517592	H19 hypomethylation is also associated with some Mullerian aplasia patients, whose congenital abnormalities of the female genital tract produce vaginal and uterine malformations that limit reproduction to methods involving surrogacy.	('H19', 'Gene', (0, 3))	('malformations', 'Disease', 'MESH:D000014', (164, 177))	('malformations', 'Disease', (164, 177))	('hypomethylation', 'Var', (4, 19))	('patients', 'Species', '9606', (67, 75))	('associated', 'Reg', (28, 38))	('congenital abnormalities', 'Disease', (83, 107))	('uterine malformations', 'Phenotype', 'HP:0000130', (156, 177))	('Mullerian aplasia', 'Disease', (49, 66))	('congenital abnormalities', 'Disease', 'MESH:D000013', (83, 107))	('Mullerian aplasia', 'Disease', 'MESH:C537371', (49, 66))	('H19', 'Gene', '283120', (0, 3))
84186	26517592	Animal studies will be important in this regard, such as those demonstrating that mice deficient for the lncRNA NEAT1 have impaired corpus luteum formation and failure to maintain pregnancy.	('mice', 'Species', '10090', (82, 86))	('lncRNA NEAT1', 'Gene', (105, 117))	('rat', 'Species', '10116', (70, 73))	('corpus luteum formation', 'CPA', (132, 155))	('failure', 'NegReg', (160, 167))	('impaired', 'NegReg', (123, 131))	('deficient', 'Var', (87, 96))
84199	24710044	While many MSY genes degenerate during evolution due to accumulation of deleterious mutations as a consequence of their suppressed recombination with their X-homologs, others avoid degeneration by being present in multiple, nearly identical copies, thereby having the chance to compensate the effects of null alleles via unequal sister chromatid exchange or Y-Y gene conversion.	('MSY genes', 'Gene', (11, 20))	('recombination', 'MPA', (131, 144))	('rat', 'Species', '10116', (187, 190))	('degenerate', 'NegReg', (21, 31))	('mutations', 'Var', (84, 93))	('accumulation', 'PosReg', (56, 68))	('rat', 'Species', '10116', (27, 30))
84205	24710044	TSPY is also expressed, although much more weakly, in epithelial cells of the prostate gland, and some TSPY ESTs derived from the medulla of human brains (BX281192, B1828033) have also been reported in databases.	('human', 'Species', '9606', (141, 146))	('BX281192', 'Var', (155, 163))	('B1828033', 'Var', (165, 173))
84232	24710044	Furthermore, no findings about the cellular testicular expression pattern of SV40 TAg driven by the used TSPY promoter fragment were published.	('TAg', 'Gene', (82, 85))	('TAg', 'Gene', '404663', (82, 85))	('SV40', 'Species', '1891767', (77, 81))	('SV40', 'Var', (77, 81))	('men', 'Species', '9606', (123, 126))
84244	24710044	The expression of SV40 large and small T antigen (TAg) in both organs seems to be rather mediated by the used TSPY promoter fragment which directed an ectopic expression of TAg also in other organs than the testis.	('TAg', 'Gene', '404663', (173, 176))	('TAg', 'Gene', '404663', (50, 53))	('men', 'Species', '9606', (128, 131))	('TAg', 'Gene', (173, 176))	('rat', 'Species', '10116', (82, 85))	('TAg', 'Gene', (50, 53))	('SV40', 'Species', '1891767', (18, 22))	('SV40', 'Var', (18, 22))
84257	24710044	It is yet uncertain whether the various different human TSPY transcripts originate from one or more specific or from all functional human TSPY transcriptional units, but this mouse model clearly demonstrates that many TSPY transcripts can be generated by one particular functional (though repetitive) TSPY transcription unit via alternative splicing.	('rat', 'Species', '10116', (202, 205))	('rat', 'Species', '10116', (246, 249))	('alternative splicing', 'Var', (329, 349))	('TSPY', 'Gene', (218, 222))	('human', 'Species', '9606', (132, 137))	('human', 'Species', '9606', (50, 55))	('mouse', 'Species', '10090', (175, 180))
84260	24710044	Hence also 2923 bp 5 -flanking region of the TSPY gene are insufficient to induce a strictly testis and prostate specific expression pattern in transgenic mice.	('TSPY', 'Gene', (45, 49))	('insufficient', 'Disease', (59, 71))	('insufficient', 'Disease', 'MESH:D000309', (59, 71))	('transgenic mice', 'Species', '10090', (144, 159))	('induce', 'Reg', (75, 81))	('2923 bp', 'Var', (11, 18))
84278	24710044	addressed the issue of whether TSPY is capable of restoring the spermatogenic failure of KIT-deficient KitW-v/KitW-v mutants and demonstrated a significant partially rescue of spermatogenesis, spermiogenesis and fertility in TSPY transgenic B6;NMRI- KitW-v/KitW-v male mice in comparison to controls (Figure 4).	('spermiogenesis', 'CPA', (193, 207))	('fertility', 'CPA', (212, 221))	('mutants', 'Var', (117, 124))	('rescue', 'NegReg', (166, 172))	('spermatogenesis', 'CPA', (176, 191))	('spermatogenic failure', 'CPA', (64, 85))	('rat', 'Species', '10116', (136, 139))	('mice', 'Species', '10090', (269, 273))	('transgenic', 'Species', '10090', (230, 240))	('KitW-v/KitW-v', 'Gene', (103, 116))
84280	24710044	The observed restoration of spermatogenesis could be due to a proliferative or apoptosis protective effect of the transgene in fetal or postnatal germ cell development.	('apoptosis protective', 'CPA', (79, 99))	('rat', 'Species', '10116', (18, 21))	('men', 'Species', '9606', (163, 166))	('spermatogenesis', 'CPA', (28, 43))	('proliferative', 'CPA', (62, 75))	('transgene', 'Var', (114, 123))	('rat', 'Species', '10116', (69, 72))	('restoration', 'PosReg', (13, 24))
84295	24710044	Especially the expression of the Cre-recombinase transgene in the brain (cerebellum and cerebral cortex) of male and female mice of the line Tg(TSPY-cre)33aYfcl and the detection of human TSPY transgenic transcripts in the brain (cerebrum) of mice of the line Tg(TSPY)9Jshm are both striking findings, and the availability of TSPY ESTs derived from the medulla of human brains (BX281192, B1828033) in databases could point to an up to now unexpected role of TSPY in the male brain.	('B1828033', 'Var', (388, 396))	('human', 'Species', '9606', (364, 369))	('human', 'Species', '9606', (182, 187))	('BX281192', 'Var', (378, 386))	('mice', 'Species', '10090', (124, 128))	('transgenic', 'Species', '10090', (193, 203))	('mice', 'Species', '10090', (243, 247))